FTEALTH   AND   ENVIRONMENTAL
         EFFECT    PROFILES
                 APRIL 30, 1980
     U.S.  ENVIRONMENTAL PROTECTION AGENCY
             OFFICE OF  SOLID WASTE

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                 BIS-(2-ETHYLHEXYL)PHTHALATE



I.    INTRODUCTION



     This profile is based on the Ambient Water Quality



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



     Bis-(2-ethylhexyl)phthalate, most commonly referred



to as di-(2-ethylhexyl)phthalate,  (DEHP) is a diester of



the ortho form of benzene dicarboxylic acid.  The compound



has a molecular weight of 391.0, specific gravity of 0.985,



boiling point of 386.9°C at 5 mm Hg, and is insoluble in



water (U.S. EPA, 1979).



     DEHP is widely used as a plasticizer, primarily in



the production of polyvinyl chloride (PVC) resins.  As much



as 60 percent by weight of PVC materials may be plasticizer



(U.S. EPA,  1979).  Through this usage,  DEHP is incorporated



into such products as wire and cable covering, floor tiles,



swimming pool liners, upholstery, and seat covers, footwear,



and food and medical packaging materials (U.S International



Trade Commission, 1978).



     In 1977, current production was 1.94 x 10  tons/year



(U.S. EPA,  1979) .



     Phthalates have been detected in soil, air, and water



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



tion.  Evidence from iri  vitro studies indicates that certain



bacterial flora may be capable of metabolizing phthalates



to the mb'noester form (Englehardt, et al. 1975). --'—'~
                             -30)-

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II.  EXPOSURE


     Phthalate esters appear in all areas of the environ-


ment.  Environmental release of the phthalates may occur


through leaching of plasticizers from PVC materials, vola-


tilization of phthalates from PVC materials, and the inciner-


ation of PVC items.  Sources of human exposure to phthalates


include contaminated foods and fish, and parenteral adminis-


tration by use of PVC blood bags, tubings, and infusion


devices (U.S.  EPA, 1979).


     Monitoring studies have indicated that phthalate concen-


trations in water are mostly in the ppm range, or 1-2 pg/liter


(U.S.  EPA, 1979).  Air levels of phthalates in closed rooms


that have PVC tiles have been reported to be 0.15 to 0.26


mg/m  (Peakall, 1975).   Industrial monitoring has measured


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


al.  1973).  Levels of DEHP have ranged from not detect-


able to 68 ppm in foodstuffs (Tomita, et al. 1977).  Cheese,


milk, fish and shellfish present potential sources of high


phthalate intake  (U.S.  EPA, 1979).  Estimates of parenteral


exposure of patients to DEHP during use of PVC medical appli-


ances have indicated approximately 150 mg DEHP exposure


from a single hemodialysis course.  An average of 33 mg


DEHP exposure is possible during open heart surgery  (U.S.


EPA, 1979).


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

bioconcentration factor for DEHP to be 95 for the edible


portions of fish and shellfish consumed by Americans.  This

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estimate is based on the measured steady-state bioconcentra-


tion studies in fathead minnow.


III. PHARMACOKINETICS


     A.   Absorption


          The phthalates are readily absorbed from  the  intes-


tinal tract, the peritoneal cavity, and the  lungs  (U.S.


EPA, 1979).  Daniel and Bratt  (1974) found that  seven days


following oral administration of radiolabelled DEHP, 42


percent of the dose was recovered in the urine and  57 per-


cent recovered in the feces of rats.  Hilary excretion of


orally administered DEHP has been noted by Wallin,  et al.


(1974).  Limited human studies indicate that 2 to 4.5 per-


cent of orally administered DEKP was recovered in the urine


of volunteers within 24 hours  (Shaffer, et al. 1945).  Lake,


et al. (1975) have suggested that orally administered phtha-


lates are absorbed after metabolic conversion to the mono-


ester form in the gut.


          Dermal absorption of DEHP in rabbits has  been


reported at 16 to 20 percent of the initial dose within


three days following administration (Autian, 1973).


     B.   Distribution


          Studies in rats injected with radiolabelled  DEHP


have shown that 60 to 70 percent of the administered dose


was detected in the liver and lungs within 2 hours  after


administration (Daniel and Bratt, 1974).  Wadell, et al.
                                                           »

(1977) have reported rapid accumulation of labelled DEHP


in the kidney and liver of rats after i.v. injection, fol-


lowed by rapid excretion into the urine, bile, and  intes-



                              2T


                             -303-

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tine.  Seven days after i.v. administration of labelled

DEEP to mice, levels of compound were found preferentially

in the lungs and to a lesser extent in the brain, fat, heart,

and blood (Autian, 1973).

          An examination of tissue samples, from two deceased

patients who had received large volumes of transfused blood,

detected DEHP in the spleen, liver, lungs, and abdominal

fat  (Jaeger and Rubin, 1970).

          Injection of pregnant rats with labelled DEHP

has shown that the compound may .cross the placental barrier

(Singh, et al. 1975).

     C.   Metabolism

          Various metabolites of DEHP have been identified

following oral feeding to rats  (Albro, et al. 1973) .  These

results indicate that DEHP is initially converted from the

diester to the monoester, followed by the oxidation of the

monoester side chain forming two different alcohols.  The

alcohols are oxidized to the corresponding carboxylic acid

or ketone.  Enzymatic cleavage of DEHP to the monoester

may take place in the liver or the gut (Lake, et al. 1977).

This enzymatic conversion has been observed in stored whole

blood, indicating widespread distribution of metabolic activ-

ity  (Rock, et al. 1978).

     D.   Excretion

          Excretion of orally administered DEHP is virtually
                                                           »
complete in the rat within 4 days  (Lake,  et al. 1975).

Major excretion is through the urine and feces, with biliary

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excretion increasing the content of DEEP  (or metabolites)



in the intestine  (U.S. EPA, 1979).  Schulz and Rubin  (1973)



have noted an increase in total water soluble metabolites



of labelled DEHP  in the first 24 hours following  injection



into rats.  Within one hour, eight percent of the DEHP was



found in the liver,, intestines and urine.  After  24 hours,



54.6 percent was  recovered in the intestinal tract, excreted



feces and urine,  and only 20.5 percent was recovered  in or-



ganic extractable form.  Blood loss of DEHP showed a  biphasic



pattern, with half-lives of 9 minutes and 22 minutes, respec-



tively (Schulz and Rubin, 1973).



IV.  EFFECTS



     A.   Carcinogenicity



          Pertinent data could not be located in  the  avail-



able literature.



     B.   Mutagenicity



          Testing of DEHP in the Ames Salmonella assay has



shown no mutagenic effects (Rubin, et al. 1979).  Yagi,



et al. (1978)  have indicated that DEHP is not mutagenic



in a recombinant  strain of Bacillus, but the monoester meta-



bolite of DEHP did show some mutagenic effects.  Results



of a dominant lethal assay in mice indicate that DEHP has



a dose and time dependent mutagenic effect (Singh, et al.



1974) .



     C.   Teratogenicity                                   .



          DEHP has been shown to produce teratogenic  effects



in rats following i.o. administration (Singh,  et al.  1972).

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Following oral administration there was a significant reduc-

tion in fetus weight at 0.34 and 1.70 g/kg/day.

     D.   Other Reproductive Effects

          Effects on implantation and parturition have been

observed in pregnant rats injected intraperitoneally with

DEHP (Peters and Cook, 1973).  A three-generation repro-

duction study in rats has indicated decreased fertility

in rats following maternal treatment with DEHP  (Industrial

Bio-Test, 1978).

          Testicular damage has been reported in rats ad-

ministered DEHP i.p. or orally.  Seth, et al. (1976) found

degeneration of the seminiferous tubules and changes in

spermatagonia; testicular atrophy and morphological damage

were noted in rats fed DEHP  (Gray, et al. 1977; Yamada,

et al, 1975).  Otake, et al. (1977) noted decreased sperma-

togenesis in mice administered DEHP by intubation.

     E.   Chronic Toxicity

          Oral feeding of DEHP produced increases in liver

and kidney weight in several animal studies  (U.S. EPA, 1979),

Chronic exposure to transfused blood containing DEHP has

produced liver damage in monkeys (Kevy, et al. 1978).  Lake,

et al. (1975) have produced liver damage in  rats by adminis-

tration of mono-2-ethylhexyl phthalate.

     F.   Other Relevant Information

          Several animal studies have demonstrated that
                                                          #
pre-treatment of rats with DEHP produced an  increase in

hexobarbital sleeping times  (Daniel and .Bratt, 1974; Rubin

and Jaeger, 1973; Swinyard, et al. 1976).


                              *
                             -3O4-

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V.   AQUATIC TOXICITY

     A.   Acute Toxicity

          Only one acute study on  the  freshwater  cladoceran

(Daphnia magna) has produced a 96-hour  static  LCcQ  value

of 11,000 jig /I (U.S. EPA, 1978).   Freshwater  fish or  marine

data have not been found in the literature.

B.   Chronic Toxicity

          Chronic studies involving  the  rainbow  trout (Salmo

gairdneri) provided a chronic value  of  4.2  ug/1  in  an embryo-

larval assay (Mehrle and Mayer, 1976).   Severe reproductive

impairment was observed at less than 3 pg/1 in a  chronic

Daphnia magna assay (Mayer and Sanders,  1973).

     C.   Plant Effects

          Pertinent information could  not be  located  in

the available literature.

     D.   Residues

          Bioconcentration factors have  been  obtained for

several species of freshwater organisms:  54  to  2,680 for

the scud  (Gamarus pseudolimnaeus) ; 14  to 50  for  the sowbug

(Ascellus brevicaudus) ; 42 to 113  for  the rainbow trout

(Salmo gairdneri) ; and 91 to 886 for the fathead  minnow

(Pimephales promelas)  (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.
                             -507-

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     A.   Human



          Based on "no effect" levels observed in chronic



feeding studies in rats or dogs, the U.S. EPA has calculated



an acceptable daily intake (ADI) level for DEHP of 42 mg/day.



          The recommended water quality criteria level for



protection of human health is 10 mg/1 for DEHP (U.S. EPA,



1979) .



     B.   Aquatic



          Criterion was not drafted for either freshwater



or marine environments due to insufficient data.

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                 BIS-(2-ETHYLHEXYL)  PHTHALATE
                          REFERENCES

Albro, P.W., et al.  1973.  Metabolism of diethylhexyl phthal-
ate by rats.  Isolation and characterization of the urinary
metabolites.  Jour. Chromatogr. 76: 321.

Autian, J.  1973.  Toxicity and health threats of phthalate
esters:  Review of the literature.  Environ. Health Perspect.
June 3.

Daniel, J.W., and H. Bratt.  1974.  The absorption, metabo-
lism and tissue distribution of di (2-ethylhexyl) phthalate
in rats.  Toxicology 2: 51.

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

Gray, J., et al.  1977.  Short-term toxicity study of di-
2-ethylhexyl phthalate in rats.  Food Cosmet. Toxicol. 65:
389.

Industrial Bio-Test.  1978.  Three generation reproduction
study with di-2-ethylhexyl phthalate in albino rats.  Plastic
Industry News 24: 201.

Jaeger, R.J., and R.J. Rubin.  1970.   Plasticizers from
plastic devices:  Extraction, metabolism, and accumulation
by biological systems.  Science 170:  460.

Kevy, S.V., et al.  1978.  Toxicology of plastic devices
having contact with blood.  Rep. N01 HB 5-2906, Natl. Heart,
Lung and Blood Inst. Bethesda, Md.

Lake, B.G., et al.  1975.  Studies on the hepatic effects
of orally administered di-(2-ethylhexyl) phthalate in the
rat.  Toxicol. Appl. Pharmacol. 32: 355.

Lake, B.C., et al.  1977.  The in vitro hydrolysis of some
phthalate diesters by hepatic and" intestinal preparations
from various species. • Toxicol. Appl. Pharmacol. 39: 239.

Mayer, F.L., Jr., and H.O. Sanders.  1973.  Toxicology of
phthalic acid esters in aquatic organisms.  Environ. Health
Perspect..3: 153.
Mehrle, P.M., and F.L. Mayer.  1976.  Di-2-ethylhexyl phthal-
ate:  Residue dynamics and biological effects in rainbow
trout and fathead minnows.  Pages 519-524.  in Trace sub-
stances in environmental health.  University of Missouri
Press, Columbia.

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Milkov,  L.E.,   et  al.   1973.   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.  175.

Otake, T.,  et  al.   1977.   The effect  of di-2-ethylhexyl
phthalate  (DEHP) on male mice.   I.  Osaka-Fuitsu  Koshu  Eisei
Kenkyusho Kenkyu Hokoku, Koshu Eisei  Hen  15:  129.

Peakall, D.B.   1975.  Phthalate  esters:   Occurrence and
biological  effects.  Residue  Rev. 54: 1.

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

Rock,  G., et  al.   1978.  The  accumulation of  mono-2-ethyl-
hexyl  phthalate (MEHP)  during storage of  whole  blood and
plasma.  Transfusion 18: 553i

Rubin, R.J.,  and R.J. Jaeger.  1973.  Some pharmacologic
and  toxicologic effects of di-2-ethylhexyl phthalate (DEHP)
and  other plasticizers.  Environ. Health  Perspect.  Jan.
53.

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.  New Orleans,  March 11.

Schulz,  C.O.,  and  R.J.  Rubin.  1973.  Distribution,  metabo-
lism and excretion of di-2-ethylhexyl phthalate in  the  rat.
Environ. Health Perspect.  Jan. 123.

Seth,  P.K., et  al.   1976.   Biochemical changes  induced  by
di-2-ethylhexyl phthalate  in  rat liver.   Page 423 in Enviorn-
mental biology.  Interprint Publications, New Dehll, India.

Shaffer, C.B.,  et  al.   1945.   Acute and subacute  toxicity
of di (2-ethylhexyl)  phthalate with  note upon  its  metabolism.
Jour.  Ind.  Hyg. Toxicol. 27:  130.

Singh, A.R.,  et al.  1972.  Te.ratogenicity of phthalate esters
in rats.  Jour. Pharmacol.  Sci.  51: 51.

Singh, A.R.,  et al.  1974.  Mutagenic and antifertility
sensitivities  of mice to di-2-ethylhexyl  phthalate  (DEHP)
and dimethoxyethyl phthalate  (DMEP).  Toxicol.  Appl. Pharmacol.
29:  35.
                                                           *
Singh  A.R., et  al.   1975.   Maternal-fetal transfer  of 14c-
di-2-ethylhexyl phthalate  and   C-diethyl phthalate in  rats.
Jour.  Pharm.  Sci.  64: 1347.
                             -VO-

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Swinyard, E.A., et al.  1976.  Nonspecific effect of bis(2-
ethylhexyl)  phthalate on hexobarbital sleep time.  Jour.
Pharmacol. Sci. 65: 733.

Tomita, I.,  et al*  1977.  Phthalic acid esters in various
foodstuffs and biological materials.  Ecotoxicology and
Environmental Safety 1: 275.

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.  1979.. Phthalate Esters:  Ambient Water Quality
Criteria  (Draft).

U.S. International Trade Commission.  1978.  Synthetic or-
ganic chemicals, U.S. production and sales.  Washington,
D.C.

Waddell, W.M., et al.  1977.  The distribution in mice of
intravenously administered   C-di-2-ethylhexyl phthalate
determined by whole-body autoradiography.  Toxicol. Appl.
Ph--— acol. 39: 339.
   .  J
Wallin, R.F., et al.  1974.  Di(2-ethylhexyl)  phthalate
(DEHP)  metabolism in animals and post-transfusion tissue
levels in man.  Bull. Parenteral Drug. Assoc.  28: 278.

Yagi, Y., et al.  1978.  Embryotoxicity of phthalate esters
in mouse.  Proceedings of the First International Congress
on toxicology, Plaa, G. and Duncan, W., eds.  Academic Press,
N.ljp. 59.

Yamada, A.,  et al.  1975.  Subacute toxicity of di-2-ethyl-
hex^.1 phthalate.  Trans. Food Hyg. Soc. Japan, 29th Meeting
p. 36 .

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                                      No. 28
             Bromofonn


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

           APRIL 30, 1980

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

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                                                          If 9
                            BROMOFORM




SUMMARY


     Bromoforra has been detected  in  finished drinking  water  in


the United States and Canada.  It  is believed  to  be  formed by  the


haloform reaction that may occur  during water  chlorination.


Bromoform can be removed from drinking water via  treatment with


activated carbon.  Natural sources  (especially red algae) produce


significant quantities of bromoform.  -There is a  potential for


bromoform to accumulate in the aquatic environment because of  its


resistance to degradation.  Volatilization  is  likely to  be an


important means of environmental  transport.


     Bromoform gave positive results in mutagenicity tests with


Salmonella typhimurium TA100.  In  a  short-term in vivo.oncogen-


icity assay it caused a significant  increase in tumor  incidence


at one dose level.


     Inhalation of bromoform by humans can  cause  irritation  of


.the respiratory tract and liver damage.  Respiratory failure  is


the primary cause of death in bromoform-related fatalities.




I.   INTRODUCTION


     This profile is based primarily on the Ambient Water Quality


Criteria document for halomethanes  (U.S. EPA 1979b).


     Bromoform (tribromomethane;  CHBr,) is  a colorless,  heavy
                                                             »

liquid similar in odor and taste  to  chloroform.   Bromoform has


the following, physical/chemical properties  (Weast, 1974'):

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               Molecular Weight:   252.75

               Melting Point:       8.3'C

               Boiling Point:      149.5'C  (at 760 mm Hg)

               Vapor Pressure:     10 ram fig al 34'C

               Solubility:         slightly soluble in water;

                                   soluble  in a variety of

                                   organic  solvents.

     A review of the production range (includes importation)

statistics for bromoform (CAS No. 75-25-2) which  is listed  in the

initial TSCA Inventory (1979a) has shown that between 100,000 and

900,000 pounds of this chemical were produced/imported in 1977.—'

     Bromoform is used as a chemical intermediate; solvent  for

waxes, greases, and oils; ingredient in fire-resistant chemicals

and gauge fluids (U.S. EPA 1978a; Hawley, 1977).



II.  EXPOSURE

     A.   Environmental Fate

     Bromoform gradually decomposes on standing; air and light

accelerate decomposition (Windholz, 1976).  The vapor pressure of

bromoform, while lower than that for chloroform and other chloro-

alkanes, is, nonetheless, sufficient to ensure that volatiliza-

tion will be an important means of environmental transport.  The
   This production range information does not include any produc-
   tion/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).

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half-life for hydrolysis of bromoform is estimated at 686 years.

Bromoform should be much more reactive in the atmosphere.  Oxi-

dation by HO.radical will result in a half-life of a few months

in the troposphere (U.S. EPA, 1977).

     B.   Bioconcentration

     The bioconcentration factor for bromoform in aquatic organ-

isms that contain about 8% lipid is estimated to be 48.  The

weighted average bioconcentration factor for bromoform  in the

edible portion of all aquatic organisms consumed by Americans  is

estimated to be 14 (U.S. EPA, 1979b).

   .  C.   Environmental Occurence

     The National Organics Reconnaissance Survey detected bromo-

form in the finished drinking water of 26 of 80 cities, with a

maximum concentration of 92 ug/1.  Over 90% of the samples con-

tained 5 ug/1 or less.  No bromoform was found in raw water

samples (Symons _et_ _al_. , 1975).  Similarly, the EPA Region V

Organics Survey found bromoform in 14% of the finished drinking

water samples and none in raw water (U.S. EPA, 1975).  Using a

variety of sampling and analysis methods, the National Organic

Monitoring Survey found bromoform in 3 of 111, 6 of 118, 38 of

113, 19 of 106, and 30 of 105 samples with mean concentrations

ranging from 12-28 ug/1 (U.S. EPA, 1978b).  A Canadian survey  of

drinking water found 0-0.2 ug/1 with a median concentration of

0.01 ug/1 (Health and Welfare Can., 1977).
                                                            »
     The National Academy of Sciences (1978) concluded that water

chlorination, via the haloform reaction, results in the produc-

tion of trihalomethanes (including bromoforn) from the organic

precursors present in raw water.

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     Significant quantities of  bromoforra  are  also  produced  from

natural sources, especially red algae.  For example,  the  essen-

tial oil of Asparagopsis  taxiformis  (a  red marine  algae  eaten  by

Hawaiians) contains approximately  80% bromoform  (Burreson et al.,

1975).



III. PHARMACOKINETICS

     Bromoform  is absorbed  through the  lungs,  gastrointestinal

tract, and skin.  Some of the absorbed  bromoform  is metabolized

in the liver to inorganic bromide  ion.  Bromide  is found  in

tissues and urine following inhalation  or rectal administration

of bromoform (Lucas, 1929).  Metabolism of bromoform  to  carbon

monoxide has also been reported (Ahmed, 1977).  Recent studies

show that phenobarbital-induced rats metabolize bromoform to.    A
                                                            (cocu
carbonyl bromide (COB^), the brominated  analog of phosgene P*>otrr

£t..al.. / 1979) .



IV.  HEALTH EFFECTS

     A. Carcinogenicity

     Bromoform  caused a significant  increase  in  tumor incidence

at one dose level in a short-term  in vivo oncogenicity assay

known  as the strain A mouse lung adenoma  test.  The increase was

observed at a. dose of 48 mg/kg/injection  with  a total dose  of

1100 rag/kg.  The tumor incidence was not  increased significantly

at doses of 4 rag/kg (total dose of 72 rag/kg)  or 100 mg/kg (total

dose of 2400 mg/kg) (Theiss et  al.,  1977.

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     B. Mutagenicity

     Bromoform was mutagenic in S. typhimurium strain TA  100

(without metabolic activation)  (Simmon, 1977).

     C. Other Toxicity

     Rats inhaling 250 mg/nr bromoform for 4 hr/day for 2 months

developed impaired liver and kidney function (Dykan, 1962).

     In humans, inhalation of bromoform causes irritation to  the

respiratory tract.  Mild cases  of bromoform poisoning may cause

only headache, listlessness, and vertigo.  Unconsciousness, loss

of reflexes, and convulsions occur in severe cases.  The primary

cause of death from a lethal dose of bromoform is respiratory

failure.  Pathology indicates that the chemical causes fatty

degenerative and centrolobular necrotic changes in the liver

(U.S. PHS, 1955).

     Acute'animal studies indicate impaired function and

pathological changes"in the liver and kidneys of animals exposed

to bromoform (Kutob and Plaa, 1962; Dykan, 1962).



V. AQUATIC EFFECTS

     A.   Fresh Water Organisms

     The 96-hr LC5Q (static) in bluegill sunfish is 29.3 mg/1.

The 48-hr LCgg (static) for Daphnia magna is 46.5 mg/1.  The  96-

hr ECcgs f°r chlorophyll A production and cell number in S.

capricornutum are 112 mg/1 and 116 mg/1, respectively (U.S. EPA,
                                                             t
1978-a) .  (See also Section II.B.)

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     B.   Marine Organisms



     The 96-hr LC^g (static) in sheepshead minnow is 17.9 mg/1.



The 96-hr LC5Q (static) in nysid shrimp is 20.7 mg/1.  The EC5Qs



for chlorophyll A production and cell number in S. costatum are,



respectively, 12.3 mg/1 and 11.5 mg/1 (U.S. EPA, 1978a).







VI.  EXISTING GUIDELINES



     A.   Human



     The OSHA standard for bromoform in air is a time weighted



average (TWA) of 0.5 ppm  (39CFR23540).



     The Maximum Contaminant Level (MCL) for total trihalometh-



anes (including bromoforra) in drinking water has been set by the



U.S. EPA at 100 ug/1 (44FR68624).  The concentration of bromoform



produced by chlorination can be reduced by treatment of'drinking



water with powdered activated carbon (Rook, 1974).  This is the



technology that has been proposed by the EPA to meet this



standard.



     B.   Aquatic



     The proposed ambient water criterion for the protection of



fresh water aquatic life from excessive bromoform exposure is 840



ug/1 as a 24-hour average.  Bromoform levels are not to exceed



1900 ug/1 at any time.   The criterion for the protection of



marine life is 180 ug/1 (24 hr avg), not to exceed 1900 ug/1



(U.S. EPA, 1979b).

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                            REFERENCES

Ahmed, A.E., _et_ _a_l_.  1977.   Metabolism  of  haloforms to carbon
monoxide, I.  In vitro  studies.   Drug  Metab.  Dispos. ,  _5_:198.   (as
cited in U.S. EPA, 1979b).

Burreson, B.J., R.E. Moore,  P.P.  Roller  1975.   Haloforms in  the
essential oil of the alga Asparagopsis  taxiformis (Rhodophyta).
Tetrahedron Letters, _7_:473-476.   (as  cited in MAS,  1978).

Dykan, V.A.   1962.  Changes  in  liver  and  kidney functions due to
methylene bromide  and  bromoform.   Nauchn.  Trucy Ukr Nauchn. -
Issled. Inst. Gigieny  Truda  i Profyabolevanii _29_:82.   (as cited
in U.S. EPA,  1979b).

Hawley, G.G.  ed.   1971.  Condensed Chemical  Dictionary.   8th ed.
Van Hostrand  Reinhold  Co.

Health and Welfare Canada   1977.   Environmental Health Direc-
torate national survey of halomethane in  drinking water.  (as
cited in. U.S. EPA, 1979b).

Kutob, S.D.,  G.J.  Plaa  1962.   A procedure for estimating the
hepatotoxic potential  of certain industrial  solvents, Tox. Appl.
Pharm., j4_:354.   (as cited in U.S.  EPA,  1979b) .

Lucas, G.H.W.  1929.   A  study of the  fate  and toxicity of bromine
and chlorine  containing  anesthetics,  J. Pharm.  Exp. Therap.,
21:223-237.   (as cited in WAS,  1978).

National Academy of Sciences 1977.  Drinking Water and Health,
Part II, Chapters  6 and  7,  Washington,  D.C.

National Academy of Sciences 1978.   Nonfluorinated Halomethanes
in the Environment, Washington,  D.C.

Pohl, L.R. _et_ _al_.  1979.  Oxidative  bioactivation of  haloforms
into hepatotoxins, prepublication.

Rook, J.J.  1974.  Formation of haloforms  during chlorination of
natural waters.  J. Soc. Water  Treat.  Examin. 23 (Part 2):234-
243.

Simmon, V.F.  1977.  Mutagenic  activity of chemicals  identified
in drinking water.  In_ Progress in genetic toxicology, S. Scott
_et_ _al_. eds.   (as cited in U.S.  EPA,  1979b) .

Symons, J.M j_t_ _al_.  1975.   National  organics reconnaissance  '
survey for halogenated organics (NORS).   J.  Amer. Water Works
Assoc. _6_7_:634-647.  (as  cited in MAS,  1978).

Theiss, J.C.  _e_t_ _al_.  1977.   Test for  carcinogenicity  of organic
contaminants  of United States drinking  waters by pulmonary tumor
response in strain A mice,  Can.  Res., _3_7_:2717.   (as cited in U.S.
EPA, 1979b).

                                 7f
                               -320-

-------
U.S. EPA  1975.  Formation of Ralogenated Organics by  Chlorina-
tion of Water Supplies.  EPA-600/1-75-002,  PB  241-511.   (as cited
in NAS, 1978).

U.S. EPA  1977.  Review of the environmental fate of selected
chemicals, EPA-560/5-77-0033.

U.S. EPA  1978a.  Indepth studies on health and  environmental
impacts of selected water pollutants, contract no. 68-01-4646,
Washington, D.C.  (as cited  in U.S. EPA, 1979b).

U.S. EPA  1978b.  The National Organic Monitoring Survey, Office
of Water Supply, Washington, D.C.

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.  Halomethanes, Ambient Water Quality  Criteria.
PB 296 797.

U.S. Public Health Service   1955.  The halc»jenated hydrocarbons:
Toxity and potential dangers. No. 414.  (as cited in U.S. EPA,
1979b).

Weast/ R.C. ed.  1972.  CRC  Handbook of Chemistry and  Physics.
CRC Press, Inc., Cleveland,  Ohio.

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

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                                      No. 29
            Bromoraethane
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

-------
                            BROMOMETHANE




                               Summary









     On acute exposure to bromomethane, neurologic and psychiatric




abnormalities may develop and persist for months or years.   There is




no information on the chronic toxicity, carcinogenicity, or  terato-




genicity of bromomethane.  Bromomethane has been shown to  be mutagenic




in the Ames S_;_ typhimurium test system.




     Acute LC5Q values have been reported in two tests as  12,000 and




11,000 pg/1 for a marine and freshwater fish, respectively.

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                            BROMOMETHANE




I.   INTRODUCTION




     This profile is based on the Ambient Water Quality Criteria




Document for Halomethanes (U.S. SPA,  1979a).




     Bromomethane (CHjBr, methyl bromide, monobromomethane, and




embafume; molecular weight 94.91*) is  a colorless gas.  Bromomethane




has a melting point of -93.6°C, a boiling point of 3-56°C, a specific




gravity of 1.676 g/ml at -20°C, and a water solubility of 17-5 g/1




at 20°C (Natl. Acad. Sci., 1978).  Bromomethane has been widely used




as a fumigant, fire extinguisher, refrigerant, and insecticide (Kantarjian




and Shaheen, 1963).   Today the major  use of bromomethane is as a




fumigating agent.  Bromomethane is believed to be formed in nature,




with the oceans as a primary source (Lovelock, 1975).  The other




major environmental source of bromomethane is from its agricultural




use as a soil, seed, feed and space fumigant.  For additional information




regarding 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 bromomethane qualitatively




in finished drinking waters in the U.S.   There are,  however, no data




on its concentration  in drinking water, raw water,  or waste water




(U.S.  EPA,  1979a).




     B.    Food




          There is no information on  the concentration of bromomethane




in food.   Bromomethane residues from  fumigation decrease rapidly




through loss to the  atmosphere and reaction with protein to form

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inorganic bromide residues.  With proper aeration and product processing,




most residual bromomethane will rapidly disappear due to methylation




reactions and volatilization (Natl. Acad. Sci.,  1978; Davis, et al.




1977).  There are no bioconcentration data for bromomethane  (U.S.




EPA, 1979a).




     C.   Inhalation




          Saltwater atmospheric background concentrations of bromomethane




averaging about 0.00036 mg/m^ have been reported (Grimsrud and Rasmussen,




1975; Singh, et al. 1977).  This is higher than reported average




continental background and urban levels and suggests that the oceans




are a major source of global bromomethane (Natl. Acad. Sci., 1978).




Bromomethane concentrations of up to 0.00085 mg/m3 may occur outdoors




locally with light traffic, as a result of exhaust containing bromomethane




as a breakdown product of ethylene dibromide, which is used in leaded




gasoline (Natl. Acad. Sci., 1978).                                       •




III. PHARMACOKINETICS




     A.   Absorption




          Absorption of bromomethane most commonly occurs via the




lungs, although it can also occur through the gastrointestinal tract




and the skin (Davis, et al. 1977; von-Oettingen,-196U).




     B.   Distribution




          Upon absorption, blood levels of residual non-volatile




•bromide increase, indicating-rapid uptake of bromomethane or its




metabolites (Miller and Haggard, 19^3).  Bromomethane is rapidly




distributed to various tissues and is broken down to inorganic bromide*.




Storage, only as bromides, occurs mainly in lipid-rich tissues.

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     C.   Metabolism




          Evidently the toxicity of bromomethane is mediated by the




bromomethane molecule itself.  Its reaction with tissue (methylation




of sulfhydryl groups in critical cellular proteins and enzymes)




results in disturbance of intracellular metabolic functions, with




irritative, irreversible, or paralytic consequences (Natl. Acad.




Sci., 1978; Davis, et al. 1977; Miller and Haggard, 1943).




     D.   Excretion




          Elimination of bromomethane is rapid initially, largely




through the lungs.  The kidneys eliminate much of the remainder as




bromide in the urine (Natl. Acad. Sci., 1978).




IV.  EFFECTS




     Pertinent information relative to the carcinogenicity, teratogenicity




or other reproductive effects, or chronic toxcity of bromomethane




were not found in the available literature.




     A.   Mutagenicity




          Simmon and coworkers (1977) reported that bromomethane was




mutagenic to Salmonella typhimurium strain TA100 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.




     B.   Other Relevant Information




          In several species, acute fatal poisoning has involved




marked central nervous system disturbances with a variety of manifestations:




ataxia, twitching, convulsions, coma,  as well as changes in lung, liver,

-------
heart, and kidney tissues (Sayer, et al.  1930; Irish, et al.  19^0;




Gorbachev, et al. 1962; von Oettingen,  1964).  Also, residual bromide




in fumigated food has produced some adverse effects in dogs  (Rosenblum,




et al. 1960).




V.   AQUATIC TOXICITY




          Two acute toxicity studies on one freshwater and one marine




fish species were reported with LC5Q values of 11,000 ug/1 for freshwater




bluegill (Lepomis macrochirus) and an LC5Q value of 12,000 jig/1 for




the marine tidewater silversides (Menidia beryllina) (U.S. EPA,




1979a).  Pertinent information relative to aquatic chronic toxicity




or plant effects for bromomethane were not found 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




         " The current OSHA standard for occupational exposure to




bromomethane (1976) is 80 mg/m3; the American Conference of  Governmental




Industrial Hygienist1s'(ACGIH, 1971) threshold limit value is 78




mg/m3. The U.S. EPA (1979a) draft water quality criteria for bromomethane




is 2 pg/1.  Refer to the Halomethane Hazard Profile for discussion




of criteria derivation (U.S. EPA, 1979b).

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     B.   Aquatic Toxicity



          The draft criterion  for protecting freshwater life is a



24-hour average concentration  of 140 ,ug/l,  not  to exceed 320 >ag/l.



The marine criterion is 170 >ig/l as a  2U-hour average,  not to exceed



380 jjg/1.

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                               BROMOMETHANE
                                References
American Conference of Governmental and Industrial Hygienists.   1971.
Documentation of the threshold limit values for substances in workroom
air. Cincinnati-, Ohio.

Davis, L.N., et al.  1977.  Investigation of selected potential  environmental
contaminants:  monohalomethanes.  EPA 560/2-77-007; TH 77-535-   Final
rep. June,  1977, on Contract No. 68-01-4315.  Off. Toxic Subst.  U.S.
Environ. Prot. Agency, Washington, D.C.

Gorbachev, E.M. , et al.  1962,.  Disturbances in neuroendocrine regulation
and oxidation-reduction by certain commercial poisons.  Plenuma  Patofiziol
Sibiri i Dal'n.  Vost. Sb. 88.

Grimsrud, E.P. , and R.A. Rasmussen.  1975.  Survey and analysis  of halocarbons
in the atmosphere by gas chromatography-mass spectrometry.  Atmos. Environ. 9:
1014.

Irish, -D.D., et al.  1940.  The response attending exposure of laboratory
animals to vapors of methyl bromide.  Jour. Ind. Hyg. Toxicol. 22:  218.

Kantarjian, A.D., and A.S. Shaheen.  1963-  Methyl bromide poisoning with nervous
 system manifestations resembling polyneuropathy.   Neurology 13:  1054.

Lovelock, J.E.  1975.  Natural halocarbons in the air and in the sea. Nature
256: 193-

Miller,  D.P., and H.W. Haggard.  1943.   Intracellular penetration of bromide as
feature in toxicity of alkyl bromides.   Jour. Ind. Hyg.  Toxicol. 25:  423.

National Academy of Sciences.  . 1978..  Nonfluorinated halomethanes in the
enviornment.  Washington, D.C.

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

Rosenblum, I., et al.  1960.  Chronic ingestion by dogs of methyl bromide-
fumigated foods.  Arch. Enviorn. Health 1:  3'6.

Sayer, R.R., et al.  1930.  Toxicity of dichlorodiflouromethane.  U.S Bur. Mines
Rep. R.I. 3013-

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.3., et al.  1977.  Urban-non-urban relationships of halocarbons, SF& ,
    and other atmospheric constituents. Atmos.  Environ.  11:  819.
U.S. EPA.  1975.  Preliminary assessment of suspected carcinogens in  drinking
water, and appendicie's.  A report to Congress, Washington, D. C.

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

U.S. EPA, 1979b.  Environmental Criteria and Assessment Office.  Halomethanes:
Hazard Profile.

-------
von Oettingen, W.F.  1964.  The halogenated hydrocarbons of industrial and
toxicological importance.  Elsevier Publ. Co., Amsterdam.
                                    --3.3J-

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                                      No. 30
     4-Bromophenyl Phenyl Ether


  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 aec-uracy.

-------
                        4-Bromophenyl phenyl ether
SUMMARY

     Very little information on 4-bromophenyl phenyl ether exists.  4-Bromophenyl
phenyl ether has been identified in raw water, in drinking water and in river
water.  4-Bromophenyl phenyl ether has been tested in the pulmonary adenoma
assay, a short-term carcinogenicity assay.  Although the results were negative,
several known carcinogens also gave negative results.  No other health effects
were available.  4-Bromophenyl phenyl ether appears to be relatively toxic
to freshwater aquatic life:  a 24-hour average criterion of 6.2 ug/L has been
proposed.

I.  INTRODUCTION

     4-Bromophenyl phenyl  ether (BrCgH OC,H_; molecular weight 249.11) is a
liquid at room temperature; it has '"•he following physical/chemical properties
(Weast 1972):
             .  Melting point:  18.72°C
               Boiling point:  310.14°C (760 mm Hg)
                               163°C (10 mm Hg)
                                     20
               Density:        1.4208
               Solubility:     Insc'^ble in water; soluble in ether

     No  information could be found on,the uses of this substance.
                                   - ,.J '
     A review of the production range (includes Importation) statistics
for 4-bromophenyl phenyl ether (CAS Nol 101-55-3) which is listed in the initial
TSCA Inventory  (1979) has shown that between 0 and 900 pounds of this chemical
were produced/imported in 1977.*
*
 This production range information does not include any product ion/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).

-------
II.  EXPOSURE

     No specific information relevant to the environmental fate of 4-bromophenyl
phenyl ether was found in the literature.  A U.S. EPA report (1975a) included this
substance in a category with several other drinking water contaminants consid-
ered to be refractory to biodegradation (i.e., lifetime greater than two years
in unadapted soil; point sources unable to be treated biologically).  However,
the authors did not present or reference experimental data to support the inclu-
sion of 4-bromopheny phenyl ether in this category.  U.S. EPA (1975a) estimated
that three tons of 4-bromophenyl phenyl ether are discharged annually.
     4-Bromophenyl phenyl ether has been identified as a contaminant in finished
drinking water on three occasions, in raw water on one occasion and in river
water on one occasion.  No quantitative data were supplied (U.S. EPA, 1976).  Fri-
loux (1971) and U.S. EPA (1972) have also reported the presence of 4-bromophenyl
phenyl ether in raw and finished water of the lower Mississippi River (New
Orleans area).  Again, no quantitative data were supplied.  U.S. EPA (1975) sug-
gest that 4-bromophenyl phenyl ether may be formed during the chlorination of
treated sewage and drinking water.

III.  PHARMACOKINETICS

     No information was located.

IV.  HEALTH EFFECTS

     A.  Carcinogenicity

     Three groups of 20 male mice were administered intraperitoneal doses
(23, 17 or 18 doses, respectively) of 4-bromophenyl phenyl ether in tricaprylin
vehicle three times a week for 8 weeks (Theiss et al. 1977).   The total doses
were 920, 1700, or 3600 mg/kg, respectively.  Animals were sacrificed at 24
weeks from the start of the experiment.  Incidences of lung adenomas were not
significantly increased, as compared with vehicle controls.  However, this short-
term assay should not be considered indicative of the nononcogenie ity of 4-
bromophenyl phenyl ether as several known oncogens tested negative in this assay.

-------
V.  AQUATIC TOXICITY

     A.  Acute

     An unadjusted 96 hour LC   of 4,940 ug/L was determined by exposing
bluegills to 4-bromophenyl phenyl ether (Table 1).  Adjusting this value for test
conditions and species sensitivity,  a Final Fish Acute Value of 690 ug/L is obtained
(U.S. EPA, undated).
     Exposure of Daphnia magna, yielded an unadjusted 48 hour LC,_ of 360 ug/L
(Table 2).  The Final Invertebrate Acute Value (and the Final Acute Value) for
4-bromophenyl phenyl ether is 14 ug/L (U.S. EPA, undated).

     B.   Chronic

     In an embryo-larval test using  the fathead minnow (in  which survival and
growth were observed), a chronic value of 61 ug/L was obtained for 4-bromophenyl
phenyl ether exposure (Table 3).  Dividing by the species sensitivity factor
(6.7), a Final Fish Chronic Value of 9.1 ug/L is derived.  Since no other
information is available, this value is also the .Final Chronic Value (U.S. EPA,
undated).

VI.  EXISTING GUIDELINES

     A.  Aquatic

     A 24 hour average concentration of 6.2 ug/L (6.2 ug/L  = 0.44 x 14 ug/L
(Final Acute Value)) is the recommended criterion to protect freshwater aquatic
life.  The maximum allowable concentration should not exceed 14 ug/L at any
time (U.S. EPA, undated).

-------
                  Table 1.   Freshwater fish acute values
Organiom
Bluegill,
Lepomis macrocjiirus
Bioassay Test     Chemical       Time
Method*  Cone.**  Description    (hrs)
  S        U    4-Bromophenyl-    96
                 phenyl ether
                                                                 4,940    2,700
*  S = static
** U = unmeasured
   Geometric mean of adjusted values:  4-Bromophenylphenyl ether
   2.700
                                                                   2,700 ug/L
    3.9
           690 ug/L
                Table 2.  Freshwater invertebrate acute values


Organism
Cladoceran,
Daphnia magna

Bioassay Test
Method* Cone.**
S U


Chemical
Description
4-Bromophenyl-
phenyl ether

Time
(hrs)
48


LC50
(ug/L)
360

Adjusted
LC50
(ug/L)
300

*  S = static
** U = unmeasured
   Geometric mean of adjusted values:  4-Bromophenyl phenyl ether
   300
                                                                    300 ug/L
   21
         14 ug/L
    Table 3.  Freshwater fish chronic values, 4-Bromophenyl phenyl ether
Organism
Fathead minnow,
Pirnephales promelas
                                          Limits
                                Test*     (ug/L)
                                E-L
                  89-167
Chronic
Value
(ug/L)
 61
*  E-L = embryo-larva
   Geometric mean of chronic values = 61 ug/L
   Lowest chronic value = 61 ug/L
                                                 |^7  =9.1 ug/L
                                   -•2,37-

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                               BIBLIOGRAPHY
Friloux J. 1971.  Petrochemical wastes as a pollution problem in the lower
Mississippi River.  Paper submitted to the Senate Subcommittee on Air and Water
Pollution, April 5 (as cited in U.S. EPA, 1975b).

Theiss JC, Stoner GD, Shimkin MB, Weisburger EK.  1977.  Test for careinogenieity
of organic contaminants of United States drinking waters by pulmonary tumor
response in strain A mice.  Cancer Research 37:2717-2720.

U.S. EPA.  1972  Industrial pollution of the Lower Mississippi River in
Louisiana Region VI.  Surveillance and Analysis Division (as cited in U.S.
EPA, 1975b) .

U.S. EPA. 1975a.  Identification of organic compounds in effluents from industrial
sources.  EPA-560/3-75-002, PB 241 641.

U.S. EPA. 1975b.  Investigation of selected potential environmental contaminants:
Haloethers.  EPA-560/2-75-006.

U.S. EPA.  1976.  Frequency of organic compounds identified in water.  EPA-
600/4-76-062.

U.S. EPA. 1979.  Toxic Substances Control Act Chemical Substance Inventory.
Production .Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.

U.S. EPA. (undated).  Ambient Water Quality Criteria Document on Haloethers,
Criteria and Standards Division, Office of Water Planning and. Management.  PB
296-796.

Weast, RC (ed.).  1972.  Handbook of Chemistry and Physics, 53rd. ed.  The
Chemical Rubber Co., Cleveland, OH.

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                                      No. 31
              Cadmium
  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.
                             -Wo-

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                       SPECIAL NOTATION










U.S. EPA1 s Carcinogen Assessment Group (CAG) has evaluated



cadmium and has found sufficient evidence to indicate that



this compound is carcinogenic.
                            - V-M -

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                                   CADMIUM
                                   Summary

     The major non-occupational routes of human  cadmium exposure are through
food and  tobacco smoke.  Drinking water  also contributes  relatively little
to the average daily intake.
     Epidemiological studies indicate that cadmium  exposure may increase the
mortality  level  for cancer  of  the prostate.   Long-term feeding  and inhal-
ation studies  in animals  have  not produced tumors,  while  intravenous admin-
istration  of cadmium  has  produced only  injection  site tumors.   Mutagenic
effects of cadmium  exposure  have  been seen in animal studies, bacterial sys-
tems,  i£  vitro  tests,  and in   the  chromosomes of occupationally  exposed
workers.
     Cadmium has produced teratogenic effects in several species of animals,
possibly through interference with zinc metabolism.   Testicular necrosis and
neurobehavioral  alterations  in animals  following exposure  during pregnancy
have been produced by cadmium in animals.
     Chronic exposure  to cadmium  has produced emphysema and a characteristic
syndrome .(Itai-Itai disease)  following  renal  damage  and   osteomalacia.   A
causal  relationship between chronic  cadmium exposure  and  hypertension  in
humans has been suggested but not confirmed.
     Cadmium is  acutely toxic  to freshwater  fish at  levels as low  as 0.55
jug/1.  Freshwater fish embryo/larval  stages  tended to be the most sensitive
to  cadmium.    Marine  fish   were  generally  more resistant  than  freshwater
fish.  The long  half-life of cadmium  in  aquatic organisms has been postu-
lated,  and severe restrictions  to gill-tissue respiration have been obs'erved
at concentrations as low as 0.5jug/l.

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                                    CADMIUM

I.    INTRODUCTION

     This profile  is based  on the  Ambient  Water Quality  Criteria Document

for Cadmium (U.S. EPA, 1979).

     Cadmium  is  a  soft,  bluish-silver-white  metal,  harder  than  tin  but

softer  than  zinc.   The  metal melts  at  321°C  and  shows a  boiling point of

765°C  (U.S.   EPA,  1978b).   Cadmium  dissolves  readily in mineral  acids.

Some  of the  physical/chemical  properties of  cadmium and  its  compounds are

summarized in Table  1 (U.S. EPA, 1978b).

     Cadmium  is   currently   used  in  electroplating,   paint   and  pigment

manufacture,  and as  a stabilizer for plastics (Fulkerson and Goeller, 1973).

         Current production;  6000 metric tons  (1968) (U.S. EPA, 1978b)

         Projected production:  12,000 metric tons (2000) (U.S. EPA, 1973b)

     Since cadmium  is  an element,  it  will  persist in  some  form in  the

environment.   Cadmium is  precipitated from  solution by carbonate,  hydrox-

ide, and sulfide  ions (Baes, 1973); this  is  dependent  on pH and  on cadmium

concentration.  Complexing of cadmium  with other anions will produce soluble

forms (Samuelson,  1963).   Cadmium  is strongly  adsorbed  to clays, muds,  humic

and organic  materials and some hydrous  oxides (Watson,  1973),  all of which

lead to precipitation from aqueous  media.   Cadmium  corrodes slightly in air,

but forms  a  protective surface film which prevents  further corrosion  (U.S.

EPA, 1978b).

II.  EXPOSURE

     Cadmium   is  universally  associated  with  zinc  and  appears  with it  in

natural deposits  (Hem,   1972).   Major sources  of cadmium  release  into  the
                                                                        »
environment  include  emissions from  metal  refining  and  smelting  plants,  in-

cineration of  polyvinyl  chloride  plastics,  emissions  from use   of  fossil

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Table 1.  Some I'ropertlea of Cadmium and  its  Importune Compounds
Primary
u;,i; or
Compound occurrence Formula
C, Minium Cadmium nickel Cd
i,..j|.il l.al Icrles
C,-i. liuluig Smelling plant CdO
oxlilt: or coal COD.IIUS-
1 Ion cmlHs Ion
Cadmium Pigment for CdS
uul 1 Ide pluul Ics mid
enamels; phos~
S^ pi. 01 a
j- Cadmium Fruit tree CdSO
f Kulfale fnmlclde
1
i:.i, Iml inn Turf treat- Cdt'O,
cai'lioual e went
lloleculnr Physical '
uelgbt Oenalty utule,
(g/uiolc) (g/ml) 20°C
112.4 6.6 Silver metal
»
12U.4 7.0 Urown powder \
i
144.5 4.8 Yellow crystal
200.5 4.7 Wblte
crystalline
172.4 4.3 Ulilte powder
or crystalline
Solubility
Melting Dolling In water
point point 20°C
("C) CC) (g/llter)
321 765 Insoluble
Decomposes 0:00015
ut 900
1750 Deconposca 0.0013
1000 755
Decomposes 0.001
below 500
Solubility
In oilier
solveiitti
Soluble lit
acid and
Soluble In
acid and
Nll-j nulls
Soluble In
acid, very
tjliglitly
soluble in
Nil, till
Insoluble
In uctd
and ulacliol
Soluble In
acid and
KCN. Ml,
suits
Acute I.etbal
doue"
9 i»g/m Is tlic
upprox Imate
letlial cuiicen-
tiutlou lit man,
InbalL-d au fume
50 uig/m Is tlie
upprox Imai e
lethal cuncen-
trntlon In mini,
Inlialed; 72
mg/kg^ rat,
l.l>50 (oral)

27 mg/kg dug,
U>50 (uuli-


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                                                   Table 1.   Some rrojiertlca of Cailmluin onil  Itu IninorCanC Compounds  (Cont'il)



<:..».,..>,m.i
Ciiilnil mil
t:lil oil de
C.lilmlum
piiliissltun
i:yanl,le
Catlnil inn
cyan tile
limili .;:;:
l-'u 1 kui'M>n ill
llaluie an>l Ki

l-i hiiiiry Molecular
use or weight Dciiulty
occurrence . Formula (g/inole) (u/nil)
Turf grass C.ICl. 103.3 4.0
fimlcl.le
tltfciioplutlng K.jCJ(CN)^ 294.7 1.U5


Electroplating Cd(CN>2 164.4


n.l C.icller. 1971
immtle, 1973

I'liyulcol
alute.
20°C
Colurleaa
crybtul
Colo.rleaa,
gluua
cryiital
Colorlesu
cryatal




Melting Dolling
pnl ut point
CO CO
568 960




Decomposes
ut 200



Solubility
III water
20°C
(g/ liter)
1400

311


17, uolublo
la liot water




Solubility
In oilier Acute l.ullial
uolventa iloue a
13.2 B/llter UU ing/kg rut.
In ulcoliol I.I) (unil)
Inaoluble In
alcoliol

Soluble In
ucld and KCH



         Oilier  il.u.i u..ni|.| I. .1 from UcuaC,  1971
 I
U)

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fuels, use of certain phosphate  fertilizers,  and  leaching of galvanized iron

pipes (U.S.  EPA,  1978b).  The major  non-occupational routes  of  human expo-

sure to cadmium are through foods and tobacco smoke (U.S. EPA, 1979).

     Based on available monitoring data,  the U.S. EPA  (1979)  has estimated

the uptake of cadmium by adult humans from air, water, and food:

                                            Adult
                Source                      jug/day
                                            Maximum conditions

                Air-ambient                   .008 mg/day
                Air-smoking                  9.0
                Foods                       75.0
                Drinking water              20.0
                           Total           304.008

                                            Minimum conditions
                Air-ambient                  0.00002
                Air-smoking                  0
                Food                        12.0
                Drinking water               1.0
                           Total            13.00002

     The variation of cadmium  levels  in  air,  food, and water is quite exten-

sive as indicated above.   Leafy  vegetables,  contaminated water,  and air near

smelting plants  all present  sources  of  high potential exposure.   The U.S.

EPA  (1979)  has  estimated  the weighted   average  bioconcentration  factor  of

cadmium to  be 17 in  the edible portions  of fish and  shellfish  consumed  by

Americans.

III. PHARMACOKINETICS

    . A.  Absorption

         The main routes by  which cadmium can enter  the body are inhalation

and  ingestion.   Particle size.and  solubility greatly influence  the biolog-

ical  fate  of inhaled cadmium.   When  a large proportion of  particles  are  in

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the respirable  range,  up to 25% of  the inhaled amount may be absorbed (EFA,
1979).  Cadmium  fumes  may have an absorption  of up to 50%,  and  it is esti-
mated  that  up to  50%  of  cadmium  in cigarette smoke may  be absorbed (WHO,
1977; Slinder, et al.  1976).   Large  particles  are trapped by the mucous mem-
branes  and  may  eventually  be  swallowed,  resulting  in   gastrointestinal
absorption (EPA, 1979).
         Only a  small  proportion of  ingested cadmium is absorbed.  Two human
studies using  radiolabelled cadmium  have  indicated mean  cadmium  absorption
from  the  gastrointestinal  tract  of  6%  and  4.6%  (Rahola,  et  al.  1973;
McLellan, et  al. 1978).   Various  dietary  factors  interact  with  cadmium ab-
sorption; these  include  calcium  levels  (Washko and Cousins,  1976), vitamin 0
levels  (Worker  and  Migicovsky, 1961),  zinc, iron,  and copper levels (Banis,
    '•  \
et  aS. 1969).  and  ascorbic acid  levels (Fox  and Fry,  1970).   Low protein
diets  enhance the uptake of cadmium  from the gastrointestinal tract (Suzuki,
et al. 1969).
         Dermal  absorption of cadmium  appears to  occur  to  a  small extent;
Wahj._erg (1965) has determined that  up  to 1.8  percent  of high levels of cad-
mium chloride were absorbed by guinea pig skin.
         Cadmium levels  have  been determined   in  human embryos  (Chaube,  et
al. 1973) and  in the blood of newborns (Lauwerys, 1978), indicating passage
of cadmium occurs across the placental membranes.
     B.  Distribution
         Cadmium is  principally  stored  in  the liver,  kidneys,  and pancreas
with  higher  levels  initially  found  in the  liver  (WHO  Task  Group,  1977).
continued exposure  leads to accumulation in all of these  organs;  levels as

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high as  200-300 mg/kg  wet  weight may  be found  in the  renal  cortex.  This
storage  appears to  be dependent  on  the association  of  cadmium with  the
cadmium binding protein, metallothionen (Nordberg et al., 1975).
         Animal  studies indicate  that  following  intraperitoneal  or  intra-
venous administration  of  cadmium most of the compound  is found in the blood
plasma.  After 12-24 hours the plasma is  cleared  and  most of the compound is
associated with red blood cells (U.S. EPA, 1978b).
         The cadmium  body burden of  humans  increases with  age (Friberg,  et
al. 1974)  from very  minimal levels at birth to an  average  of up to 30-40 mg
by  the  age of  50  in  non-occupationally exposed  individuals.   Liver  accumu-
lation  continues  through  the last  decades of  life,  while kidney  concen-
trations increase  until the fourth  decade  and then  decline (Gross,  et  al.
1976).   The  pancreas  and salivary  glands also contain  considerable  concen-
trations of  cadmium   (Nordberg,  1975).   Smoking  effects  the body  burden  of
cadmium; levels  in the renal cortex of smokers may be  double those found in
non-smokers (Elinder, et al. 1976; Hammer, et al.  1971).
     C.  Metabolism
         Pertinent data were not found in the available literature.
     D.  Excretion
         Since only about 6  percent  of  ingested cadmium is  absorbed,  a large
proportion of  the  compound   is eliminated by the feces  (U.S.  EPA, a  or  b).
Some  biliary   excretion  of   cadmium  has  been  demonstrated  in   rats  (Stowe,
1976);. this  represented less than 0.1  percent  of  a  subcutaneously adminis-
tered dose.
         Urinary excretion  of  cadmium is  approximately 1-2  mg/day   in  the
                                                                        f
general  population (Imbus,  et al. 1963;  Szadkowski,  et  al.  1969).  Occupa-
tionally  exposed  individuals  may  show  markedly  higher urinary  excretion

-------
levels (Friberg, et al.  1974).   A  modest increase in human urinary excretion
of cadmium has been noted with increasing age (Katagiri, et al. 1971).
         Additional sources  of cadmium  loss are  through  salivary excretion
and shedding of hair (U.S. EPA, 1979).
         Biological half-life calculations  for  exposed  workers  have  given
values of up  to 200 days  (urine).   Direct comparisons of  urinary excretion
levels and  estimated  body burden using  Japanese,  American,  and German data,
suggest a  half-time of  13-47 years.  Using  more complex  metabolic models,
Frieberg,   et  al.  1974  concluded  that  the  biologic  half-time  is  probably
10-30 years. . The  most recent estimate  of biologic half-time  is 15.7 years
by Ellis (1979).
IV.  EFFECTS
     A.  Carcinogenicity
         The results  of several epidemiology studies of the relationship of
cancer to occupational exposure  to cadmium  are summarized in  Table 3 (U.S.
EPA,  1978a).    The  only  consistent  trend   seen  in   these  studies  is  an
increased incidence of prostate cancer in  cadmium-exposed  workers.  A recent
study  by  Kjellstrom,   et al.  (1979)  of 269  cadmium-nickel  battery factory
workers found increased  cancer mortality from nasopharyngeal cancer (signif-
icant) and  increased  mortality  trends  for prostate, lung,  and colon-rectum
cancers (not  significant).   After  reviewing  these  studies,  EPA  (1979)  has
concluded that  cadmium cannot be  definitely  implicated as  a  human carcino-
gen with the available data.
         Animal  experiments  with  the administration  of  cadmium by  subcu-
taneous or  intravenous  injection  have  demonstrated that  cadmium  produces

-------
injection site  sarcomas  and  testicuiar tumors  (Leydigiomas) (see  Table 2;
U.S. EPA, 1978a).   A  large number of  metals and irritants  produced compar-
able injection sits sarcomas.  Long  term feeding  and  inhalation  studies with
cadmium have not produced tumors (Schroeder, et al. 1964,  Levy,  et al. 1973;
Decker, et al. 1958; Anwar, et al.  1961; Paterson, 1947; Malcolm, 1972)
         At the present  time,  the  draft ambient  water  quality criterion for
protection of human health is based on the toxicity of cadmium rather than
on  any  carcinogenic effects.   Though  the  studies summarized  above  qualita-
tively  indicate  a  carcinogenic  potential   for  cadmium, quantitatively-,  the
issue has not been resolved.
     B.  Mutagenicity
         An increased incidence of chromosomal aberrations  has been.noted in
workers occupationally exposed to cadmium  and in  Japanese  patients suffering
cadmium, toxicity  (Itai-Itai disease)  (Bauchinger, et  al.  1976;  Bui,  et al.
1975; Deknudt and Leonard, 1976;  Shiraishi  and Yoshida,  1972).
         Cadmium has been shown to produce mutagenic  effects in  vitro and _in
vivo in several systems (see Table 4;  U.S.   EPA, 1978  a  or  b).  These effects
include induction of point  mutations in bacterial systems,  chromosome aberr-
ations  in cultured  cells and  cytogenetic  damage  in  vivo,  and  promotion of
error prone base  incorporation in  ONA _in  vitro.  Several  investigators have
been unable to show dominant  lethal  effects of cadmium in mice  (Epstein, et
al. 1972; Gillivod  and  Leonard,  1975; Suter, 1975).  Point  mutation studies
with cadmium in Drosophila  have  also produced negative  findings (Shabalina,
1963; Friberg et al.,  1974; Sorsa and Pfeiffer,  1973).
     C.  Teratogenicity
                                                                       »
         Damage to  the  reproductive  tract resulting  from  a single  dose of
parenterally administered  cadmium  chloride (2 mg/kg) have  been observed in

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                                                          TA11LE  2

                                STUDIES ON CADMIUM CARCINOGENESIS  IN EXPERIMENTAL ANIMALS*
Authors
Animals
Compounds and routes
Tumors
Heath £t £l. ,  1062;  Heath  and Daniel,  1964   Rats

KuziiittzJs,  1063;  Kazautzis and llanbury, 1966 Rats

lladdow j£t u\_.,  1964;  Roe et_ al^.,  1964         Rats

Outhrie, 1964                                 Clilckens

ttunn £t aj.. ,  1963i  196/i; 1965; 1967          Rats, Mice

Schroedcr <;t  .a_l. ,  1965; Kanlsaua  and         Rats, Mice
St:hrouilcr,  1969

Nunurl ut aj.. ,  1967;  Favion _et al_., 1968     Rats

Knorre, 1970;  1971  '                          Rats

Lucia £t ^ij_. ,  1972;  1973                      Rats

Keil.ly ^t u_j_. ,  1973                            Rats

Levy ia u\_. , 1973                             Rats

Levy 
-------
                                               TABLE  3
                 SUMMARY OF RESULTS OF HUMAN EPIDEMIOLOGY STUDIES OF CANCER EFFECTS
                          ASSOCIATED WITH OCCUPATIONAL EXPOSURES TO CADMIUM

Population Cadmium Compound . Incidences of Incidences of
Croup Studied Exposed To All Cancers Lung Cancer
Hattery factory Cadmium oxide High Normal
workers
liuttury factory Cadmium oxide Normal Normal
workers

Cadmium smelter Cadmium oxide, High High
workers others
Rubber industry Cadmium oxide High Normal
Incidences of
Prostrate Cancer Reference
High Potts (1965)
t
High Kipling and
Uaterhouse
(1967)
High Lemon et al.
(1976)
High McMichael et al.
workers
(1976)

-------
rats,  rabbits,  guinea  pigs,  hamsters,  and mice  (Parizek and  Zahor,  1956;
Parizek, 1957;  Meek,  1959).  This  susceptibility  appears to  be genetically
regulated since  different  strains  of mice  show  differential susceptibility
(Wolkowski,  1975).
         Teratogenic effects  of cadmium  compounds  administered parenterally
have been reported in mice  (Eto, et al.  1975),  hamsters (Ferm and Carpenter,
1963;  Mulvihill,  et al.  1970;  Ferm,  1971;  Gale  and  Ferm,  1973)  and  rats
(Chernoff,  1973;  Barr,  1973).  Oral  administration  of cadmium  (10  ppm)  has
demonstrated  teratogenic  effects  in rats  (Schroeder and Mitchener,  1971),
but no teratogenicity has been  reported  in rats and monkeys  (Cuetkova, 1970;
Pond and Walker, 1975;  Willis, et al. 1976; Campbell and Mills, 1974).
     0.  Other Reproductive Effects
         Rats  in late  pregnancy  are  apparently  more sensitive  to cadmium
than non-gravid  animals  or  those immediately post-partum.  A single dose of
2-3 mg/kg of  body weight given during the last 4 days of pregnancy resulted
in high mortality (76 percent).
         In  addition to  the  embryotoxic  effects  of  cadmium  indicated  in
Section C,  persisting effects  of cadmium exposure  during pregnancy on postu-
lated development and growth  of  offspring have  been observed.  This includes
neurobehavioral alteration  in  newborn rats (Chowdbury and Lauria,  1976)  and
growth deficiencies in lambs (U.S.  EPA, 1978a).
     E.  Chronic Toxicity
         Friberg . (1948,  1950)  observed emphysema in  workmen  exposed to  cad-
mium dust  in  an  alkaline  battery  factory.  This  finding has  subsequently
been well documented (U.S. EPA, 1979).

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                                                     TABLE 4

                                      SUMMARY OF MUTAGENICITY TEST RESULTS
Test  System
Genetic Effect
Reported
Mutagenicity
               References
Human cells
        Hamster Cells
Systems in vitro

Cltromosomal damage
Point imitation
Point mutation
.PI. s11htj'l_ 1 s recomblnant  Gene mutation
     assay
Polynueleotides          Base mispairlng
+
+

+

+
                    Shiraishl et_ al.', 1972
                    Costa _et^ al., 1976
                    Takahoslii, 1972
                    Nlshioka, 1975

                    Sirover and Loeb, 1976
Human leukocytes
Human leukocytes
Human leukocytes
Human leukocytes
KiiL b|)orinatogoni.a »
Motive OOCytUS
Mt)iise I) feed ing
Mouse breeding
Mouse breeding
Mammals
I), me lauoga.-iter
Systems in vivo

Chromosomal damage
Chromosomal damage
Chromosomal damage
Chromosomal damage
Altered spermatogenesis
Cytogenetic damage
Dominant lethal mutations
Dominant lethal mutations
Dominant lethal mutations
Chromosomal abnormalities
Sex-linked recessive lethal
                    Shirashi and Yoshida, 1972
                    Bui et^^l., 1975
                    Deknudt and Leonard, 1975
                    Bauchinger et al., 1976
                    Lee and Dixon, 1973
                    Shlmada ej^ al., 1976
                    Epstein et_ al., 1972
                    Gllliavod and Leonard, 1975
                    Suter, 1975
                    Shlmada e£ £l., 1976
                    Sorsa and Pfeifer, 1973

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         Chronic  cadmium  exposure  produces  renal  tabular  damage  that  is
characterized  by  the  appearance  of  a  characteristic  protein   9B_-micro-
globulin)  in the  urine.   Renal  damage  has  been  estimated  to  occur when
cadmium  levels   in  the  renal  cortex  reach  200  mg/kg  (Kjellstron,   1977).
Itai-Itai disease is  the result of cadmium  induced  renal damage plus  osteo-
malacia (U.S. EPA, 1978a).
         Exposure to  high  ambient  cadmium levels may contribute to the etio-
logy of  hypertension  (U.S. EPA, 1979).   Several studies, however, have been
unable  to show  a .correlation between  renal levels  of  cadmium  and  hyper-
tension (Morgan 1972; Lewis, et al. 1972; Beevers, et al.  1976).
         Friberg  (1950)  and Blejer (1971) have noted abnormal liver function
tests  in workers  exposed   to  cadmium;  however,  these  workers  were occupa-
tionally exposed to a variety of agents.
         The immunosuppressive  effects  of cadmium exposure,  including an in-
creased  susceptibility  to  various infections, have  been reported  in several
animal studies (Cook, et al. 1975; Koller, 1973; Exon, et  al. 1975).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Acute toxicity  in freshwater  fish  has  been studied  in a number of
96-hour bioassays consisting of one static  renewal, 22  static,  and 19 flow-
through  tests.   L(-5n values  ranged  from  1 ug/1  for  stripped  bass,  larvae
(Roccus  saxatilus)   (Hughes,   1973)   to  73,500  for   the   fathead  minnow
(Pimephales promelas)  (Pickering  and Henderson,  1966).  Increased  resistance
to  the  toxic  action  of  cadmium  in  hard  waters  was  observed.   The LC_n
values   for   freshwater    invertebrates   ranged   from   3.5   for   Cladoceran
(Simoeohalus serrulatus)  to 28,000 pg/1  for the mayfly  (Eohemerella orandis
grandis).  Acute LC--  values   for  marine  fish  ranged  from  1,600 yg/1  for

-------
larval  Atlantic  silversides  (Menidia  menida)  (Middaugh  and Dean,  1977) to
114,000 jjg/1  for juvenile mummichog  (Fundulus heteroclitus)  (Voyer,  1975).
Intraspecific and  life stage  differences  have shown  that  larval  stages of
the Atlantic  silversides and  mummichog  are  four  times more  sensitive  than
adults  under  the  same test  conditions  (Middaugh  and  Dean,  1977).   Marine
invertebrates are  more sensitive  to  cadmium  than  are marine  fishes.    LC_Q
values  ranged from  15.5  ug/1 for the mysid  shrimp  (Nimmo, et  al.  1977a) to
46,600 for the fiddler crab (Uca puqilator) (O'Hara, 1973).
     8.  Chronic Toxicity
         Chronic values  for  freshwater  fish ranged from 0.9 ug/1 in a brook
trout  (Salvelinus  fontinalis)  embryo  larval  assay  (Sauter,  et  al.  1976) to
50 pg/1 in  a life  cycle  (or partial  life  cycle) assay for  the  bluegill
(Lepomis  marcochirus)   in  hard water   (Eaton,  1974).    Salmonids  were  in
general the  most sensitive  species examined.  Data for  freshwater  inverte-
brates  depend  on a  single  jug/1 obtained  for  Daphnia  maqna  (Biesinger  and
Christensen,  1972).   No chronic studies were available for cadmium effects
in  marine  fishes.   The  only  marine  invertebrates  data reported  was  the
chronic value of 5.5 jug/1  for the mysid shrimp,  Mysidoosis  bahia.   In  this
animal  no  measurable  effects  on  brood  appearance in  the  pouch,  release,
average number  per  female,  or survival were  observed  at concentrations of
     C.  Plant Effects
         Effective concentrations  for  freshwater plants ranged  from  2 jug/1,
which  causes  a  10  fold growth  rate  decrease  in  the diatom,  Asterionella
formosa (Conway,  1978),  to  7,400 pg/1, which causes a 50% root  weight, inhi-
bition in Eurasian water-milfoil (Myrioohyllum  soicatum) .   In marine algae,

-------
96-hour  EC.Q growth  rate  assays  yielded  values  of  160  and  175  pq/l  for
Cyclotslla nana and  Skeletonema costatum respectively  (Gentile and Johnson,
1974).
     0.  Residues
         Bioconcentration  factors  ranged from  151 for brock  trout to  1,988
for the  flagfish  (Jordanella floridae).  One characteristic  of cadmium tox-
icity  in aquatic  organisms  was  the  possible long  half-life  of the chemical
in certain tissues  of exposed brook trout  even after being  placed in  clean
water  for  several weeks.   Testicular  damage to  adult  mallards was observed
when  fed 20 mg/kg  cadmium  in  the diet  for 90  days.   In marine  organisms
bioconcentration  values  ranged  from 37  for the  shrimp  Cranqon  crangon to
1,230  for  the  American oyster,  Crassostrea  virginica  (Schuster and Pringle,
1969).                                             ^
     E.  Miscellaneous
         Several,  studies on  marine  organisms  have  demonstrated  significant
reduction  in gill-tissues  respiratory  rates  in  the cunner,  Tautoqolabrus
adepersus,  the  winter  flounder,  Pseudopleuron&Jtes  americanus,  and   the
stripped bass, MOrone saxatilis, at concentration? ^s low as 0.5 pg/1.
VI.  EXISTING GUIDELINES
     A.  Human
         It  is  not recommended  that cadmium be  considered a  suspect-  human
carcinogen for purposes  of calculating a water quality criterion (U.S. EPA,
1979).
         The  EPA  Primary  Drinking  Water  Standard  for  protection  of  human
health is  10 pg/1.   This level was  also  adopted  as the draft  ambient water
                                                                         »
quality criterion (U.S. EPA, 1979).

-------
         The  OSHA time-weighted  average exposure  criterion  for  cadmium  is
100 jjg/m .
     8.  Aquatic
         The  draft  criterion  proposed  for  freshwater organisms  to- cadmium
has been prepared following the Guidelines,  and is listed  according to the
following equation:
                          (0.867 In-(hardness) - 4.38)
                         e
for a 24-hour average and not to exceed  the  level described by the following
equation:

                          (1.30 In-(hardness) - 3.92)

The proposed marine criterion derived following the Guidelines  is  1.0 ug as
a 24-hour average not to exceed 16 jug/1 at any time (U.S. EPA, 1979).

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                             CADMIUM

                            REFERENCES
Anwar, R.A.,  et al.   1961.   Chronic  toxicity  studies.   III. Chronic
toxicity of cadmium and chromium  in dogs.   Arch.  Environ. Health
3: 456.

Baes,  C.F.,  Jr.   1973.   The  properties  of  cadmium.   Pages 29
to 54  in W.  Fulkerson,  and H.E. Goeller,  eds.   Cadmium, the  dis-
sipated element.  Oak Ridge Natl. Lab., Oak  Ridge, Tenn.

Banis, R.J., et al.   1969.   Dietary cadmium, iron and zinc inter-
actions in the growing rat.  Proc.  Soc. Exp. Biol. Med.  130:  802.

Barr, M.   1973.   Teratogenicity of  cadmium chloride in two stocks
of Wiser rats.  Teratology  7:  237.

Bauchinger, M.E., et al.  1976.  Chromosome  aberrations  in lympho-
cytes  after  occupational  lead and  cadmium  exposure.   Mut.   Res.
40: 57.

Beevers,  D.C., et  al.    1976.   Blood  cadmium  in hypertensives
and normotensives.  Lancet  2:  1222.

Biesinger, K.E.,  and  G.M.  Christensen.   1972.   Effects of various
metals on survival,  growth,  reproduction, and metabolism of Daphnia
magna.  Jour. Fish. Res. Board Can.   29: 1691.

Blejer, H.P., et al. 1971.  Occupational health aspects of cadmium
inhalation poisoning  with  special  reference to welding and silver
brazing.   2nd  ed.   State  of Calif.  Dept. Pub.  Health, Bur. Occup.
Health Environ. Epidemiol.

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9: 187.

Campbell and  Mills.   1974.   Effects of dietary  cadmium and  zinc
on  rats  maintained on  diets  low  in copper.   Proc.  Nutr.    Foe.
33: 15a.

Chaube, S., et al.  1973.  Zinc and cadmium  in normal  human embryo
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Chen,  R.W-. ,  et  al.    1975.   Selenium-induced  redistribution of
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protection against cadmium toxicity.  Bioinorg. Chem.  4: 125.
                                                              »
Chernoff,  N.    1973.    Teratogenic  effects  of  cadmium  in  rats.
Teratology.  8: 29.

-------
Chowdbury, P.  and D.B. Lauria.   1976.   Influence  of cadmium and
other trace  metals  on human a-,-antitrypsin  - An _i_n  vitro study.
Science  191: 480.

Conway,  H.L.   1978.   Sorption of  Arsenic  and cadmium  and their
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Board Can.  35: 286.

Cook, J.A.,  et al.   1975.   Factors modifying  susceptibility  to
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Rev. Tox.  3:  201.

Cuetkova,   R.    1970.    Materials on  the study  of  the  influence
of cadmium compounds on the  generative  functions.   Gig.  Tr. Prof.
Zabol.  14: 31.

Decker,  L.E.,  et  al.   1958.   Chronic toxicity studies.   I.  Cad-
mium  administered in  drinking water  to rats.   AMA Arch.  Ind.
Health 18: 228.

Deknudt,  Gh.  and  A.  Leonard.    1976.   Cytogenic  investigations
on  leucocytes of workers  occupationally  exposed   to cadmium.
Mut. Res.   38: 112.

Eaton,  J.G.    1974.   Chronic  cadmium  toxicity  to  the  bluegill
(Lepomis macrochirus Rafinesque).  Trans.  Am. Fish.  Soc.   4: 729.

Blinder,  C.G.,  et  al.    1976.    Cadmium  in kidney  cortex,  liver
and pancreas  from  Swedish autopsies.  Arch. Environ. Health 30:  292.

Ellis,  K.J.,  et  al.    1979.   Cadmium:   In  vivo  measurement  in
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Epstein,  S.,  et  al.    1972.   Detection  of chemical  mutagens  by
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23: 288.

Eto, K., et al.  1976.  Developmental effects of teratogens influ-
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Exon, et  al.   1975.   Cited  in Health  Assessment  Document  for
Cadmium, U.S. EPA, p.  2-91.

Ferm, V.   19.71.    Developmental  malformations induced by  calcium
— A study at timed injections during embryogenesis.  Biol. Nenon.
19: 101.

Ferm, V.  and S.  Carpenter.    1968.   The relationship of  cadmium
and  zinc  in  experimental mammalian  teratoaenesis.    Lab.  Invest.
18: 429.

Fox,  M.R.S.   and  B.E.  Fry..   1970.   Cadmium toxicity  decreased
by dietary ascorbic acid supplements.   Science  169: 98~9.

-------
Friberg, L.   1948a.   Proteinuria  and  kidney injury among workers
exposed to cadmium and nickel dust.  Jour. Ind. Hyg.  30: 33.

Friberg, L.   1950.   Health hazards in the manufacture of alkaline
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Supplement CCXL.

Friberg, L.,  et  al.    1974.    Cadmium  in  the environment.   2nd
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Fulkerson,   W.  and H.E.  Goeller,   eds.  1973.  Cadmium  the  dissi-
pated element.  Oak Ridge  Natl. Lab., Oak Ridge, Tenn.

Gale,  T.  and V.  Ferm.    1973.   Skeletal  malformations resulting
from cadmium treatment in  the hamster.   Biol. Neou.  23: 149.

Gentile, J.  and M.  Johnson.  1974.   EPA Semi-annual Rep.,  Narra-
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Gilliavod,   N.  and A.  Leonard.    1975.   iMutagenicity  tests with
cadmium in the mouse.  Toxicology  5: 43.

Gross,  S.B.,  et  al.   1976.   Cadmium  in  liver,   kidney  and hair
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Hammer, D.I., et  al.  1971.   Hair  trace metal levels and environ-
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Hem,  J.    1972.   Chemistry  and   occurrence  of  cadmium  and zinc
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Hughes, J.S.  1973.  Acute toxicity of thirty chemicals to striped
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Imbus, H.R.,  et al.   1963.   Boron,  cadmium,  chromium  and  nickel
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Katagiri,   Y.,  et al.   1971.    Concentration of cadmium  in urine
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Kjellstrom,  T. ,  et  al.    1979.    Mortality  and cancer  morbidity
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Roller, L.D.   1973.   Immunosuppression produced by lead, cadmium,
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Lauwerys,   R. , et  al.  1978.   Placental transfer  of lead, mercury,
cadmium and  carbon monoxide  in women.    I. Comparison of  the fre-
quency  distribution   of  the  biological indices   in maternal  and
umbilical cord blood.  Environ. Res.  15: 278.

-------
Levy, L.S.,  et al.   1973.   Absence  of prostatic  changes  in rts
exposed to cadmium.  Ann. Occup. Hyg.  16: 111.

Lewis, G.P., et al.  1972.  Cadmium accumulation in man: Influence
of smoking occupation, alcoholic habit and disease.  Jour. Chronic
Dis.   25: 717.

Malcolm,  D.    1972.   Potential  carcinogenic  effect  of  cadmium
in animals and man.  Ann. Occup. Hyg.  15: 33.

McLellan, J.S.,  et  al.   1978.   Measurement of  dietary  cadmium
in humans.  Jour. Toxicol. Environ.  Health.  4: 131.

Meek, E.S.   1959.   Cellular  changes induced  by  cadmium in mouse
testis and liver.  Br. Jour. Exp. Pathol.  40: 503.

Middaugh, D.P. and  Dean.  1977.   Comparative sensitivity of eggs,
larvae and adults of the estuarine telebsts, Fundulus heteroclitus
and  menidia  menidia to cadmium.  Bull.  Environ.  Contain^Toxicol.
17:  5T5T

Middaugh, D.P.,  et  al.   1975.   The  response  of  larval fish Leio-
stomus  xanthurus  to  environmental  stress  following  sublethal
cadmium exposure.  Contrib.  Mar. Sci.  19.

Morgan,  J.M.   1972.   "Normal"  lead and  cadmium content  of  the
human kidney. . Arch. Environ.  Health.  24: 364.

Mulvihill, J.F. ,  et al.  1970.   Facial  formation in  normal  and
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Nimmo, D.R.,  et  al.   1977a.  Mysidopis  bahia;   An estuarine spe-
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Nordberg, G.F.    1974.    Health  hazards of. environmental  cadmium
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Nordberg, G.F.,  et al.   1975.    Comparative  toxicity of cadmium-
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O'Hara,  J.    1973.   The influence   of  temperature  and salinity
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Parizek,  J.    1957.    The destructive  effect of  cadmium  ion  on
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15:  56.

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testicular tissue.  I. Nature.   177:   1036.

-------
 Paterson,  J.C.   1947.    Studies on  the  toxicity of  inhaled  cad-
•mium.   III. The  pathology of cadmium  smoke  poisoning in  man and
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•Pickering,  Q.H.  and C.  Henderson.    1966.    The acute  toxicity
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•Potts',  C.L.   1965.   Cadmium proteinuria  - The  health of  battery
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 Sauter, S., et  al.  1976.   Effects of  exposure to  heavy metals
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 Schroeder,  H.A.  and M. Mitchener.   1971.   Toxic  effects  of trace
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 Schroeder,  H.A.,  et  al.   1964.   Chromium, lead,  cadmium, nickel
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 Schuster,  C.N. and B.H.  Pringle.   1969.   Trace metal accumulation
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 Shabalina,  F.P.    1968..   Industrial  hygiene  in the  production
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 Shiraishi,  Y.  and  T.A. Yoshida.   1972.  Chromosomal  abnormalities
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 Shiraishi,  Y., et  al.  1972.  Chromosomal  aberrations in cultured
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                                                               f
,-Sorsa,  M.  and S.  Pfeifer.   1973.   Effect of  cadmium  on develop-
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 Hereditas.   75:  2.73.
                               -3,63-

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Stowe, H.D.  1976.   Biliary  excretion  of cadmium by rats: Effects
of  zinc,   cadmium  and  selenium  pretreatments.    Jour.  Toxicol.
and Environ. Health.

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Hemisphere Pub. Corp., John Wiley and Sons,  New York.

Suter, K.E.  1975.   Studies  on the dominant-lethal  and fertility
effects  of  the  heavy  metal  compounds  methymercuric  hydroxide,
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Mut. Res.  30:  365.

Suzuki, S., et al.   1969.  Dietary factors influencing upon reten-
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Szadkowski,  D.,  et  al.    1969.    Relation  between  renal  cadmium
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Tsuchiya,  K.   1970.   Distribution of cadmium  in  humans in Kankyo
Hoken.  Report No.  3.  Japanese Association  of Public Health.

U.S. EPA.   1978a.  Health  Assessment Document  for  Cadmium.  Draft
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1978.

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ants:  IV. Cadmium.  EPA 600/1-78-026,  1978.

U.S.  EPA.    1979.    Cadmium:   Ambient  Water  Quality.  Criteria.
Environmental Protection Agency,  Washington,  D.C.

Voyer,  R.A.    1975.    Effect  of  dissolved  oxygen  concentration
on the acute toxicity of cadmium to te  mummichog, Fundulus hetero-
clitus.  Trans. Am. Fish. Soc.  104:  129.                        ~~

Wahlberg,  J.E.   1965.   Percutaneous  toxicity of  metal compounds
-  A comparative  investigation  in  guinea pigs.   Arch.  Environ.
Health.  11: 201.

                                                          109
Washko,  P.W.  and  R.J.  Cousins.    1976.   Metabolism of    Cd  in
rats fed normal and low-calcium diets.  Jour. Toxicol. and Environ.
Health.  1: 1055.

Watson, M.R.   1973.   Pollution control in metal  finishing.  Noyes
Data Corp., Park  Ridge,  N.J.
                                                              *
Weast,  R.C.  . {ed.)    1975.    Handbook  of chemistry  and  physics,
56th ed.  CRC Press,  Cleveland.
                               -341-/-

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WHO Task  Group.   1977.   Environmental health aspects of cadmium.
World Health Organ., Geneva.

Willis, J.,  et  al.   1976.   Chronic and multi-generation toxicity
of  cadmium  for   the  rat  and  the Rhesus  monkey.    Environ. Qual.
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Worker, N.A.  and  B.B.  Migicovsky.    1961.   Effect  of  Vitamin D
on  the utilization  of  zinc,  cadmium and  mercury  in  the  chick.
Jour. Nutr.  75: 222.
                              -36.5--

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                                      No. 32
          Carbon Disulfide


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

           APRIL 30, 1980

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

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                                CARBON DISULFIDE

I.   PHYSICAL AND CHEMICAL PROPERTIES
     It is soluble in water at 0.294% at 20°C.  It can chelate trace metals,
especially Cu and Zn.  Its formula weight is 76.14 and it is a colorless,
volatile, and extremely flammable liquid at Rt.   No odor when pure.  At 27°C,
its vapor pressure is 200 mm Hg.
II.PRODUCTION AND USE
     It is produced in pretroleum and coal tar refining.   Its principal uses
are in the manufacture of rayon, rubber, chemicals, solvents, and pesticides.
                                                                      2
In 1974, 782 million pounds of CS2 were produced in the United States.   In
1971, 53% was used in production of viscose rayon and cellphane and 25% for
manufacture of CC,..
III.  EXPOSURE
                                                                   3       25
     It was detected in 5 of 10 water supplies surveyed by the EPA.   NIQSH
estimates that 20,000 employees are potentially exposed to CS- fulltime in the
United States.
III.  PHARMACOKINETICS
     A.  Absorption:   Absorption differs with species and route of administra-
     4
tion.
     B.  Distribution:  Large concentrations of both free and bound CS2 are
found in brain (guinea pig) and peripheral nerves (rats) of exposed animals.
The ratio of bound to free CS2 in brain is 3:1.   Blood and fatty tissues
                                                          4
contain mainly bound CS« while liver contains mainly free.
     C.  Metabolism:   It is 90% metabolized by the P-450 system to inorganic
sulfate.   A portion of the S released by CS2 is thought to react with SH
groups of. cysteine residues in the microsomal protein to form hydro-sulfide.
                                                            M. Greenberg
                                                           . ECAO/RTP NC

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     0.   Excretion:  Small amounts are excreted (0.5%) as thiourea, 5-mercapto-



thioazolidone, and inorganic constituents in urine.   Some portion (8-10%)  is



also excreted unchanged in the breath.  Inhalation studies have shown that  18%



of the.CS2 inhaled is exhaled unchanged.  Of the remaining inhaled dose, 70%



is excreted as free or bound CS- and urinary sulfates and 30% is stored in  the



body and slowly excreted as CS- and its metabolites.



V.  EFFECTS ON MAMMALS

                                             4
     A.   Carcinoqenicity:  No available data.


                                          4
     B.   Mutagenicity:  No available data.


                                         8                                  3
     C.   Teratogenicity:  Bariliah et al.  showed that inhalation of 10 mg/m



was lethal to embryos before and after implantation.  C$2 at 2.2 gm/m  for  4



hr/day was embryotoxic if given to female rats during gestation and had no

                    Q

effect on male rats.   Inhalation of lower concentrations (0.34 mg/1 for 210



days) caused disturbances of estrus.    In a dominant lethal test, inhalation


          3                                                         8
of 10 mg/m  by male rats before copulation proved lethal to.embryos.



     D.



     E.   Toxicity



         1.  Humans



          The lowest lethal concentration has been reported as 4,000 ppm in 30



minutes.    In the same study, a person subjected to a concentration of 50



mg/m  for 7 years had CNS.effects.  Moderate chronic exposure of humans at


                 3                                              12
less than 65 mg/m  for' several years has been reported by Cooper   to cause



polyneuropathy.   In a study by Baranowska et al.   humans have been shown to



absorb 8.8-37.2 mg from an aqueous solution containing 0.33-1.67 q/1.   This



was over a period of 1 hour of hand-soaking.



     The most thoroughly documented studies on health effects of CS^ exposure


                                   2g—29                 26 27
have been on cardiovascular system.       Heinberg et al.  '   reported significantly

-------
elevated rates of coronary heart disease mortality, angina, and high blood
pressure.   In a 5-year followup of these vicose rayon workers, he reported
again increased coronary heart disease mortality and higher than expected
incidences of total infarctions, nonfatal infarctions, angina.  In an 8-year
followup in 1976, Heinberg   found no excess coronary heart disease mortality
during the last 3 years of the followup.
     2.    Other species.
                                                                         14
     IP injection of 400 mg/hg was the lowest lethal dose in guinea pigs.
An IV LD50 of 694 mg/kg in mice was reported by Hylen and Chin.
     With SC injection, LD50 was 300 mg/kg in rabbits.    Toxic effects have
been observed at 1.7 mg/kg in rabbits.    Rats showed toxic SC effects at 1
      17                                                       18 19
mg/kg.    Oral doses in rats produce .Joxic effects at 1 mg/kg.  '    Vinogradov
showed that 1 ppm in drinking water was nbntoxic to rabbits; 70 ppm was fatal.
                                       21
     In a chronic study, Paterni et al.   found that 6 mg/kg/day produced
toxic effects in rabbits.   The lowest lethal chronic dose for rabbits was
                                               22
shown to be 0.1 ml 3 times a week fo,J7 months.
     Applied topically, it produced a higher incidence of anemia in female than
                                                   23
in male rats and teratogenic effects were observed.    When rats inhaled CS2
at 10 mg/m  , abnormalities of genitourinary, and skeletal systems were found.
Disturbances of ossification and blood formation and dystrophic changes in
                            rt
liver and kidney were noted.
                                     - 370-

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VI.  EXISTING GUIDELINES AND STANDARDS

            4

     The NAS  did not recommend limits for drinking water because estimates of



effects of chronic oral exposure cannot be made with any confidence.

              24                               3

     The NIOSH   recommended standard IS 3 mg/m .



     Human studies have shown that exposure effects the cardiovascular system,


                                                                         24
the nervous system, the eyes, the reproductive organs, and other systems.


                                 25                   3
     The current federal standard   is 20 ppm (62 mg/m ) with a ceiling



concentration of 30 ppm (93 mg/m ) for an 8-hour day, 5 day work week.
                                    -371-

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REFERENCES
 1.   U.S.  Environmental Protection Agency.  Identification  of organic compounds
     in effluents from industrial sources, 1975.
 2.   U.S.  International Trade Commission, Syn. Org. Chem.,  1974.
 3.   U.S.  Environmental Protection Agency.  Preliminary Assessment of suspected
     carcinogens in drinking water.  Report to Congress.  EPA 560-14-75-005 PB
     260961, 1975.
 4.   NAS.  Drinking Water and Health, 1977.
 5.   Oalve et al.  Chem. Biol. Inter. 10:347-361,  1975.
 6.   Catiguani and Neal.  BBRC 65(2):629-636, 1975.
.7.   Theisinger.  Am. Ind. Hyg. Assoc.  35(2):55-61,  1974.
 8.   Bariliah et al.  -Anat. Gistol. Embriol. 68(5):77-81, 1975.
 9.   Sal'nikova and Chirkova.  Gig. Tr. Prof. Zabol 12:34-37, 1974.
10.   Rozewiski et al.  Med. Pr. 24(2):133-139, 1973.
11.   Registry of Toxic Effects of Chemical Substances, 1975.
12.   Cooper.  Food Cosmet. Toxicol. 14:57-59, 1976.
13.   Baranowska et al.  Ann. Acad. Med. Lodz 8:169-174, 1966.  Chem.  Abs.
     70-.31443W, February 24, 1969.
14.   Davidson and Feinlab.  Am. Heart J. 83(1):100-114, 1972.
15.   Hylin and Chen.  Bull. Environ. Contam. Toxicol. 3(6):322332, 1968.
16.   Merch Index, 1968.
17.   Okamoto.  Tokyo  Jikeikai Ika Daigaku Zasshi  74:1184-1191, 1959.
18.   Freundt et al.   Int. Arch Arbeitsmed. 32:297-303, 1974.
19.   Freundt et al.   Arch. Toxicol. 32:233-240, 1974.
20.   Vinogradov.  Gig. Sanit. 31(1):13-18, 1966.
21.   Paterm et al.  Folia Med. 41:705-722, 1958.
22.   Michalova et al.  Arch. Gewerbepth Gewerbehgy 16:653-665, 1959.
                                     -372-

-------
23.   Gut. Prac. Lek. 21(10):453-458,  1969.

24.   NIOSH.   Criteria for a Recommended  Standard  CS-,  May,  1977.

25.   29 CFR 1910, 1000.

26.   Hernberg.  Br. J. Ind. Med. 27:313-325,  1970.

27.   Hernberg et al.  Work Env. Health 8:11-16, 1971.

28.   Hernberg et al.  Work Env. Health 10:93-99,  1973.

29.   Tolonen et al.  Br. J. Ind. Med. 32:1-10, 1975.

30.   Heinberg et al.  Work Env. Health 2:27-30, 1976.
                                      si
                                     -373-

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                                          No.  33
Carbon Tetrachloride (Tetrachlororaethane )


     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.
                               -375-

-------
                       SPECIAL NOTATION










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



carbon tetrachloride and has found sufficient evidence to



indicate that this compound is carcinogenic.

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                             CARBON TETRACHLORIDE
                                    Summary

     Carbon  tetrachloride  (CCl^)  is  a haloalkane  with a  wide  range of  in-
dustrial and  chemical applications.   Toxicological data  for non-human mam-
mals are  extensive and  show  that CC1. causes  liver  and kidney damage, bio-
chemical  changes  in  liver   function,  and  neurological  damage..   CCl^  has
been found to  induce  liver cancer in rats and  mice.   Mutagenic effects have
not been observed  and teratogenic effects have  not been conclusively demon-
strated.
     The data  base on  aquatic toxicity  is  limited.   LCcg (96-hour) values
for bluegill range from  27,300  to 125,000 pg/1  in static tests.  For Oaphnia
magna,   the  reported  48-hour  EC5Q  is  35,200  jug/1.    The  96-hour  LC5Q  for
the tidewater  silverside  is  150,000 pg/1.   An  embryo-larval  test  with  the
fathead minnow showed no adverse effect from carbon tetrachloride concentra-
tions up to  3,400  jug/1.   No plant  effect data are  available.   The bluegill
bioconcentrated carbon tetrachloride  to a factor of  30 times within 21 days
exposure.  The biological half-life in the bluegill was less than 1 day.
                                    -•2,77-

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                             CARBON TETRACHLORIDE
I.   INTRODUCTION
     Carbon tetrachloride  (CCl^) is  a haloalkane  with  a wide  range  of in-
dustrial and chemical  applications.   Approximately 932.7 million  pounds are
produced at 11  plant  sites in the U.S.  (U.S.  EPA,  1977b;  Johns, 1976).  The
bulk of  CC1.  is  used  in the  manufacture  of fluorocarboris  for  aerosol pro-
pellants.  Other  uses  include grain  fumigation,  a component  in fire extin-
guisher solutions, chemical solvent,  and a  degreaser  in the dry cleaning in-
dustry (Johns,  1976).
     Carbon tetrachloride  is  a heavy, colorless  liquid  at  room temperature.
Its physical/chemical properties  include:   molecular  weight, 153.32; melting
point,   -22.99°C;   solubility   in water,  800,000  jug/1  at  .25°C;  and  vapor
pressure,  55.65 mm  Hg  at  10°C.  CCl^  is  relatively non-polar  and  misci^
ble with alcohol, acetone and most organic solvents.
     Carbon tetrachloride  may be quite stable  under  certain environmental
conditions.  The  hydrolytic  breakdown of CC1   in water is  estimated  to re-
quire 70,000 years  for  50 percent decomposition  (Johns,  1976).   This decom-
position is accelerated  in  the presence of  metals  such as  iron (Pearson and
McConnell, 1975).  Hydrolytic  decomposition  as a  means of removal from water
is  insignificant  when  compared  with evaporation.    In  one  experiment  the
evaporative half-life  of CCl^ in water  at ambient  temperatures was  found
to be 29 minutes (Dilling,  at  al. 1975), but this is  highly dependent on ex-
perimental conditions, such as surface area to bulk  volume ratios.   For ad-
ditional information regarding Halomethanes  as a  class,  the reader is refer-
red to  the Hazard Profile on Halomethanes (U.S. EPA, 1979b).

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II.  EXPOSURE
     A.  Water
         CC1.  has been  found  in many  water  samples including  rain,  sur-
face, potable, and sea,  in  the  sub-part per billion range (McConnell,  et ai.
1975).   The National  Organics  Monitoring Survey  (NOMS)  found CC14  in  10
percent of  113 public water  systems  sampled, with mean  values ranging  from
2.4-6.4jjg/l (U.S. EPA,  1977a).
         Although CCl^ is a  chlorinated hydrocarbon,  it  is 'not produced  in
finished drinking water  as  a result of  the chlorination process (Natl.  Res.
Coun., 1977,1978).
     3.  Food
         Carbon  tetrachloride has been  detected in a variety of  foodstuffs
other  than  fish  and  shellfish in  levels ranging from 1  to  20 ;jg/kg  (McCon-
nell, et al. 1975).
         Results  of  various  studies  on CC1,  fumigant residues  in food  in-
dicate that the amount of residue is  dependent upon fumigant dosage,  storage
conditions,  length  of  aeration  and  the  extent  of  processing  (U.S.  EPA,
1979a).   Usually,  proper  storage  and  aeration  reduce  CC1.   residues  to
trace amounts.
         The U.S.  EPA (1979a) has estimated  the weighted average  bioconcen-
tration factor for.carbon tetrachloride  to be 69  for  the edible portions  of
fish and shellfish consumed  by  Americans.   This estimate is based  on measur-
ed steady-state bioconcentration studies in bluegills.
     C.  Inhalation
         The  occurrence  of  CC1.  in  the  atmosphere   is  due  largely  to  the
                                                                       »
volatile  nature   of  the  compound.   Concentrations  of  CC1,   in continental
ana  marine  air   masses  range  from  .00078 - .00091  ma/m"5.   Although  some
                                      Z'

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higher quantities  (.0091  mg/m3) have  been  measured in urban, areas,  concen-
trations  of  CC1.  are  universally widespread  with little  geographic varia-
tion (U.S. EPA, 1979a).
III. PHARMACQKINETICS
     A.  Absorption
         CC1.  is  readily  absorbed  through  the  lungs,  and  more  slowly
through the  gastrointestinal  tract (Nielsen and.Larsen,  1965).   It can also
be absorbed  through the skin.   The rate and amount of absorption are enhanc-
ed  with  the  ingestion of  fat and alcohol  (Nielson and  Larson,  1965;  Moon,
1950).  Robbins  (1929) found that  considerable  amounts  of CC14  are absorb-
ed  from the  small  intestine,  less  from the colon, .and  little  from the stom-
ach.   Absorption from  the  gastorintestinal  tract  appears  to vary by species,
i.e.,  it occurs more rapidly in rabbits than dogs.
     B.  Distribution
         The  organ distribution of  GC1.  varies  with  the route  of adminis-
tration, its concentration, and the duration of exposure  (U.S. EPA, 1979a).
         After oral administration  to  dogs,  Robbins (1929)  found the highest
concentrations of  CC1. in the  bone  marrow.  The  liver,  pancreas and spleen
had one-fifth  the  amount  found in  the bone marrow.  The highest concentra-
tions  of  CCl^ after inhalation, however,  were found in  the  brain (Von Oet-
tingen, et al.  1949,1950).  After  inhalation  of CC14  by monkeys,  the high-
est levels were detected in fat, followed by liver and  bone marrow (McColli-
ster,  et  al. 1950).   McConnell, et  al. (1975) found human tissue levels of
CCl^ to  range as  follows:  kidney,  1-3 mg/1;  liver,  1-5 mg/1  and fat,  1-13
mg/1.
         On  the  cellular  level,  McClean,   et  al.  (1965)  found CC14  in  all
cell fractions with higher concentrations in ribosomes.
                                    -3SO-

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      C.  Metabolism
         When CC1.  is  administered  to  mammals,   it  is  metabolized  to  a
 small extent, the  majority being  excreted through  the lungs.  The  metabo-
 lites include chloroform, hexachloroethane, and carbon  dioxide.   These meta-
.oolites  play an  important role  in the overall toxicity  of CCl^  (U.S.  EPA,
 1979a).   Some  of  the  CCl^  metabolic products  are  also  incorporated  into
 fatty acids  by  the  liver and into  liver microsomal  proteins  and  lipids (Gor-
 dis,  1969).
         The chemical  pathology  of  liver injury  induced  by  CCl^ is a  re-
 sult  of  the  initial homolytic cleavage of the C-C1  bond which  liberates  tri-
 chloromethyl- and chlorine-free  radicals  (Fishbein,  1976).   The next  step
 may  be one  of  two  conflicting  reactions:  direct  attack  via alkylation  on
 cellular constituents (especially  sulfhydryl groups), or peroxidative decom-
 position of  lipids of  the endoplasmic  reticulum  as a  key  link between  the
 initial  bond • cleavage  and  the   pathological  phenomena  characteristic  of
 CC14  (Butler, 1961; Tracey and  Sherlock,  1968).
      D.  Excretion
         The largest  portion  of  absorbed  CC14  is  rapidly  excreted.   Ap-
 proximately   50-79   percent  of  absorbed  radioactive  CC14   is   eliminated
 through  the  lungs,  and  the remainder is excreted in the urine  and  faces.   No
 CCl^  was detected in the  blood  or  in the expired air,  48  hours and  6 days,
 respectively,  after  CC14 inhalation  (Beamer,  et  al.  1950).   CC1,  is  ex-
 creted as 85 percent  parent compound, 10 percent carbon dioxide, and  smaller
 quantities of other products  including chloroform  (NRC,  1977).
 IV.   EFFECTS
                                                                       »
      A.  Carcinogenicity
         CC14  has  been  shown  to  be  carcinogenic  in  rats,  mice,  and ham-
 sters via subcutaneous  injection,  intubation,  and  rectal  instillation (U.S.

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EPA, 1979).  Current knowledge  lead  to  the  conclusion that carcinogenesis is
a non-threshold, non-reversible process.   However,  some  scientists  do argue
that a threshold may occur.
         Rueber  and  Glover  (1970)  administered  injections  of 1.3  ml/kg of
body  weight of  a 50  percent  solution of  CCl^ in  corn oil to  rats,  two
times per  week until death.   Carcinoma of the  liver were present  in 12/15
(80 percent) .Japanese male  rats,  4/12 (33 percent)  Wistar rats, and 8/13 (62
percent) Osborne-Mendel  rats,  whereas Black Rats or  Sprague-Oawley  rats did
not develop carcinomas.   The  incidence  of  cirrhosis of  the  liver also dif-
fered with  the  strain of the rat.  Carcinoma of  the  liver tended to develop
along  with mild  or moderate,  rather  than severe  cirrhosis of  the  liver.
When  administered  with  CC1,,   methylcholanthrene  (a potent  enzyme  inducer)
was  found  to  increase  the incidence  of  hyperplastic  hepatic  nodules  and
early carcinomas in  rats (Rueber, 1970).   Females were found to be more sus-
ceptible to the development of  hyperplastic nodules and carcinomas.
         The National  Cancer  Institute  (1976)  studied  the  carcinogenic ef-
fect  of.CCl^  in  male  and  female mice  (1,250  mg/kg or 2,500  mg/kg  of body
weight, oral gavage  5  times/week/78 weeks).  Hepatocellular  carcinomas were
found in  almost all of  the mice receiving CC1,.  Andervant  and  Dunn (1955)
transplanted 30  CC1.-induced tumors into mice.   They observed growth  in 28
of the hepatomas, through 4 to  6  transplant generations.
     8.  Mutagenicity
         Conclusive evidence  on the mutageniciity of CC14 has not  been  re-
ported.   Kraemer, et al. (1976)  found  negative  results•using  the Ames- bac-
terial reversion tests.   However,  they  explain  that  halogenated hydrocarbons
                                                                       »
are usually negative in the Ames test.
                                     -3*2-

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     C.  Teratogenicity
         Very  little data  are available  concerning the  teratogenic  effects
of  CC1,.   Schwetz,  et  al.  (1974)  found  CC14 to  be  slightly  embryotoxic,
       Jf                                       *+
and  to  a  certain degree  retarded  fetal  development,  when administered  to
rats  at 300 or  1,000 mg/1  for  7 hr/day  oh  days  6 through 15  of  gestation.
Bhattacharyya  (1965)  found  that . subcutaneous injection  occasionally  gave
rise to  changes  in  fetal liver.
     0.  Other Reproductive Effects
         Pertinent  data concerning  other  reproductive  effects  of CCl^  were
not encountered  in the  available literature.
     E.  Chronic Toxicity
         Cases of  chronic  poisoning  have  been reported  by  Butsch  (1932),
Wirtschafter  (1933), Strauss  (1954),  Von  Oettingen (1964), and  others.   The
 clinical  picture  of  chronic  CCl^  poisoning  is  much  less  characteristic
 than  that of  acute  poisoning.   Von  Oettingen (1964)  has  done an  excellent
..job  of reviewing  the  symptoms.   Patients  suffering  from this condition  may
 i -
 /
 complain  of fatigue, lassitude,  giddiness, anxiety, and  headache.   They  suf-
 ~.3r  from  paresthesias  and muscular twitchings, and show  increased  reflex  ex-
 citability.   They  may be  moderately jaundiced, have  a tendency to  hypogly-
 cemia,  and  biopsy specimens  of  the  liver  may show fatty infiltration.   Pa-
 tients  may  complain  of a lack of appetite, nausea, and occasionally  of diar-
 rhea.   In some instances,  the  blood pressure  is  lowered and  is accompanied
 by pain in  the cardiac region and mild anemia.  Other patients have  develop-
 ed  pain  in  the kidney  region,  dysuria,  and  slight nocturia,  and have  had
 urine containing small amounts  of albumin  and  a  few  red blood cells.  Burn-
                                                                       #
 ing  of the eyes and,  in a  few  instances, blurred vision  are frequent com-
 plaints of  those exposed.   If these  symptoms  are  not  pronounced,  or of long
                                     -333-

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standing, recovery  usually  takes place upon discontinuation  of the exposure
if the proper treatment is received (Von Oettingen, 1964).
         Reports  on pathological  changes  in  fatalities  from  CCl^ poison-
ings are generally  limited to  findings in the liver  and  kidneys.   The brain
and  lungs  may  be edematous.   The  intestines may  be hyperemic  and covered
with numerous petechial  hemorrhages and the spleen  may be enlarged and hy-
peremic.  Occasionally  the adrenal glands  may show  degenerative  changes of
the cortex and the heart may undergo toxic myocarditis (Von Oettingen, 1964).
     F.  Other Relevant Information
         The  toxic effects  of  CCl^  are potentiated by  both  the habitual
and occasional  ingestion of alcohol (U.S. EPA,  1979a).   Pretreatment of lab-
oratory  animals with ethanol,  methanol_,  or  isopropanol  increases the suscep-
tibility of the liver to CC14 (Wei, et al. 1971; Traiger and Plaa,  1971).   -
         Hafeman  and  Hoekstra  (1977)   reported   that   protective  effects
against  CCl.-induced  lipid  peroxidation are  exhibited  by vitamin E,  sele-
nium, and methionine.
         According  to  Davis  (1934), very obese or  undernourished  persons or
those  suffering  from  pulmonary diseases,  gastric  ulcers  or a  tendency  to
vomiting, liver or. kidney diseases, diabetes or glandular disturbances,  are
especially sensitive to the toxic effect of CCl.'CVon Oettingen, 1964).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Two  studies  have investigated  the  acute  toxicity of  carbon tetra-
chloride to bluegills (Leoomis  macrochirus) in  static tests.   The determined
LC5Q  varied  from  27,300  )jg/l  to  125,000 jjg/1  (Dawson,   st  al.  1977;  U.S.
                                                                      »
EPA,  1978).   With  Daohnia  maana,   the  reported 48-hr.  EC=0  is  35,200  jug/1
(U.S. EPA,  1978).  The  96-hr.  LCCQ for  the  tidewater silversides (Menidia
bervllina) is 150,000 ,ug/l (Oawson,  et al. 1977).

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       8.  Chronic Toxicity
           An embryo-larval  test  with the fathead minnow (Pimeohales promelas)
  showed  no  adverse  effect  from carbon  tetrachloride  concentrations  up  to
  3,400 jjg/1 (U.S. EPA, 1978).  Other chronic data are not available.
       C.  Plant Effects
           There  are  no data  in  the  available  literature  describing  the ef-
  fects of carbon tetrachloride on freshwater or saltwater plants.
       0.  Residues
           The bluegill bioconcentrated  carbon  tetrachloride to a factor of 30
  times  within  21 days.  The  biological half-life  in  these tissues  was less
  than 1 day.
  VI.  EXISTING GUIDELINES AND STANDARDS
       Neither the  human  health  nor  the aquatic criteria derived  by  U.S. EPA
  (1979a), which are summarized below, have  been reviewed;  therefore,  there is
  a possibility that these criteria will be changed.
       A.  Human
           The  American  Conference   of  Governmental   Industrial  Hygienists
'  (1971)  recommends a threshold limit  value   (TLV)  of  10 mg/m   for  CC1 ,
  with  peak  values not  to  exceed  25 mg/m   even  for  short periods  of  time.
  The Occupational  Safety  and Health  Administration adopted the American Na-
  tional Standards  Institute  (ANSI, 1967)  standard  Z37.17 -  1967 as the Feder-
  al  standard  for  CCl^  (29  CFR  1910.1000).  This  standard is 10 mg/m3 for
  an  8-hour  TWA,  with an  acceptable  ceiling of 25 mg/m   and   a maximum peak
  for 5 minutes in any  4-hour period of 200 mg/m .
           The draft ambient  water quality  criteria for carbon tetrachloride
  has been  set to  reduce  the  human  carcinogenic  risk levels  to  10" ,  10~°
  or  10"   (U.S.  EPA,   1979a).   The corresponding criteria  are   2.6 jjg/1,  0.26

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ug/1, and 0.026 jjg/1,  respectively.   Refer  to  the Halomethane Hazard Profile
for discussion of criteria derivation (U.S.  EPA, 1979b).
     3.  Aquatic
         For  carbon  tetrachloride,  the  drafted  criteria  to  protect fresh-
water aquatic  life  is 620 jjg/1  as a 24-hour  average and  the concentration
should never  exceed  1,400 ug/1  at  any  time.   To protect  saltwater aquatic
life, the drafted criterion is 2,000  ug/1 as 24-hour  average and the concen-
tration should not exceed 4,600 ug/1 at any time (U.S. EPA,  1979a).
                                    -38-6-

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                                      No.  34
              Chloral
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

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                                    CHLORAL
                                    Summary

     Chloral  (trichloroacetaldehyde)  is  used  as  an intermediate  in the manu-
 facture of DDT, methoxychlor, DDVP,  naled,  trichlorfon,  and  TCA.   Chloral is
 readily  soluble  in water, forming  chloral hydrate.  Chloral  hydrate  decom-
 poses to chloroform with  a half-life of two days.  Chloral  hydrate  has  been
 used as a therapeutic agent due to its hypnotic and sedative  properties.
     Chloral  (as  chloral hydrate) has been  identified  in chlorinated  water
 samples  at  concentrations as high  as 5.0  pg/l.   Chloral hydrate is  formed
 through the chlorination of  natural humic  substances  in the raw water.   At-
 mospheric chloral  concentrations up to  273.5  mg/m3 have been reported  from
 spraying and  pouring  of  polyurethanes in Soviet factories.  Similar data  on
 exposure levels in U.S. plants were not found in the available  literature.
     Specific information  on the pharmacokinetic  behavior,  carcinogenicity,
 mutagenicity, teratogenicity, and other  reproductive  effects of chloral was
 not  found  in the  available   literature.   However, the  pharmacokinetic be-
 havior of chloral may be similar  to  chloral hydrate where  metabolism to  tri-
chloroethanol and trichloroacetic acid and excretion via the urine (and  pos-
                                                                     *
 sibly bile)  have  been observed.   Chloral  hydrate  produced skin  tumors in A
of 20 mice  dermally exposed.   Information on the chronic or acute effects  of
chloral in  humans  was not found in  the available literature.  Chronic ef-
fects  from   respiratory  exposure  to  chloral  as  indicated  in   laboratory
 animals include reduction  of kidney  function  and serum transaminase activ-
ity, change  in  central nervous  system  function .(unspecified),  decrease  in

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antitoxic and enzyme-synthesizing  function  of the liver,  and  alteration of
morphological characteristics of peripheral blood.  Slowed growth rate, leu-
kocytosis and changes in  arterial  blood  pressure  were also observed.  Acute
oral LD5Q values in rats  ranged  from 0.05 to  1.34 g/kg.
     U.S. standards and  guidelines for chloral were not  found  in the avail-
able literature.
                                   -390-

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                                    CHLORAL

                              ENVIRONMENTAL FATE

     Chloral  (trichloroacetaldehyde)  is  freely  soluble in  water,  forming
chloral hydrate  (Windholz,  et al.  1976).   Chloral hydrate was  identified  in
drinking water from 6 of  10 cities  sampled (Keith,  1976).   The  author postu-
lated that chloral hydrate  was  formed  by  the  chlorination of  other  compounds
during the  addition  of  chlorine to the water  supplies.  Chloral  hydrate was
not identified prior to chlorination.   Chloral hydrate may  be  formed  by the
chlorination of  ethanol or  acetaldehyde and may occur as an  intermediate  in
the reaction involving the conversion of ethanol to  chloroform as  follows:
     Ethanol - Acetaldehyde - Chloral - Chloral hydrate - Chloroform
Chloral hydrate decomposes  to chloroform with  a half-life of  2  days at pH 8
and  35°C  (Luknitskii,  1975).   Rook  (1974)  demonstrated  the  formation   of
haloforms from the chlorination of  natural humic substances  in raw water.
     Chloral polymerizes under the influence of  light  and in  the  presence  of
sulfuric acid,  forming  a white  solid  trimer  called  metachloral (Windholz,
1976).  Oilling, et  al. (1976)  studied the effects  of chloral on the  decom-
position rates of  trichloroethylene,  NO,  and  N02 in  the atmosphere and ob-
served  that- chloral  increases  the  photodecomposition  rate  of  trichloro-
ethylene to  a greater extent than it  does  NO or N02.

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                                    CHLORAL
I.   INTRODUCTION
     This  profile  is based on  literature searches in Biological  Abstracts,
Chemical Abstracts, MEDLINE, and TOXLINE.
     Chloral  [CI^CCHO],   also  referred  to  as  trichloroacetaldehyde,  anhy-
drous chloral, and   trichloroethanol,  is an  oily  liquid with a pungent,  ir-
ritating odor.   The physical properties of  chloral are:  molecular  weight,
147.39;  melting  point,   -57.5°C;   boiling  point,  97.75°C  at  760  mm  Hg;
density, 1.5121  at 20/4°C  (Weast,  1976).  The compound  is  very soluble  in
water, forming chloral hydrate,  and is soluble in  alcohol and ether.
     Industrial production  of  chloral involves direct chlorination of  ethyl
alcohol  followed   by  treatment  with  concentrated  sulfuric   acid   (Stanford
Research Institute,  1976).  Production may also occur by  direct chlorination
of either  acetaldehyde or paraldehyde in the presence of  antimony  chloride.
Prior to 1972,  essentially  all chloral produced was used  in the manufacture
of DOT.  Production of chloral was  greatest  in 1963 at 79.8 million  pounds,
decreasing to 62.4  million  pounds  in 1969.   Production data after  1969 were
not reported.  Consumption  of  chloral for DDT  manufacture was estimated  at
25 million pounds  in  1975,  with  an  additional 500,000 pounds used  in  the
                                                                     •»
manufacture of' other .pesticides, including methoxychlor,  DDVP,  naled, tri-
chlorfon,  and TCA  (trichloroacetic  acid).  Mel'nikov, et al. (1975)  identi-
fied chloral as  an impurity in  chlorofos.
     Chloral is  also used  In  the  production'of  chloral  hydrate,  a thera-
peutic agent  with  hypnotic' and  sedative effects  used  prior to  the  intro-
                                                f
duction of barbituates.  Production of U.S.P. (pharmaceutical)  grade chloral
hydrate was  estimated  to  be  300,000 pounds per  year  in  1575   (Stanford
Research Institute, 1976).
                                      X

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 II.  EXPOSURE
     Scitsov,  et  al.  (1970)  noted that  chloral is evolved  in  spraying  and
 pouring  of polyurethane.   The  authors  reported  chloral concentrations  as
 high  as 273.5  mg/rrr  in  Soviet  factories.   Similar  information on  atmos-
 pheric  occupational  exposure  to chloral  in  Western countries was not  found
 in the  available literature.
     Chloral  exposure  from water  occurs  as  chloral hydrate.   Keith  (1976)
 reported chloral  hydrate  concentrations ranging  from  0.01 ;ug/l to  5.0 ^ig/1
 in chlorinated  drinking water  supplies  of six  of ten U.S.  cities  studied.
 The  mean concentration of  chloral hydrate  in  drinking  water  for  the  six
 cities was 1.92 jug/1.
     Chloral hydrate has been used as a hypnotic, and  sedative  agent.  Alco-
                                                  • .\
hoi synergistically  increases  the  depressant  effect of the compound, creat-
 ing  a  potent  depressant commonly  referred to as "Mickey Finn"  or "knockout
drops".  Addiction to  chloral hydrate through intentional abuse of  the com-
pound has been reported (Goodman and Gillian,  1970).
 III.  PHARMACOKINETICS
     A.   Absorption                             ,• •) '
          Specific information on  the absorption of chloral was  not  found  in
                                                                     *
the  available  literature.   Goodman and Gilman  (1970)  reported   that chloral
hydrate readily penetrates  diffusion barriers  in the body.
     8.   Distribution
          Specific information  on  the distribution of chloral was not found
in the  available  literature.    Goodman  and Gilman  (1970),  reporting on the
distribution of chloral hydrate from  oral  adminis.tration, noted  its  presence
in cerebrospinal fluid, milk,  amniotic  fluid,  and fetal blood.   The auth'ors

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noted that  other  investigators were unable to detect significant  amounts of
chloral  hydrate  in the  blood after oral  administration  (owing probably  to
its rapid reduction).
     C.   Metabolism
          Information on  the metabolic reaction of  chloral is obtained  in-
directly through  a metabolic  study  of trichloroethylene (Henschler,  1977).
The  author  reported  that  trichloroethylene oxidizes  to  a  chlorinated epoxide
which undergoes molecular rearrangement to chloral,  which is  further metabo-
lized  to either  trichloroethanol  or  trichloroacetic  acid.   The 'rearrange-
ment, detected by  in vivo studies, is hypothesized  to  occur  by a  catalytic
action of the trivalent iron of P-450.
          Goodman and Oilman  (1970) noted that chloral hydrate  is reduced to
trich loroethanol in the liver  and  other tissues, including whole blood, with
the  reaction  catalyzed  by   alcohol  dehydrogenase.    Additional trichloro-
ethanol  is  converted to  trichloroacetic  acid.   Chloral hydrate may be  di-
rectly oxidized'to trichloroacetic  acid in  the  liver  and kidney.
     D.   Excretion
          Both chloral  and  chloral hydrate  are  metabolized  to trichloro-
ethanol  or  trichloroacetic   acid   (Goodman   and  Gilman,   1970;  Henschler,
                                                                     %
1977).    Trichloroethanol  is  then  conjugated  and excreted in  the urine as  a
glucuronide (urochloralic acid) or  is  converted to trichloroacetic   acid  and
slowly excreted in the  urine.   The glucuronide  may  also be concentrated  and
excreted in the bile.  The fraction of the total dose excreted  as trichloro-
ethanol, glucuronide, and trichloroacetic acid is quite variable, indicating
other possible routes of elimination.

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 IV.  EFFECTS
     A.   Carcinogenicity
          Specific  information  on the  carcinogenicity of  chloral was  not
 found  in the  available  literature.   However,  Keith  (1976)  reported  skin
 tumors  in  4 of 20 mice  dermally exposed to chloral hydrate (4  to  5 percent
 solution in  acetone).   Further interpretation of the results  and  discussion
 of the study methodology were not given.
     3.   Mutagenicity, Teratogenicity, and Other Reproductive  Effects
          Specific information  on the mutagenicity,•teratogenicity,  and  re-
 productive effects of chloral was not found in the available literature.
     C.   Chronic Effects
          Rats  receiving  0.1 mg/kg chloral exhibited  a reduction  of  kidney
 function  and  serum   transaminase  after  seven  months'  exposure   (Kryatov,
 1970).  No-physiological  effects were observed in rats receiving 0.01 mg/kg
 chloral for periods of seven months.  The route of exposure was not  reported.
          Chronic respiratory exposure of rats and rabbits to  chloral  at  0.1
 mg/1  (100  mg/m^)  produced changes in central nervous  system  function,   de-
 creased antitoxic and enzyme synthesizing function of the  liver, and altered
 morphological characteristics of  peripheral blood  (Pavlova,  1975).   Boitsov,
 et al.  (1970)  reported  slowed  growth  rate,  leukocytosis,  decreased  albumin-
 globulin ratio,  and  changes  in  arterial blood  pressure and central nervous
 system responses  (unspecified)  following prolonged  respiratory  exposure of
mice to chloral at 60 mg/m-'.
          Goodman and Oilman (1970)  reported gastritis, skin eruptions,   and
parenchymatous  renal injury  in  patients suffering from chronic  chloral   hy-
drate  intoxication.   Habitual  use of  chloral  hydrate may  result  in  the
                                    -39.5-

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development of tolerance, physical dependence,  and  addiction.   Death  may  oc-
cur  either  as a  result of  an  overdose or  a failure of  the  detoxification
mechanism due to hepatic damage.
     F.   Acute Toxicity
          According  to  Hann  and  Jensen (1974),  the human  acute oral LDgn
of chloral is between 50 and 500 mg/kg.
          Kryatov  (1970)  reported  the  following  LD5Q values  for chloral:
mice, 0.850 g/kg; rats,  0.725 g/kg; and guinea pigs, 0.940 g/kg.   The routes
of exposure  were  not stated.   Verschueren  (1977)  reported an oral LD50  for
rats of 0.05 to 0.4  g/kg,  while Pavlov (1975) reported  an  acute oral LD5Q
of 0.94 and  1.34' g/kg for mice and rats,  respectively.   Pavlov  (1975) also
reported  inhalation  LC5Q.  values  of  25.5  g/m3  and  44.5  g/m3  for mice
and  rats,  respectively.   Boitsov,  et  al.  (1970)  reported an  LD5Q Of 0.710
g/kg in mice.  The route of exposure was not stated.  Hawley (1971) reported
that chloral  is  a highly toxic, strong  irritant  and noted ingestion or  in-
halation may be fatal.  Information on acute toxic effects from occupational
exposure to chloral was  not  found in the  available  literature.
     G.   Other Relevant Information
          Verschueren (1977)  reported  an  odor  threshold concentration  of
chloral in water  of 0.047 ppm.  The  author  also  reported an  inhibition of
cell multiplication in Pseudomonas' sp. at a chloral hydrate concentration of
1.6 mg/1.
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          Verschueren (1977)  reported  inhibition' of cell multiplication  in
Microcystis  sp.- at  78 mg/1  chloral hydrate.   Hann  and  Jensen  (1974)   rartked
the 96-hour  Tl_m aquatic  toxicity of chloral in the range from 1 to  10 ppm.

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     8.   Chronic Toxicity
          Information  on the  chronic  aquatic  toxicity  of  chloral was  not
found in the available  literature.
     C.   Plant Effects
          Shimizu,  et  al.  (1974)  reported  chloral inhibited the  growth  of
rice  stems  by  63.4 percent  relative to  controls, but  slightly  stimulated
root growth.  The concentration of chloral in water culture was not reported.
     0.   Residue
          Keith  (1976)   identified  chloral  hydrate In chlorinated  drinking
water in six of ten cities  sampled.   The sample locations and concentrations
of  chloral  hydrate identified were:  Philadelphia,  PA,  5.0 jug/1;  Seattle,
WA, 3.5/jg/1; Cincinnati, OH,  2.0 ug/1;  Terrebonne  Parish, LA,  1.0 jug/1;  New
York City, NY,  0.02 jug/1; Grand Forks, NO, 0.01 jug/1.
     E.   Other Relevant Information
          Hann and  Jensen  (1974)  ranked  the  aesthetic effect of chloral  on
water as very  low  (zero),  noting that  the chemical neither  pollutes waters
nor causes aesthetic problems.
VI.  EXISTING GUIDELINES AND STANDARDS
     Eoitsov, et  al.  (1970) reported  a maximum recommended  chloral concen-
tration  in  workroom  air of 0.22  mg/1  (220  mg/nv5)  (USSR).   Kryatov (1970)
reported a maximum  recommended permissible concentration  in  bodies of water
as 0.2 mg/1  (USSR).  Verschueren (1977)  reported a  maximum allowable chloral
concentration of  0.2  mg/1  in  Class I  waters  used  for  drinking,  but  the
nation applying this standard was  not identified.

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                                  References


Boitsov,  A.N.,  et al.    1970.   lexicological evaluation  of chloral  in  the
process  of  its  liberation  during   spraying  and  pourina  of  polyurethane
foams.  Gig. Tr. Prof. Zabol.  14: 26.  (Chemical Abstracts" CA 73:96934P).

Dilling,  W.L.,  et al.   1976.  Organic photochemistry-simulated  atmopsheric
photodecomposition rates  of methylene chloride,   1,1,1-trichloroethane,  tri-
chloroethylene,  tetrachloroethylene,   and other  compounds.   Environ.  Sci.
Techno 1.  10: 351.

Goodman, L.S.  and  A.  Gilman.  1970.   The Pharmacological Basis of  Therapeu-
tics.  The MacMillan Co.,  New York.   p. 123.

Hann, R.W.  and P.A. Jensen.   1974.  Water Quality Characteristics of Hazard-
ous Materials. Texas A and M Univ.,  College  Station, TX.

Haw ley,  G.G.   1971.   Condensed Chemical Oistionary, 8th  ed.  Von  Nostrand
Reinhold Co., New York.  p.  195.

Henschler, D.   1977.  Metabolism  and  mutagenicity of  halogenated olefins -  a
comparison of structure and  activity.   Environ. Health Perspec.   21:  61.

Keith,  L.H.  (ed.)   1976.   Identification and Analysis of Organic Pollutants
in Water.  Ann Arbor Science Publishers,  Inc.,  Ann  Arbor,  Michigan,   p.  351.

Kryatov, I.A.   1970.  Hygienic  assessment of sodium salts of p-chlorobenzene
sulfate  and chloral  as  contaminating factors  in   bodies   of  water.   Gig.
Sanit.  35:  14.  .(Chemical Abstracts  CA 73:69048).

tuknitskii, F.I.  1975.   The chemistry of chloral.   Chem. Rev.   75:  259.

Mel'nikov,  N.N.,  et  al.   1975.   Identification  of impurities  in  technical
chlorofos.  Khim. Sel'sk.  Khoz.  13:  142.   (Chemical  Abstracts CA 82:165838K).

Pavlova,  L.P.   1975.   Toxicological  characteristics of   trichloroacetal-
dehyde.   Tr. Azerb.  Nauchno-Issled.   Inst.   Gig.  Tr.  Pro.  Zabol.   J.O: 99.
(Chemical Abstracts CA 87:19499611).

Rook,  J.J.   1974.  Formation of haloforms  during  chlorination  of  natural
waters.  Water Treatment Exam.  23: 234.

Shimizu,  K., et  al.    1974.  Haloacetic acid  derivatives  for controlling
Gramineae growth.  Japan 7432,063 (Cl.A Oln)  27 Aug.  1974,  Appl. 70  77, 535,
05 Sep. 1970 (Chemical Abstracts CA 82:81709F).

Stanford Research Institute.  1976.   Chemical  Economics  Handbook.    Stanford
Research Institute, Menlo  Park,  CA.  p. 632.2030A.'

Verschueren, K.   1977.    Handbook  of  Environmental  Data  on Organic  Chem-
icals.  Von Nostrand Reinhold Co., New York.  p. 170.

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Weast,  R.C.  (ed.)   1976.   Handbook  of Chemistry  and  Physics.  CRC  Press,
Cleveland, OH.  p. C-76.

Windholz, M., et  al.   1576.   The Merck  Index.   Merck  and Co.,  Inc.,  Rahway,
N.J.  p. 1,236.

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                                      No. 35
             Chlordane


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

           APRIL 30, 1980
                -HOC-

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

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                       SPECIAL NOTATION










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



chlordane and has found sufficient evidence to indicate



that this compound is carcinogenic.
                             - s o 2 -

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                                   CHLQRDANE '
                                    Summary

     Chlordane is  an organochlorinated cyclodiene  insecticide commonly used
as  a  formulation  consisting  of  24% trans-,  19% cis-chlordane,  10% hepta-
chlor, 21.5%  chlordenes,  7% nonachlor, and  18.5% of other organochlorinated
material.  Since  heptachlor is also  an insecticide  and  is more  toxic than
chlordane, technical chlordane is generally more  toxic than pure chlordane.
     Pure chlordane, which  is a cis/trans mixture  of isomers, induces liver
cancer in mice and  is  mutagenic  in some assays. Chlordane has not been shown
to  be teratogenic.  Little information  is available  on  chronic  mammalian
toxicity.  Repeated  doses of chlordane produced  alterations  in brain poten-
tials  and changes   in  some  blood  parameters.  Chlordane  is   a  convulsant.
Chlordane and its toxic metabolite oxychlordane accumulate in adipose tissue.
     Ten  species  of freshwater  fish have  reported 96-hr LC^g  values rang-
ing from  8 to 1160  jjg/1.   Freshwater invertebrates  appear  to  be  more resis-
tant  to  chlordane,  with  observed  96-hr' LC_n  values ranging  from  4  to  40
pg/1.  Five  species of saltwater  fish  have LC^ values of 5.5  to  160 ug/1,
and  marine  invertebrate  LC5Q  values  range  between  0.4  and  480  pg/1.
Chronic  studies  involving  the  bluegill  Daphnia  maona gave  an LCCO  of  1.6
                                          —      —-~—            ^u
ug/i.

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                                  CHLORDANE
     INTRODUCTION
     This profile  is based  on  the Ambient  Water  Quality  Criteria Document
for Chlordane (U.S. EPA,  1979).
     Chlordane is a  broad spectrum  insecticide of  the  group of organocnlori-
nated polycyclic hydrocarbons called cyclodiene  insecticides.   Chlordane has
been used  extensively over  the  past 30 years  for- termite control in homes
and gardens, and as a control for soil insects.
     Pure Chlordane  (1,2,4,5,6,7,8,8-octachloro-2,3,3a,4,7,7a-hexahydro-4,7-
methanoindene)  is  a  pale  yellow  liquid  having the  empirical  formula C,_-
Hx-Clg  and   a  molecular  weight  of  409.8.   It is  composed of a  mixture  of
stereoisomers, with  the  cis- and  trans- forms predominating,  commonly  refer-
red  to  as   alpha- and  gamma-isomers,  respectively.)   The  solubility  of pure
Chlordane in water is approximately 9 jug/1 at 25°C (U.S.  EPA,  1979).
     Technical grade Chlordane is a mixture  of chlorinated hydrocarbons with
a  typical composition  of approximately  24  percent  trans(gamma)-Chlordane,  19
percent  cis(alpha)-chlordane,  10  percent heptachlor  (another  insecticidal
ingredient),  21.5  percent  chlordene  isomers, 7  percent nonachlor,  and 18.5
percent closely  related  chlorinated hydrocarbon  compounds.   Technical  chlor-
                                                                   »
dane is  a   viscous,  amber-colored liquid  with a cedar-like odor.   It  has  a
vapor  pressure   of  1  x  10"  mm  Hg -at  25°C.    The  solubility  of ' technical
Chlordane in water is 150 to 220 pg/1 at 22°C (U.S. EPA,  1979).
     Production  of  Chlordane was  10,000  metric  tons  in  1974 (41  FR  7559;
February 19,  1976).   Both  uses  and production  volume have  declined exten-
sively since  the issuance  of a  registration .suspension notice by  the U.S.
EPA  (40  FR34456; December  24,  1975) for  all food, crop,  home,  and garden

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uses of chlordane.  However, use  of chlordane for termite control and limit-
ed usage  (through 1980) as  an  agricultural  insecticide  are  still permitted
(43 FR 12372; March, 1978).
     Chlordane persists  for  prolonged periods in  the  environment (U.S.  EPA,
1979).  Photo-cis-chlordane  can be produced  in  water and on  plant surfaces
by the  action of  sunlight  (Benson,  et  al.  1971)  and has been  found  to be
twice as  toxic  as chlordane to fish  and  mammals (Ivie,  et al.  1972;  Podow-
ski,   et  al.  1979).   Photo-cis-chlordane  (5  ng/1)  is accumulated  more  (ca.
20%)  by  goldfish (Carassius auratus)  than  chlordane  (5  ng/1)  itself (Ducat
and Khan, 1979).
     Air  transport  of chlordane  has  been hypothesized to account  for  resi-
dues in  Sweden  (Jansson,  et al.  1979).   Residues in  agricultural  soils may
be as high as 195 ng/g-dry weight of soil (Requejo, et al. 1979).
II   EXPOSURE
     A.  Water
         Chlordane has been  detected  in finished waters  at a maximum concen-
tration of  8 jjg/1 (Schafer,  et al.  1969) and in rainwater  (Sevenue, et al.
1972;  U.S.   EPA,  1976).   There have  been  reports  of  individual  household
wells becoming contaminated  after a house is  treated with chlordane for ter-
                                                                   •»
mite control (U.S.  EPA, 1979). A recent  contamination  of a  municipal  water
system has been  discussed  by Harrington,  et  al.  (1978).   Chlordane  has  also
been detected in rainwater (U.S. EPA, 1976).
     B.  Food
         Chlordane has  been  found  infrequently  in  food  supplies  since  1965,
when the  FDA began  systematic monitoring for  chlordane  (Nisbet,  1976).   The
only quantifiable  sample  collected was 0.059 mg chlordane/kg measured!  in a
sample of grain  in 1972  (Manske  and Johnson, 1975).   In the most  recently

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published  results  (for  1975),   chlordane  was  not  detected   (Johnson  and
Manske,  1977).   Fish are thought  to  represent the most  significant dietary
exposure.  The  average  daily uptake -from  fish is  estimated at 1 jjg (Nisbet,
1976).
         The  U.S.  EPA  (1979)  has estimated the weighted  average bioconcen-
tration  factor  for chlordane to be  5,500  for the edible portions of fish and
shellfish consumed by Americans.  This  estimate was based on measured steady-
state  bioconcentration  studies in.the  sheepshead minnow (Cyprinodon varieqa-
tus).
         Eighty-seven percent  of  200  samples  of milk  collected in Illinois
from  1971  to .1973  were positive  for  chlordane.   The  average, concentration
was  50  ug/1  (Moore, 1975  as. reviewed by Nat.  Acad.  Sci.,  1977).   Cyclo-
dienes,  such  as chlordane,  apparently are ingested  with forage  and tend to
concentrate  in lipids.   Oxychlordane,  a  metabolite of  chlordane and hepta-
chlor,  was  found in 46 percent  of 57 human  milk samples  collected during
1973-74  in  Arkansas  and Mississippi.   The  mean  value  was 5 jug/1,  and the
maximum  was 20  ug/1  (Strassman and. Kutz, 1977).
     C.  Inhalation
         In  a  survey of the extent of  atmospheric contamination  by pesti-
cides,  air.was sampled  .at  nine  localities representative  of  both'urban and
agricultural  areas.   Chlordane was. not detected in any  samples (Stanley, et
al.  1971).   In  a  larger survey,  2,479  samples were collected  at 45 sites in
16 states.   Chlordane was'detected in only  two samples,  with concentrations
of  84  and  204 ng/m   (Nisbet,  1976).   The vapor  concentrations  to  which
spray  operators are exposed have not been estimated.

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     0.   Dermal Effects                    ' •


         Chlordane can be absorbed  through, the skin to produce toxic effects


(Gosselin, et al.. 1976).  Spray  operators, Chlordane formulators and farmers


may  be  exposed.  Chlordane has  been known  to persist  for as  long  as  two


years on  the hands  (Kazen,  et al.  1974).  Dermal  LD5Q values  in rats  range


from 530 to 700 mg/kg (U.S. EPA,  1979).


III. PHARMACOKINETICS


     A.  Absorption


         Gastrointestinal absorption  of Chlordane'- in rats ranged from 6 per-


cent with  a  single  dose to  10-15 percent with  smaller daily doses (Barnett


and Dorough, 1974).


     8.  Distribution


         In  a study  of the  distribution of  Chlordane  and its metabolites


.using  radioactive  carbon,  the  levels of  residues  in  the  tissues  were low,


except  in  the fat (Barnett  and  Dorough, 1974).  Rats  were  fed  1,  5,  and  25


mg chlordane/g in food  for  56 days.  Concentrations of Chlordane residues  in


fat, liver,  kidney,  brain,  and  muscle  were  300,  12,  10,  4,  and 2 percent,


respectively,  of the  concentration   in the  diet.   All  residues  declined


steadily  for 4  weeks,  at  which time  concentrations were  reduced  about  60


percent.  During the next four weeks,  residues declined only slightly.


     C.  Metabolism


         Mammals  metabolize  Chlordane  to  oxychlordane,  via  1,2-dichloro-"


chlordene which  is  about twenty  times  more  toxic  than  the parent, compound


and persists  in adipose tissue  (Polen,  et al.  1971;  Tashiro and Matsumura,


1978; Street and 81au, 1972).   Oxychlordane  can degrade to  form l-hydroxy-2-
                                                                       *

cyclochlordenes,  and  l-hydroxy-2-chloro-2,3-epoxy-chlordenes  (Tashiro  and


Matsumura, 1973).  In general, the  metabolism  of Chlordane takes place  via a
                                     -V07-

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series of  oxidative enzyme reactions.   None  of the  metabolic intermediates
(except  for  oxychlordane) and  end products  are more  toxic  than  chlordane
(Barnett and  Oorough,  1974;  Tashiro  and Matsumura,  1977;  Mastri,   et  al.
1969).   Trans-nonachlor,  a major  impurity  in technical  chlordene,  is  con-
verted  to  trans-chlordane  in  rats,  but this  is not  important in  humans.
This explains the fact that trans-nonachlor accumulates in  humans but not in
rats  (Tashiro  and  Matsumura,  1978).  A  very  small amount  of cis-  or trans-
chlordane can  be  converted to  heptachlor  in  rat  liver  (Tashiro and Matsu-
mura, 1977).
     0.  Excretion
         Chlordane  is  primarily excreted in  the feces of  rats, only about
six percent of the  total  intake being eliminated in  the urine.   Urinary ex-
cr '"' ;n  of chlordane  in  rabbits is greater than excretion  in the feces (Nye
   •  .'
and Dorough,  1976).
         The half-life  of chlordane  in  a young boy  was  reported  to be ap-
proximately 21 days (Curley and Garrettson, 1969),  while  for  rats  it was 23
day'VCBarnett  and  Dorough, 1974).  The  half-life  of chlordane  in  the serum
of a young girl was 88 days (Aldrich and Holmes,  1969).
IV. - 'EFFECTS
     A.  Carcinogenicity
         Hepatocellular carcinomas were,  induced in both sexes of two strains
of mice  fed pure (95%) chlordane (56.2 mg/kg) in  the diet  for 80 weeks  (Na-
tional Cancer Institute,  1977;  Epstein,  1976).  In contrast to findings with
mice, a  significantly  increased  incidence of hepatocellular  carcinomas  did
not  appear  in  rats administered chlordane.   Dosages were  near  the  maximum
permissible (National Cancer Institute,  1977).

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     8.  Mutagenicity
         Purs or  technical  chlordane  induced  unscheduled  ONA  synthesis  in
the SV-40 transformed  human fibroblast cell line  VA-4.  Metabolic activation
eliminated this effect  (Ahmed,  et  al.  1977).  .Chlordane did not induce muta-
tions in the dominant lethal assay in mice (Arnold, et al. 1977).
         While neither  pure cis-chlordane nor  pure trans-chlordane was muta-
genic in  the Ames Salmonella microsome assay,  technical grade chlordane was
mutagenic.   Microsomal  activation did  not  enhance  the mutagenic  activity
(Simmon, et al. 1977).
     C.  Teratogenicity
         Chlordane was  found not to be teratogenic  in rats when fed at con-
centrations of 150 to 300 mg/kg during gestation (Ingle, 1952).
     D.  Other Reproductive Effects
         Pertinent data could not be located in the available  literature.
     E.  Chronic Toxicity
         There appears  to  be  little  information  on  chronic  mammalian toxi-
city.  Daily injections of  0.15 to 25  mg  chlordane/kg in adult rats resulted
in  dose-dependent  alterations  of brain potentials  (Hyde and  Falkenberg,
1976).  As changes were directly related  to length of  exposure,  it  was con-
                                                                   »
eluded  that  chlordane  may  be a cumulative  neurotoxin.  Length  of  exposure
was  not  specified.   Repeated  doses of chlordane  given to  gerbils  produced
changes in serum  proteins,  blood glucose, and  alkaline  and acid phosphatase
activities (Karel and Saxena,  1976).  Again,  duration of  treatment  was not
specified.
     F.  Other Relevant Information
         Carbon tetrachloride  produced more extensive  hepatocellular necro-
sis  in chlordane-pretreated  rats   than  in  rats   which  were  not  pretreated
(Stenger,  et al.  1975).   Rats suffered greater cirrhosis when chlordane (50

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jjg/kg/day) exposure  for  ten weeks followed prior  exposures  of ten weeks  for
carbon  tetrachloride  above (110 mg/1)  or with chlordane  (Mahon  and Oloffs,
1979).   Quail treated  with  chlordane  followed  by  endrin  had considerably
more  chlordane  residues  in their brains  than did quail  treated  with chlor-
dane  alone (Ludke,  1976).   Quail pretreated with 10 rug/kg chlordane exhibit-
ed decreased  susceptibility to  parathion  (Ludke,  1977).   Chlordane is a con-
vulsant  and   emetic.   It  induces  twitching,  seizures  and electroencephalo-
graphic  dysrhythmia  in humans.   Acute symptoms  can be alleviated with pheno-
barbital.   Acute oral LD5Q values  for the rat  range from  100 to 112 mg/kg
(U.S. EPA, 1979).  The no  observable  effect level was found to be 2.5 mg/kg/
day over 15 days  (Natl.  Acad. Sci., 1977).
          Chlordane  inhibits  growth  of  human viridans  streptococci  of   the
buccal  cavity.   Complete  inhibition  of growth occurred  at  3 ppm, and about
20 percent inhibition was  seen  at 1 ppm (Goes, et  al. 1978).
V.    AQUATIC  TOXICITY
      A.   Acute Toxicity
          Ten  species  of  freshwater  fish  have  reported 96-hr  LC-n values
ranging  from 8  to  1160 jjg/1  resulting  from technical  and  pure chlordane
exposure with a geometric  mean of 16 jjg/1.  Rainbow trout,  Salmo gairdneri
                                                                   •>
(Mehrle,  et   al.  1974)  was the  most  sensitive  species   tested,  the channel
catfish  (Ictalurus punctatus)  the least  sensitive.   The  freshwater inverte-
brates  were   more  sensitive to  chlordane,  with  a reported  LC5Q  value rang-
ing  from 4.0 for freshwater  shrimp Palaemonetes  kadiakensis  (Sanders, 1972)
to  40 /jg/1  (Gammarus  fasciatus), with  a geometric  mean of 0.36.pg/l.    In
goldfish (Carassius  auratus), only 0.13 percent of  cis-chlordane  is metabo-
lized  in 24  hours.   Only  0.61 percent  is converted  after  25  days.   Some
metabolites  were chlordene chlorohydrin  and  monohydroxy  derivatives  (Feroz
and Khan, 1979).
                                       /
                                     - w/o-

-------
         The LC50's  for four  species of saltwater  fish,  sheepshead minnows
(Cvprinodon verieqatus),  striped bass  (Morone saxatilis),  pinfish (Lagodon
rhomboides), and white  mullet  (Mugil cursma),  ranged  from 5.5 to 24.5 pg/1.
The  three-spine  stickleback  (Gasterosteus  aculsatus)   yielded   96-hr  LC^Q
values which  ranged  from 90-160  pg/1 (Katz,  1961).   Invertebrate LC.-n val-
ues ranged  from  0.4  for the pink shrimp,  Penaeus duorarum  (Parrish,  et al.
1976) to  480  pg/1.  The geometric  mean of  the adjusted  LC,-n values for in-
vertebrates was O.lSjug/1 (U.S. EPA,  1979).
     Q.  Chronic Toxicity
         In a  life cycle bioassay involving freshwater organisms, the chron-
ic values  for. the  bluegill Lepomis  macrochirus (Cardwell,  et  al.  1977) was
1.6 jug/1.   In  two  tests involving the sheepshead minnow,  Cycrinodon variega-
tus, the chronic values were 0.63 ug/1 for  the life  cycle test (Parrish,  et
al. 1978) and 5.49 ug/1 for an embryo-level  test (Parrish, et al. 1976).
         Many  blood  parameters (clotting  time, mean  corpuscular hemoglobin
and cholesterol  level)  are  lowered  after the teleost, Sacco-branchus fossil-
us, is  exposed to 120  pg/1 of chlordane  for 15 to  60  days  (Verna,  et al.
1979).   Similar  results were  obtained  in  Labeo  rohita  at  doses  — 23 jag/1
after 30 to 60 day exposures (Bansal, et al. 1979).
     C.  Plant Effects •         .                                  *
         A  natural saltwater phytoplankton  community suffered a 94 percent
decrease  in productivity during  a  4-hour  exposure  at  1,000  ug/1 (Butler,
1963).
     0.  Residues
         In Oaphnia  maana,  chlordane  was   bioconcentrated  6,000-fold  after
seven days' exposure and 7,400-fold  by  scuds (Hyallela azteca) after 55 days
of exposure  (Cardwell,  et  al.  1977).   After  33 days' exposure,  the fresh-
                                     - HI / -

-------
water  alga  (Oedeqonium  sp.)  bioconcentrated chlordane  98,000-fold;  Physa

sp., a snail,  concentrated  it 133,000-fold (Sanborn,_et  al.  1976).   Equili-

brium bioconcentration  factors for  the  sheepshead minnow ranged  from 6,580

to 16,035 (Goodman, et al. 1978; Parrish, et al.  1976).

VI.  EXISTING GUIDELINES AND STANDARDS

     A.  Human

         The  issue of the  carcinogenicity of chlordane  in  humans  is being

reconsidered;  thus,  there  is  a  possibility  that the  criterion for human

health will  be changed.   Based on the data  for  qarcinogenicity in mice (Ep-

stein, 1976),  and  using  the "one-hit" model,  the  U.S. EPA (1979)  has esti-

mated  levels  of chlordane 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       0.012 ng/1     0.12 ng/1      1.2 ng/1
and consumption of 18.7
grams fish and shellfish.

Consumption of fish and       0       0.013 ng/1     0.13 ng/1      1.3 ng/1
shellfish only.


         The  ACGIH  (1977)   adopted  a  time-weighted  average   value  of  0.5

mg/m   for chlordane,  with  a  short-term  exposure limit  (15  minutes)  of 2

mg/m .

         A  limit  of  3 ;jg/l for  chlordane  in  drinking  water  is  suggested

under  the  .proposed Interim  Primary  Drinking  Water  Standards   (40 FR 11990,

March 14, 1975).
                                              s
         Canadian  Drinking  Water  Standards   --(Dept.   Natl.  Health  Welfare,
                                                                       »
1968) limit chlordane to 3 jug/1 in raw water supplies.

-------
     8.   Aquatic
         For chlordane, the  proposed criterion to protect freshwater aquatic
life is  0.024  ;jg/l for a  24-hour average,  not to  exceed 0.36 jug/I  at any
time (U.S.  EPA,  1979).  For  saltwater aquatic species,  the  draft criterion
is 0.0091 jug/1  for a  24-hour  average, not  to  exceed 0.18 ;jg/l  at  any time
(U.S. EPA, 1979).
                                    -HJ3-

-------
                          CHLORDANE
                          REFERENCES

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and  its  repair  in  cultured  human  cells.   Mutat.  Res.  42:
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Aldrich,   F.D.,   and  J.H.  Holmes.    1969.   Acute  chlordane
intoxication in a child.  Arch. Environ. Health 19: 129.

ACGIH.   1977.    TLVs  thresholds limit values  for  chemical
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Arnold,  D.W. ,  et al.   1977.    Dominant  lethal  studies with
technical  chlordane,  HCS-3260,  and  heptachlor :   heptachlor
epoxide.   Jour. Toxicol. Environ. Health 2: 547.

Bansal,  S.K.,  et al.   1979.    Physiological  dysfunction  of
the  haemopoletic system  in a freshwater  teleost,  Rabeo ro-
hita, following chronic chlordane exposure.  Part 1.  Altera-
tions in certain haemotological parameters.   Bull.  Environ.
Contam. Toxicol.  22: 666.

Barnett,  J.R., and H.W. Dorough.  1974.  Metabolism of chlor-
dane in rats.  Jour. Agric. Food Chem. 22: 612.
Benson, W.R.,
ducts:  Their
Food Chem. 19:
               et  al.   1971.   Chlordane photoalteration pro
               preparation and  identification.   Jour. Agric
                857.
Bevenue,  A.,  et  al.    1972.   Organochlor ine  pesticides in-
rainwater  Oahu,  Hawaii,  1971-72.    Bull.  Environ.  Contam.
Toxicol. 8: 238.                                         t

Butler,  P. A.,  et al.   1963.   Effects  of pesticides  on oy-
sters.  Proc. Shell Fish. Assoc. 51: 23.

Cardwell,  R.D.,  et al.   1977.   Acute and  chronic toxicity
of  chlordane to  fish  and   invertebrates.    EPA  Ecol.   Res.
Ser., U.S. Environ. Prot. Agency, Duluth,  Minn.
Curley,  A.,  and  L.K.  Garrettson.   1969.
poisoning.  Arch. Environ. Health 18: 211.
                                             Acute  chlordane
Department of  National  Health  and Welfare.   1963.   Canadian
drinking water standards and objectives.  Ottawa, Canada.

Ducat, D.A-.and M.A.Q.  Khan.   'L9Ti.   Absorption and elimina-
tion  of    C-cis-chlordane  and    C-photo-cis-chlordane  by
goldfish, Carassius auratus.  Arch. Enviorn. Contam. 8: 409.
                             -HIM-

-------
Epstein,  S.S.    1976.    Carcinogenicity  of  heptachlor  and
chlordane.  Sci. Total Environ. 6: 103.

Feroz, M. ,  and M.A.Q. Khan.   1979.   Fate of 14C-cis-chlor-
dane in goldfish, Carassius auratus.  Bull. Enviorn.  Contain.
Toxicol. 23: 64.

Goes, T.R., et  al.   1978.   In vitro inhibition of oral Viri-
dous  streptococei  by  chlordane.    Arch.  Environ.    Contam.
Toxicol. 7: 449.

Goodman, L. ,  et al.   1978.   Effects  of heptachlor  and toxa-
phene on laboratory-reared  embryos  and  fry of the sheepshead
minnow.  Proc.  30th Annu. Conf. S.E. Assoc. Game Fish Comm.

Gosselin, R.E., et al.  1976.  Clinical toxicology of commer-
cial products.   4th  ed.  Williams  and Wilkdns Co., Baltimore,
Md.

Harrington,  J.M.,  et  al.    1978.    Chlordane contamination
of a municipal  water system.  Environ. Res. 15: 155.

Hyde,  K.M., . and  R.L.  Falkenberg.    1976.   Neuroelectrical
disturbance  as  indicator  of  chronic  chlordane  toxicity.
Toxicol. Appl.  Pharmacol. 37: 499.

Ingle,  L.    1952.    Chronic -oral toxicity  of  chlordane  to
rats.  Arch. Ind. Hyg. Occup. Med. 6: 357.

Ivie, G.W., et al.  1972.   Novel  photoproducts of heptachlor
epoxide, trans-chlordane and  trans-nonachlor.  Bull. Environ.
Contam. Toxicol. 7: 376.

Jansson, B.,  et al.   1979.   Chlorinated  terpenes and chlor-
dane  components  found   in  fish,   guilleiuot  and   seal  from
Swedish waters.  Chemosphere  8: 181.

Johnson, R.D.,  and D.D.  Manske.   1977.   Pesticide  and .other
chemical residues in  total diet samples (XI).   Pestic. Monitor.
Jour. 11: 116.

Karel,  A.K. ,   and  S.C..  Saxena.    1976.   Chronic  chlordane
toxicity:  effect on blood  biochemistry of Meriones hurrianae
Jerdon,  the Indian desert gerbil.  Pestic. Biochem. Physiol.
6: 111.

Katz, 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.

Kazen C.,  et  al.   1974.   Persistence  of pesticides  on  ttie
hands of some occupationally  exposed people.  Arch.   Environ.
Health 29: 315.

-------
Ludke, J.L.  1976.  Organochlorine pesticide residues associ-
ated  with  mortality:   additivity of  chlordane  and  endrin.
Bull.  Environ. Contam. Toxicol. 16:  253.

Ludke, J.L.   1977.   DDE increases the  toxicity  of parathion
to coturnix quail.  Pestic. Biochem.  Physiol. 7:  28.

Mahon, D.C. ,  and  P.C.  Oloffs.   1979.   Effects  of subchronic
low-level dietary intake of  chlordane  on rats with cirrhosis
of the liver.  Jour. Environ. Sci. Health 314: 227.

Manske,  D.D.,  and R.D.. Johnson.   1975.   Pesticide residues
in total diet samples  (VIII).  Pestic.  Monitor.  Jour. 9: 94.

Mastri, C., et al.  1969.   Unpublished data.  Iji 1970 evalua-
tion  of  some  pesticide residues in food.   Food  Agric.   Org.
United Nations/World Health Org.

Mehrle,  P.M.,  et  al.   1974.   Nutritional  effects  on chlor-
dane  toxicity  in  rainbow  trout.   Bull.  Enviorn.  Contam.
Toxicol.  2: 513

Moore,  S.,  III.  . 1975.   Proc.  27th  Illinois  Custom  Spray
Operators Training School.   Urbana.

National Academy  Science.   1977.   Drinking water and health.
Washington, D.C.

National  Cancer  Institute.    1977.    Bioassay   of  chlordane
for possible carcinogenicity.  NCI-CG-TR-8.

Nisbet,  I.C.T.   1976.  Human  exposure  to  chlordane,  hepta-
chlor,  and  their  metabolites.    Contract WA-7-1319-A.   U.S.
Environ.  Prot. Agency.

Nye,  D.E.,  and H.W.  Dorough.    1976.    Fate  of  insecticides
administered endotracheally,to  rats.   Bull. Environ.  Contam.
Toxicol. 15: 291.                                        *

Parrish, P.R.,  et al.   1976.   Chlordane:  effects on several
estuarine  organisms.   Jour.   Toxicol.  Environ.  Health  1:
485.

Parrish, P.R.,  et al.   1978.   Chronic  toxicity  of chlordane,
trifluralin   and  pentachlorophenol  to  sheepshead  minnows
(Cyprinodon variegatus).  EPA 600/3-78-010: 1.  U.S. Environ.
Prot. Agency.
                                       /•
Podowski,  A.A.,  et  al.   1979.   Photolysis of  heptachlor
and  cis-chlordane  and toxicity   of  their  photoisomers  to
animals.  Arch. Environ. Contam. Toxicol. 8: 509.

Polen,  P.3.,  et  al.    1971.   Characterization  of  oxychlor-
dane, animal metabolites of chlordane.   Bull. Enviorn. Contam.
Toxicol. 5: 521.

-------
Requejo,  A.G.,   et  al.    1979.    Polychlorinated  biphenyls
and chlorinated pesticides in soils  of  the Everglades National
Park and adjacent agricultural areas.  Environ.   Sci. Technol.
13: 931.

Sanborn,.  J.R.,   et  al.   1976.   The  fate  of  chlordane and
toxaphene in a terrestrial-aquatic model ecosystem.  Environ.
Entomol. 5: 533.

Sanders, H.O.   1972.   Toxicity  of  some insecticides to four
species of malacostracan  crustaceans.   U.S.  Dept.  Interior.
Fish Wildlife Tech. p. 66, August.

Schafer, M.L.,  et  al.   1969.   Pesticides  in drinking water.
Environ. Sci. Technol. 3: 1261.

Simmon, V.F.,  et al.   1977.   Mutagenic activity of chemicals
identified  in  drinking water.   Presented at  2nd Int.  Conf.
Environ. Mutagens, Edinburgh, Scotland, July 1977.

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

Stenger, R.J., et al.   1975.   Effects  of chlordane pretreat-
ment  on the  hepatotoxicity  of  carbon tetrachloride.   Exp.
Mol.  Pathol. 23: 144.

Strassman, S.C.,  and  F.W. . Kut'z.   1977.  Insecticide residues
in human milk from Arkansas and Mississippi,  1973-74.  Pestic.
Monitor. Jour. 10: 130.

Street, J.E.,  and S.E. Blau.   1972.   Oxychlordane:   accumu-
lation  in  rat  adipose tissue  on feeding  chlordane isomers
or technical chlordane.   Jour. Agric. Food Chem.  20: 395.

Tashiro,  S. ,  and  F.  Matsumura.   1977.    Metabolic  routes
of  cis- and  trans-chlordane  in rats.    Jour.  Agric.  Food
Chem. 25: 872.                                          •»

Tashiro, S.,  and F.  Matsumura.   1978.   Metabolism of trans-
nonachlor  and  related chlordane  components  in  rat  and  man.
Arch. Enviorn. Contam. Toxicol. 7: 413.

U.S. EPA.   1976.   Consolidated heptachlor/chlordane hearing.
Fed. Register 41: 7552.

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

Verna,  S.R.,  et  al.   1979.   Pesticide induced  haemotological
alterations  in  a  freshwater  fish  Saccobranchus  fossilis.
Bull. Environ. Contam. Toxicol. 22:  467.
                                -HI7-

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                                      No.  36
        Chlorinated Benzenes
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION-AGENCY
       WASHINGTON, D.C.  2046O

           APRIL 30, 1980

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

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                     CHLORINATED BENZENES



                           Summary









     The chlorinated benzenes are a group of compounds with



a wide variety of physical and chemical characteristics



depending on the degree of chlorination.  As chlorination



increases, the persistance of the compound in the environ-



ment increases.  On chronic exposure liver and kidney changes



are noted, while the degree of toxicity increases with the



degree of chlorination.  The chlorinated benzenes have not



been shown to be teratogens or mutagens.  Only hexachloro-



benzene has been demonstrated to be carcinogenic in labora-



tory animals.



     Aquatic toxicity data indicate a trend to increasing



toxicity with increasing chlorination for all species tested.



The bluegill for example, has the following 96-hour LC5Q



values; chlorobenzene, 15,900 jag/1; 1,2,4-tr ichlorobenzene



3,360 ug; 1,2,3 ,5-tetrachlorobenzene, 6,420 micrograms/Lf



1, 2, 4 , 5-tetrachlorbenzene 1,550 jag/1 and pentachlorobenzene ,



200 pg/1.  Other freshwater and saltwater fish, invertebrates



and plants were generally less sensitive to chlorobenzenes



toxicity than the bluegill.  The sheepshead minnow yielded



a chronic value of 14.5 ^tg/1 for I, 2 , 4 , 5-tetrachlorobenzene



in an embryo-level test.  After 28 days /exposure, the biocon-



centration factor for the bluegill for pentachlorobenzene



and 1, 2 , 4 , 5-tetrachlorobenzene were 3,400 and 1,800, respec-



tively.
                             -M2.O-

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                     CHLORINATED BENZENES

I.    INTRODUCTION

     This profile is based on the Ambient Water Quality

Criteria Document for Chlorinated Benzenes  (U.S. EPA,  1979).

This document will summarize the general properties of the

chlorinated benzenes.  For further information on monochloro-

benzene, 1,2,4-trichlorobenzene, or hexachlorobenzene, refer

to the specific EPA/ECAO Hazard Profiles for  these compounds.

For detailed information on the other chlorinated benzenes

refer to the Ambient Water Quality Document  (U.S. EPA, 1979).

     The chlorinated benzenes, excluding dichlorobenzenes,

are monochlorobenzene  (CgH3Cl), 1,2,4-tr ichlorobenzene (CgH-jCl3),

1,3,5-trichlorobenzene (CgH^Cl,), 1, 2 ,3 , 4-tetrachlorobenzene

(CgH2Cl4), 1,2,3,5-tetrachlorobenzene (CgH2Cl4), 1,2,4,5-

Tetrachlorobenzene (CgH2Cl4), pentachlorobenzene (CgHClc),

and hexachlorobenzene  (CCC1,;) .  All chlorinated benzenes
                        b  o
are colorless liquids or solids with a pleasant aroma.

The most important properties imparted by chlorine .to  these

compounds are solvent power, viscosity, and moderate chemi-
                                                       •»
cal reactivity.  Viscosity and nonflammability tend to in-

crease from chlorobenzene to the more highly  chlorinated

benzenes.  Vapor pressures and water solubility decrease

progressively with the. degree of chlorination  (U.S. EPA,

1979) .

     The current production, based on annual  production
                                                           »
in the U.S., was 139,105 kkg of monochlorobenzene in 1975,
                         * t
12,849 kkg of 1,2,4-trichlorobenzene, 8,182 kkg of 1,2,4,5-
       ^ *s                                   * ^

-------
tetrachlorobenzene and 318 kkg of hexachlorobenzene  in 1973

(West and Ware, 1977; EPA, 1975a).  The remaining chlori-

nated benzenes are produced mainly as by-products from the

production processes for the above four chemicals.   Chlori-

nated benzenes have many and diverse uses in industry depend-

ing upon the individual properties of the specific compound.

Some uses are as solvents, chemical intermediates, flame

retardants, and plasticizers.

II.  EXPOSURE

     A.   Water

          Mono-, tri-, and hexachlorobenzene have been de-

tected in ambient water.  Because of its high volatility,

monochlorobenzene has a short half-life of only 5.8  hours

(Mackay and Leinonen, 1975).  However, hexachlorobenzene

has an extremely long residue time in water, appearing to

be ubiquitous in the aqueous environment.  Monochloroben-

zene has been detected in "uncontaminated" water at  levels

of 4.7 p.g/1.  Both trichlorobenzene and hexachlorobenzene

have been detected in drinking waters at concentrations
                                                        •»
of 1.0 ug/1 and 4 to 6 ng/1 respectively (U.S. EPA,  1979).

There is no information available on the concentration of

the other chlorinated benzenes in water.

     B.   Food

          There is little data on the consumption of chlorin-
                                       f
ated benzenes in food.  All the chlorinated benzenes appear

to concentrate in fat, and are capable of being absoroed

-------
by the plants from contaminated  soil.  Both  pentachloroben-

zene and hexachlorobenzene have  been detected  in meat  fat

(e.g.  Stijve, 1971; Ushio and Doguchi,  1977).  Hexachloro-

benzene, the most extensively studied compound, has  been

found in a wide variety of foods  from cereals  to milk  (includ-

ing human breast milk), eggs, and meat.  The U.S. EPA  (1979)

has estimated the weighted bioconcentration  factor of  the

following chlorinated benzenes:

                                          Weighted
          Chemical                 bioconcentration  factor

     monochlorobenzene                         13
     1,2,4-trichlorobenzene                  290
     1,2,4,5-tetrachlorobenzene            1,000
     pentachlorobenzene                    7,800  •
     hexachlorobenzene                    12,000  .. ;


     These estimates were based on the octanol/water parti-

tion coefficient of the chlorinated benzenes.

     C.   Inhalation                              .s
                                                   >,
          There is no available data on  the concentration

of chlorinated benzenes in ambient air with the e>. .l-ption

of measurements of aerial fallout of particulate bound 1,2,4-

trichlorobenzene in southern California.  Five sampling

sites showed median levels of 1,2,4-trichlorobenzene of

less than 11 ng/m2/day (U.S. EPA, 1979).  The primary  site

of inhalation exposure to chlorinated benzenes is the  work-

place in industries utilizing and/or producing these compounds.

III. PHARMACOKINETICS

     A.   Absorption

          There is little data on the absorption of orally

administered chlorinated benzenes.  It is apparent from

                              2

                            -H23-

-------
the toxicity of orally administered compounds that absorp-



tion does take place, and tetrachlorobenzene has been shown



to be absorbed relatively efficiently by rabbits (Jondorf,



et al. 1958).   Pentachlorobenzene was absorbed poorly after



subcutaneous injection (Parke and Williams, 1960).  Hexa-



chlorobenzene was absorbed poorly from an orally administered



aqueous solution (Koss and Kornasky, 1975), but with high



efficiency when administered in oil (Albro and Thomas, 1974).



The more highly chlorinated compounds in food products will



selectively partition into the lipid portion and be absorbed



far better than that in an aqueous medium (U.S. EPA, 1979).



     A.   Distribution



          The chlorinated benzenes are lipophilic, compounds



with greater lipophilic tendencies in the more highly chlor-



inated compounds.  The predominant disposition site is either



suspected to be, or shown to be, in the lipid tissues of



the body (Lee and Metcalf, 1975; U.S.  EPA,  1979).



     C.   Metabolism



          The chlorinated benzenes are metabolized -in the



liver by the NADPH-cytochrome P-448 dependent microsomal



enzyme system (Ariyoshi,  et al. 1975;  Koss, et al. 1976).



At least for monochlorobenzene, there is evidence that toxic



intermediates are formed during metabolism (Kohli, et al.



1976).  Various conjugates and phenolic derivatives are



the primary excretory end products of chlorinated benzene



metabolism.  In the more highly chlorinated compounds, such'



as hexachlorobenzene, conjugates are formed to only a limited



extent, and metabolism is relatively slow.

-------
     D.   Excretion


          The less-chlorinated benzenes are  excreted  as


polar metabolites or conjugates in the urine.  An  exception


occurs with monochlorobenzene where 27 percent of  an  admin-


istered dose appeared as unchanged compounds  in  the expired


air of a rabbit  (Williams, 1959).  The two highly  chlorinated


compounds, pentachlorobenzene and hexachlorobenzene,  are


eliminated predominately by fecal excretion  as unchanged


compounds (Koss and Koransky, 1975; Rozman,  et al. press) .


The biological half -lives of these two compounds are  extremely


long in comparison to that of the less-chlorinated compounds


(U.S. EPA, 1979) .


IV.  EFFECTS


     A.   Carcinogencity


          Mono- and tetrachlorobenzene  have  not been in-


vestigated for carcinogenic potential  (U.S. EPA, 1979).


In one study, trichlorobenzene was not shown  to produce


any significant increase in liver tumors  (Gotto, et al.


1972) .  There is one report, which was not critically evalu-
                                                        »

ated by U.S. EPA (1979), which alludes to the carcinogencity


of pentachlorobenzene in mice and the absence of this activity


in rats and dogs (Preussman, 1975) .  Life-time feeding studies


in hamsters (Cabral, et al. 1977)  and mice (Cabral, et al.


1978) have demonstrated the carcinogenic activity of  hexa-


chlorobenzene.  However, shorter term studies failed  to


demonstrate an increasd tumor incidence in strain A mice


or ICR mice (Theiss, et al. 1977;  Shirai, et al. 1978).
                            -H2S-

-------
     B.   Mutagenicity


          There are no available studies conducted to evalu-


ate the mutagenic potential of mono-, tri-, tetra-, and


pentachlorobenzene (U.S. EPA, 1979).  Hexachlorobenzene


was assayed for mutagenic activity in the dominant lethal


assay, and shown to be inactive (Khera, 1974) .


     C.   Teratogenicity


          There are no available studies conducted to evalu-


ate the teratogenic potential of mono-, tri-,  tetra-, and


pentachlorobenzene (U.S. EPA, 1979).  Khera (1974) concluded


hexachlorobenzene was not a teratogen when given to CD-I


mice at 50 mg/kg/day on gestation days from 7 to 11.


     D.   Other Reproductive Effects


          Hexachlorobenzene can pass through the placenta


and cause fetal toxicity in rats (Grant, et al. 1977).


The distribution of .hexachlorobenzene in the fetus appears


to be the same in the adult, with the highest concentration


in fatty tissue.


     E.   Chronic Toxicity


          There is no available data on the chronic effects


of pentachlorobenzene (U.S. EPA, 1979).  Mono- and trichloro-


benzene produce histological changes in the liver and kidney


(Irish, 1963; Coate, et al. 1977).   There is also some evi-


dence for liver damage occurring with prolonged exposure


of rats and dogs to tetrachlorobenzene (.Fomenko, 1965; Braun,
                                                           »

et al. 1978).  Hexachlorobenzene has caused histological


changes in the livers of rats (Koss, et al. 1978).  In humans

-------
exposed to undefined amounts of hexachlorobenzene  for an


undetermined time, porphyrinuria has been shown to occur


(Cam and Nigogosyan, 1963).


     F.   Other Relevant Information


          Chlorinated benzenes appear to increase  the activity



of microsomal NADPH-cytochrome P-450 dependent enzyme systems.


Induction of microsomal enzyme activity has been shown to


enhance the metabolism of a wide variety of drugs, pesticides


and other xenobiotics (U.S. EPA, 1979).



V.   AQUATIC TOXICITY


     A.   Acute Toxicity



          The dichlorobenzenes are covered in a separate


EPA/ECAO hazard profile and will not be covered in this


discussion on chlorobenzenes.



          All data reported for freshwater fish are from


96-hour static toxicity tests.  Pickering and Henderson


(1966) reported 96-hour LC5Q values for goldfish, guppys


and bluegills to be 51,620, 45,530, and 24,000 jjg/1, respec-


tively, for chlorobenzene.  Two 96 hour LCcQ values for ,


chlorobenzene and fathead minnows are 33,930 pg/1 in salt-


water and 29,120 pg/1 in hard water.  Reported 96-hour values


for the bluegill exposed to chlorobenzene, 1,2,4-trichloro-


benzene, 1,2,3,5-tetrachlorobenzene, 1,2,4,5-tetrachloro-



benzene and pentachlorobenzene are 15,900, 3,360, 6,420,


1,550 and 250 ug/1, respectively (U.S. EPA, 1978).  These
                                                           «

data indicate a trend to increasing toxicity with chlorina-


tion, except for 1,2,3,5-tetrachlorobenzene (U.S. EPA, 1973).
                            - 427-

-------
EC5Q (48 hour) values reported for Daphnia magna are: chloro-


benzene 86,000 pg/1, 1,2,4-trichlorobenzene 50,200 pg/1,


1,2,3,5-tetrachlorobenzene 9,710 pg/1, and pentachlorobenzene


5,280 pg/1 (U.S. EPA, 1978).-


          Toxicity tests with the sheepshead minnow, Cypri-


nodon variegatus, performed with five chlorinated benzenes


under static conditions and yielded the following 96-hour


LC5Q values:  chlorobenzene 10,500 pg/1, 1,2,4-tr ichloroben-


zene 21,400 pg/1, 1,2,3,5-tetrachlorobenzene 3,670 ,ug/l,


1,2,4,5 tetrachlorobenzene 840 pg/1, and pentrachlorobenzene


835 pg/1 (U.S. EPA, 1978).  As with sheepshead minnows,


sensitivity of the mysid shrimp, Mysidopsis bahia, to chlori-


nated benzenes generally increases with increasing chlorina-


tion.  The reported 96-hour LC5Q values are as follows:


chlorobenzene 16,400 pg/1, 1,2,4-tr ichlorobenzene 450 ug/1,


1,2,3,5-tetrachlorobenzene 340 pg/1, 1,2,4,5-tetrachloro-


benzene 1,480 pg/1, and 160 pg/1 for pentachlorobenzene


(U.S. EPA, 1979).


     B.   Chronic Toxicity
                                                        -»

          Chronic toxicity data are not available for fresh-


water fish or invertebrate species.  Only one saltwater


species, Cyprinodon yeriegatus, has .been chronically exposed


to any of the chlorinated benzenes.  In an embryo-level


test, the-limits for 1,2,4,5-tetrachlorobenzene are 92 to


180 pg/1, with a final chronic value of..64.5 pg/1 (U.S.


EPA, 1978).

-------
     C.   Plant Effects


          The green freshwater algae  Selenastrum  capricornutum


has been exposed to five chlorinated benzenes.  Based  on


cell number, the 96-hour HC-Q values are as  follows:   chloro-


benzene 220,000 p.q/1, 1, 2,4-trichlorobenzene  36,700 ^g/1,


1,2,3,5-tetrachlorobenzene 17,700 jig/1, 1, 2,4 , 5-tetrachloro-


benzene 46,800 /jg/1, and pentachlorobenzene  6,780  ;ag/l.


     D.   Residues


          No measured bioconcentration factor  (BCF) is avail-


able for chlorobenzenes.  However, the average weighted


BCF of 13 was calculated from octanol-water partition  coeffi-


cient and other factors.  (U.S. EPA, 1979).


VI.  EXISTING GUIDLINES 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


          Monochlorobenzene:  The American Conference  of

                                                        i
Governmental Industrial Hygienists (ACGIH, 1971) threshold


limit value for monochlorobenzene is 350 mg/m .  The U.S.


EPA draft ambient water quality criterion for monochloro-


benzene is 20/pg/l based on the threshold concentration


for odor and taste (U.S. EPA, 1979).


          Trichlorobenzene:   The American Conference of


Governmental Industrial Hygienists (ACGIH, 1977) threshold  '


limit value for 1,2,4-trichlorobenzene is 40 mg/m  (5 ppm).

-------
The U.S. EPA (1979) draft ambient water quality criterion

for 1, 2, 4-tr ichlorobenzene is 13 pg/1 based on the threshold

concentration for odor and taste.

          Tetrachlorobenzene:  The U.S. EPA (1979) draft

ambient water quality criterion for tetrachlorobenzene  is

17 jig/1.

          Pentachlorobenzene:  The U.S. EPA (1979) draft

ambient water quality criterion for pentachlorobenzene  is

0.5 ug/1.

          Hexachlorobenzene :  The value of 0.6 ug/kg/day

hexachlorobenzene was suggested by FAO/WHO as a reasonable

upper limit for residues in food for human consumption  (FAO/WHO,

1974).  The Louisiana State Department of Agriculture has

set the tolerated level of hexachlorobenzene in meat fat

a 0.3 mg/kg (U.S. EPA, 1976).  The FAO/WHO recommendations

for residues in foodstuffs were 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 cancer bioassy 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 Criteria
      (per day)   ~                     _?            _6         _s
                              0       10 '          10  °       10  3

2 liters of drinking water    0    O.OL25 ng/1   0.125  ng.l   1.25 ng/1
and consumption of 18.7
grams fish and shellfish.

Consumption of fish and       0    0.126 ng/1    0.126  ng/1   1.26 ng/1
shellfish only.
                            -M30-

-------
     B.   Aquatic

          The drafted criteria to protect  freshwater  aquatic

life as is follows:   (U.S. EPA, 1979)
Compound
Chlorobenzene
1,2,4-trichlorobenzene
1,2,3,5-tetrachlorobenzene
1,2,4,5-tetrachlorobenzene
Pentachlorbenzene
                Concentration not to
               be exceeded at anytime
                        3,500
                          470
                          390
                          220
                           36
          The drafted criteria to protect saltwater  aquatic

life are as follows:  (U.S. EPA, 1979)
Comoound
Chlorobenzene
1,2,4-Trichlorobenzene
1,2,3,5-Tetrachlorbenzene
1,2,45-Tetrachlorobenzene
Pentachlorobenzene
24-hr.
Average
 Jig/1

 120
   3.4
   2.6
   9.6
   1.3
 Concentration not to
be exceeded at anytime
         ug/1

         280
           7.8
           5.9
          26
           2.9

-------
                             CHLORINATED BENZENES

                                  REFERENCES
Albro, P.W.,  and  R.  Thomas.  1974.   Intestinal  absorption of hexachloroben-
zene  and hexachlorocyclohexane  isomers  in  rats.   Bull.  Environ.  Contam.
Toxicol.   12: 289.

American Conference  of Governmental  Industrial  Hygienists.   1971.  Documen-
tation of the threshold limit values for substances in workroom air.  3rd ed.

Ariyoshi, T., et  al.   1975a.  Relation between  chemical  structure and acti-
vity.  I. Effects of the number of  chlorine atoms  in chlorinated benzenes on
the components of drug metabolizing systems and  hepatic constituents.  Chem.
Pharm. Bull.  23: 817.

Braun, W.H.,  et al.   1978.   Pharmacokinetics and toxicological evaluation of
dogs  fed 1,2,4,5-tetrachlorobenzene in the diet for two  years.   Jour. Envi-
ron. Pathol. Toxicol.  2: 225.

Cabral, J.R.P., et al.   1977.   Carcinogenic activity of hexachlorobenzene in
hamsters.  Nature (London)  269: 510.

Cabral, J.R.P., et al.   1978.   Carcinogenesis study  in mice with hexachloro-
benzene.   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.

Coate, W.B.,  et al.   1977.   Chronic inhalation exposure of rats, rabbits and
monkeys to. 1,2,4-trichlorobenzene.  Arch. Environ. Health.  32: 249.

Fomenko,  v.N.  1965.   Determination of the maximum permissible concentration
of tetrachlorobenzene in water basins.  Gig. Sanit.  30: 8.

Food  and  Agriculture  Organization.   1974.   1973 evaluations of some pesti-
cide  residues in  food.  FAO/AGP/1973/M/9/1;  WHO  Pestic. Residue  Ser.  3.
World Health Org., Rome, Italy,   p. 291.                            *

Gotto, M.,  et al.  1972.  Hepatoma  formation in  mice after administration of
high doses of hexachlorocyclohexane isomers.  Chemosphere  1:  279.

Grant, D.L.,  et  al.    1977.  Effect of hexachlorobenzene  on  reproduction in
the rat.   Arch. Environ. Contam. Toxicol.  5: 207.

Irish, D.D.   1963.  Halogenated hydrocarbons:  II. Cyclic.  In Industrial Hy-
giene and Toxicology,  Vol.  II,  2nd ed., F.A.  Patty,  (ed.) Interscience, New
York.  p. 1333.

Jondorf,  W.R.,  et al.   1958.   Studies  in  detoxication.   The metabolism of
halogenobenzenes  1,2,3,4-,  1,2,3,5- and  1,2,4,5-tetrachlorobenzenes.   Jour.
Biol. Chem.   69:  189.

-------
Khera,  K.S.   1974.   Teratogenicity  and  dominant  lethal  studies  on hexa-
chlorobenzene in rats.  Food Cosmet. Toxicol.  12: 471.

Kohli,  I.,  et  al.   1976.  The metabolism  of higher chlorinated benzene iso-
mers.  Can. Jour. Biochem.  54: 203.

Koss, G.,  and  W.  Koransky.  1975.  Studies  on the toxicology of hexachioro-
benzene.  I. Pharmacokinetics.  Arch. Toxicol.  34: 203.

Koss,  G.,  et  al.   1976.   Studies on  the  toxicology  of hexachlorobenzene.
II.   Identification   and  determination   of  metabolites.    Arch.  Toxicol.
35: 107.

Koss,  G.,  et  al.   1978.   Studies on  the  toxicology  of hexachlorobenzene.
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.

Mackay, D., and. P.J.  Leinonen.   1975.   Rate of evaporation of low-solubility
contaminants  from  water  bodies  to  atmosphere.   Environ.  Sci.  Technol.
9: 1178.

Parke,  O.V.,  and  R.T.  Williams.   1960.   Studies in  detoxification  LXXXI.
Metabolism  of  halobenzenes:  (a). Penta-  and hexachlorobenzene:  (b) Further
ob- servations of 1,3,5-trichlorobenzene.  Biochem. Jour.  74: 1.

Parrish, P.R.,  et  al.   1974.  Hexachlorobenzene:  effects on  several  estua-
rine  animals.   Pages  179-187  In:  Proc.  28th Annu.  Conf.  S.E'.  Assoc.  Game
Fish Comm.

Pickering,  Q.H., and  C.  Henderson.  1966.   Acute  toxicity  of some  important
petrochemicals to fish.  Jour. Water Pollut. Control Fed.  38: 1419.

Preussmann, R.  1975.  Chemical  carcinogens  in the human environment.   Hand.
Allg. Pathol.  6: 421.

Rozman, K.,  et  al.   Metabolism and pharmacokinetics  of penta- chlorobenzene
in rhesus monkeys.   Bull. Environ. Contam. Toxicol.  (in press)

Shirai,  T., et  al.   1978.   Hepatocarcinogenicity  of  polychlorinated  ter-
phenyl  (PCT)  in ICR  mice  and  its enhancement  by  hexachlorobenzene  (HCB).
Cancer Lett.  4: 271.

Stijve, T.  .1971.   Determination  and  occurrence  of  hexachlorobenzene resi-
dues.  Mitt. Geb.  Lebenmittelunters. Hyg.  62: 406.

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

-------
U.S. EPA.  1975.   Survey of  Industrial  Processing Data:  Task I, Hexachloro-
benzene and nexachlorobutadiene pollution  from  chlorocarbon processes.  Mid.
Res. Inst. EPA, Off.  Toxic Subs. Contract, Washington, O.C.

U.S. EPA.  1976.   Environmental contamination  from  hexachlorobenzene.  EPA-
560/6-76-014.  Off. Tox. Subst. 1-27.

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

U.S.  EPA.   1979.    Chlorinated  Benzenes:  Ambient   Water  Quality  Criteria
Document. (Draft)

Ushio,   F.,  and M.  Doguchi.    1977.   Dietary  intakes of  some  chlorinated
hydrocarbons  and   heavy metals  estimated  on  the  experimentally  prepared
diets.   Bull. Environ. Contam. Toxicol.  17: 707.

West,  W.L.,  and  S.A.  Ware.   1977.    Preliminary Report,  Investigation  of
Selected  Potential Environmental  Contaminants: Halogenated Benzenes.  Envi-
ron. Prot. Agency,  Washington, D.C.

Williams, R.T.  1959.   The  metabolism of  halogenated aromatic hydrocarbons.
Page 237 I.n:  Detoxication mechanisms.   2nd ed.   John Wiley  and Sons,  New
York.                                                  v  )
                                      -H3H-

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                                       No.  37
        Chlorinated Ethanes


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION










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



chlorinated ethanes and has found sufficient evidence to



indicate that this compound is carcinogenic.

-------
                     CHLORINATED ETHANES



                           SUMMARY



     Four  of  the  chlorinated  ethanes  have  been  shown  to



produce  tumors  in  experimental  animal  studies  conducted



by  the  National  Cancer  Institute   (NCI).    These  four  are



1,2-dichloroethane,   1,1,2-trichloroethane,   1,1,2,2-tetra-



chloroethane,  and  hexachloroethane.    Animal  tumors  were



also  produced by  administration  of  1,1,1-trichloroethane,



but this  bioassay  is being repeated  due to premature deaths



in one initial study.



     Two  of   the   chlorinated   ethanes,  1,2-dichloroethane



and 1,1,2,2-tetrachloroethane, have  shown  mutagenic activity



in the Ames  Salmonella assay and in E.  coli. 1,2-Dichloroethane



has also shown mutagenic action in pea plants and in Drosophila.



     No evidence  is available indicating that the chloroethanes



produce  teratogenic  effects.    Some  toxic effects  on fetal



development  have  been  shown  following  administration  of



1,2-dichloroethane and hexachloroethane.



     Symptoms produced by toxic exposure to the chloroethanes



include  central  nervous system  disorders, liver  and  kidney



damage, and cardiac effects.



     Aquatic  toxicity  data  for   the  effects  of  chlorinated



ethanes to freshwater and marine life are  few.  Acute studies



have  indicated that hexachloroethane is  the  most  toxic  of



the  chlorinated  ethanes  reviewed.     Marine  organisms  tend



to  be more  sensitive  than freshwater organisms  with acute



toxicity values as low as 540  ug/1 being reported.

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                     CHLORINATED ETHANES

I.    INTRODUCTION

     .This profile is based on the draft Ambient Water Quality

Criteria Document for Chlorinated Ethanes  (U.S. EPA, 1979).

     The  chloroethanes  (see table  1)  are  hydrocarbons   in

which one  or  more of  the  hydrogen atoms  have been replaced

by  chlorine  atoms.    Water  solubility  and  vapor  pressure

decrease  with  increasing  chlorination,   while   density  and

melting point  increase.   Monochloroethane is a  gas  at room

temperature, hexachloroethane  is  a solid,  and the remaining

compounds are liquids.   All  chloroethanes  show some solubility

in  water,  and all,  except  monochloroethane,  are more dense

than water.

     The  chloroethanes are  used  as  solvents,  cleaning  and

degreasing agents, in the manufacture of plastics and textiles,

and in the chemical synthesis of a number  of  compounds.

          Current production:

               monochloroethane    335 x 10-,  tons/yr in 1976
             1,2-dichloroethane  4,000 x 10^  tons/yr in 1976
          1,1,1-trichloroethane    215 x 10   tons/yr in 1976

     The  chlorinated  ethanes  form  azeotropes  with  t/ater

(Kirk and  Othmer, 1963).   All  are  very  soluble in organic

solvents (Lange, 1956). Microbial degradation of  the chlorin-

ated ethanes has not been demonstrated  (U.S.  EPA, 1979).

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.   Water   monitoring  studies

-------
     have  shown  the  following  levels  of  various  chloroethanes:

     1,2-dichloroethane, 0.2-8  ug/1;  1,1,2-trichloroethane,  0.1-

     8.5  ug/1;  1,1,1,2-tetrachloroethane,  0.11  ^g/1  (U.S.  EPA,

     197,9) .  In general, air levels  of  chloroethanes  are produced

     by  evaporation  of volatile  chloroethanes  widely  used  as

     degreasing agents  and  in  dry cleaning operations  (U.S.  EPA,

     1979).  Industrial monitoring studies have  shown  air  levels

     of  1,1,1-trichloroethane  ranging  from 1.5  to  396  ppm (U.S.

     EPA, 1979).


                                  TABLE 1

                         Chloroethanes  and  Synonyms

Compound Name       Synonyms
Monochloroethane

1,1,-Dichloroethane

1,2-Dichlorpethane

1,1,1-Tr ichloroethane

1,1,2-Trichloroethane

1,1,1,2-Tetrachloroethane

1,1,2,2-Tetrachloroethane

Pen tach loir oe thane

Hexachloroethane
Chloroethane

Ethylidene Dichloride

Ethylene Dichloride

Methyl Chloroform

Ethane Trichloride

Tetrachloroethane

Acetylene Tetrachloride

Pentalin

Perchloroethane
Ethyl chloride

Ethylidene Chloride

Ethylene Chloride

Chlorothene

Vinyl Trichloride



Sym-Tetrachloroethane

Ethane Pentachloride
          Sources  of  human  exposure  to  chloroethanes  include

     water, air,  contaminated foods and. fish,  and dermal absorption.
                                                                 »
     The  two most  widely  used  solvents, 1,2-dichloroethane  and

     1,1,1-trichloroethane, are  the  compounds  most often detected

     in foods.  Analysis of several foods indicated 1,1,1-trichloro-

-------
ethane  levels  of  1-10  ug/kg   (Walter,  et al.  1976), while

levels of  1,2-dichloroethan'e  found in 11  of  17 species  have

been  reported  to  be  2-23 ug/g   (Page  and  Kennedy,   1975) .

Fish  and   shellfish  have  shown levels  of  chloroethanes  in

the nanogram range (Dickson and Riley, 1976).

     The U.S.  EPA  (1979) has  derived  the following weighted

average  bioconcentratioa  factors  for  the   edible  portions

of  fish -and  shellfish consumed by Americans:  1,2-dichloro-

ethane, 4.6; 1,1,1-trichloroethane,  21;  1,1,2,2-tetrachloro-
                                          ».
ethane,  18;  pentachloroethane,  150;  hexachloroethane,  320.

These  estimates  were  based   on   the  measured steady-state

bioconcentration  studies   in   bluegill.      Bioconcentration

factors for 1,1,2-trichloroethane (6.3) and 1,1,1,2-tetrachloro-

ethane  (18)  were derived  by  EPA  (1979)  using octanol-water

partition coefficients.

III. PHARMACOKINETICS

     A.   Absorption

          The  chloroethanes are  absorbed  rapidly   following

ingestion or inhalation  (U.S.  EPA,  1979).   Dermal absorption

is  thought to be slower  in rabbits based on studies  by  Sryth,

et  al.  (1969).   However,  rapid  dermal  absorption  has  been

seen in guinea pigs  with the  same trichloroethane (Jakobson,

et  al. 1977).

          Human studies  on the absorption of  inhaled 1,1,2,2-

tetrachloroethane  indicate that  the compound  is  completely

absorbed  after  exposure  to   trace  levels   of radiolabeled

vapor  (Morgan,  et  al.,  1970, 1972).    At  higher  exposure

levels absorption  is  rapid in  man and  animals, but  obviously

not complete.

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     B.    Distribution



          Studies on the  distribution of 1,1,1-trichloroethane



in  mice  following   inhalation  exposure  have  shown  levels



in the  liver  to  be  twice that found in  the  kidney and brain



(Holmberg,  et  al.  1977).    Postmortem  examination  of human



tissues   showed   1,1,1-trichloroethane  in  body fat  (highest



concentration)  kidneys,  liver,  and  brain  (Walter,   et  al.



1976).   Due to  the  lipid  solubility of  chloroethanes,  body



distribution may be expected  to  be widespread.    Stahl,  et



al.  (1969)  have  noted  that human  tissue samples  of  liver,



brain,  kidney, muscle,  lung, and blood  contained 1,1,1-tri-



chloroethane following acute exposure, with the liver contain-



ing the  highest concentration.



          Passage  of  1,1,1,2-tetrachloroethane  across  the



placenta  has  been  reported by  Truhaut,  et  al.  (1974)  in



rabbits  and rats.



     C.    Metabolism



          The  metabolism   of  chloroethanes  involves  both



enzymatic dechlorination  and hydroxylation  to corresponding



alcohols  (Monster, 1979;  Truhaut,  1972).   Oxidation reactions



may produce unsaturated metabolites which are then transformed



to the alcohol and ester  (Yllner,  1971 a,b,c,d).



          Metabolism  appears  to  involve  the  activity  of



the mixed function oxidase enzyme system (Van  Dyke  and Wineman,



1971).  Animal experiments by Yllner  (1971 a,b,c,d,e) indicated



that  the  percentage of  administered '-compound  metabolized
                                                           »


decreased  with  increasing   dose,  suggesting  saturation  of



metabolic pathways.

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     D.   Excretion



          The  chloroethanes  are  excreted  primarily  in  the



urine  and  in expired air  (U.S.  EPA,  1979).   As  much as 60



to  80  percent  of  an  inhaled dose  of 1,1,1-trichloroethane



(70 or  140  ppm for 4  hours)  was expired unchanged  by human



volunteers  (Monster, et  al.  1979).   Animal studies conducted



by  Yllner   (1971  a,b,c,d)   indicate  that  largest amount of



chloroethanes,  administered  by  intraperitoneal (i.p.) injec-



tion is  excreted  in the urine;  this  is  followed  by  expira-



tion  (in the  changed  or  unchanged  form),  with  very little



excretion  in  the  feces.    Excretion  appears  to be rapid,



since  90 percent of  i.p. administered doses of 1,2-dichloro-



ethane or 1,1,2-trichloroethane were  eliminated  in the first



24 hours (U.S.  EPA,  1979).  However,  the  detection of  chloro-



ethanes  in   postmortem   tissue  samples  indicates  that   some



portion  of   these  compounds  persists  in the body   (Walter,



et al.  1976).



IV.  EFFECTS



     A.   Carcinogenicity



          Several  chlorinated  ethanes  have   been shown to



produce  a variety  of  tumors in rats and  mice in  experiments



utilizing oral administration.    Tumor types  observed after



compound  administration   include   squamous   cell  carcinoma



of  the stomach, hemangiosarcoma, adenocarcinoma  of  the  mam-



mary gland,  and hepatocellular  carcinoma (NCI, 1978a,b,c,d).



The  four  chlorinated  ethanes   which   have   been  classified



as  carcinogens based  on  animal  studies are:  1,2-dichloro-



ethane,   1,1,2-trichloroethane,   1,1,2,2-tetrachloroethane,

-------
and  hexachloroethane.    Increased  tumor production  was also

noted  in  animals  treated  with  1,1,1-trichloroethane,   but

high mortality  during  this  study  (NCI,  1977)  caused  retest-

ing  of  the compound to  be  initiated.    In vitro transforma-

tion of  rat  embryo  cells and  subsequent fibrosarcoma  produc-

tion  by these  cells when  injected _in vivo,  indicate that

1,1,1-trichloroethane does have  carcinogenic potential  (Price,

et al. 1978).

     B.   Mutagenicity
                                          ».
          Two of  the chlorinated  ethanes, 1,2-dichloroethane

and  1,1,2,2-tetrachloroethane,  have  shown mutagenic activity

in the Ames  Salmonella assay and for DNA polymerase deficient

stra-.n of E. coli (Brem, et al. 1974).  In these two systems,
       )  . —

1,1,2,2-tetrachloroethane  showed   higher   mutagenic  activity

than 1,2-dichloroethane  (Rosenkranz, 1977).

          Mutagenic effects  have been produced by 1,2-dichloro-

ethane  in  pea  plants   (Kirichek,  1974)   and  in  Drosophila
     j
(Nylander,  et  al.  1978).   Several metabolites  of dichloro-
       ' /
etha'i...-' (chloroacetaldehyde/ chloroethanol,  and S-chloroethyl

cysteine  have  also  been shown to  produce mutations  in  the

Ames assay  (U.S. EPA, 1979).

          Testing of hexachloroethane  in  the Ames Salmonella

assay or in  a yeast assay system failed to show any mutagenic

activity (Weeks, et al.  1979).

     C.   Teratogenicity

           Inhalation  exposure  of  pregnant  rats  and  mice

to   1,1,1-trichloroethane  was  shown  to   produce   some  soft

-------
tissue  and  skeletal  deformities;  this  incidence   was  not



judged statistically  significant by the  Fisher  Exact proba-



bility test (Schwetz, et al. 1975).



          Testing  of hexachloroethane  administered  to   rats



by intubation or inhalation exposure did  not show an  increase



in  teratogenic  effects  (Weeks,  et al.  1979).   Inhalation



exposure of pregnant rats  to  1,2-dichloroethane  also failed



to  demonstrate  teratogenic  effects  (Schwetz,  et  al.  1974;



Vozovaya, 1974) .



     D.   Other Reproductive Effects



          Decreased .litter  size,  reduced fetal  weights  and



a reduction in live births have been reported in rats exposed



to 1,2-dichloroethane (57 mg/m  m four hours/day,  six days/week)



by  inhalation  (Vozovaya, 1974).   1,1-Dichloroethane  retarded



fetal  development  at  exposures  of  6,000 ppm.  (Schwetz, et



al. 1974).   Higher  fetal  resorption  rates  and  a  decreased



number  of  live  fetuses per   litter  were  observed  in   rats



following  administration  of  hexachloroethane  by  intubation



(15,  48  or  260 ppm,  6 hours/day) or   inhalation  (50,  100



or 500 mg/kg/day)  (Weeks,  et al. 1979).



    .E.   Chronic Toxicity



          Neurologic  changes  and  liver  and  kidney damage



have  been  noted following   long  term human  exposure  to   1,2-



dichloroethane (NIOSH, 1978) . Cardiac effects  (overstimulation)



have been noted following human exposure'  to 1,1-dichloroethane



(U.S.  EPA,  1979).



          Central nervous system disorders have been  reported



in  humans  exposed  to 1,1,1-trichloroethane.   Symptoms noted

-------
were altered reaction time, perceptual speed, manual dexterity,


and equilibrium  (U.S. EPA, 1979).


          Animal  studies  indicate that  the general symptoms


of  toxicity  resulting  from  exposure  to  the  chloroethanes


involve effects  in the central nervous system, cardiovascular


system,  pulmonary system,  and  the  liver  and  kidney  (U.S.


EPA, 1979).  Laboratory animals and humans  exposed to  chloro-


ethanes show similar symptoms of  toxicity  (U.S. EPA, 1979).


          Based  on  data  derived from  animal  studies,   the


U.S.   EPA  (1979)  has concluded  that  the  relative  toxicity

of  the  chloroethanes  is  as  follows:   1,2-dichloroethane>


1,1,2,2-tetrachloroethane p-1,1,2-tr ichloroethane >hexachloro-


ethane 1,1-dichloroethane;>!,!,1-trichloroethane;? monochloro-

ethane.


     F.   Other  Relevant  Information


          The  hepatotoxicity  of  1,1,2-trichloroethane   was


increased  in  mice   following  acetone  or  isopropyl   alcohol


pretreatment  (Traiger  and  Plaa,  1974).    Similarly,   ethanol


pretreatment of  mice  increased  the  hepatic effects of 1,1,1-


trichloroethane  (Klassen  and  Plaa, 1966).


          Hexobarbital sleeping  times  in  rats  were  reported


to  be  decreased  following  inhalation  exposure  to 1,1,1-tri-


chloroethane (3,000 ppm) ,  indicating an effect of  the compound


on  stimulation  of   hepatic   microsomal  enzymes  (Fuller,  et


al. 1970).


V.   AQUATIC TOXICITY
                                                           »
     A.   Acute  Toxicity


          Acute   toxicity  studies  were   conducted  on three


species  of  freshwater   organisms and   two marine  species.


                              i

-------
For  freshwater  fish,   96-hour  static  LC50  values  for   the

bluegill sunfish,  Lepomis macrochirus, ranged  from 980 pg/1

hexachloroethane  to 431,000  ug/1  1,2-dichloroethane,  while

the range of 48-hour LC50 values  for the freshwater  inverte-

brate Dap'nnia  magna was 8,070  ug/1 to 213,000 ug/1 for hexa-

chloroethane  and   1,2-dichloroethane  respectively.    Among

marine  organisms,   the  sheepshead minnow  (Cyprinodon vagie-

gatus)  produced  LC5Q   values  ranging  from  2,400 pg/1   for

hexachloroethane   to   116,000   ug/1  for  pentachloroethane.

The  marine mysid   shrimp  (Mysidopsis  bahia)  produced  LC,-Q

values  ranging  from 940 ug/1 for hexachloroethane  to 113,000

pg/1  for 1,2-dichloroethane.   The  general  order of  acute

toxicities  for the  chlorinated  ethanes  reviewed  for fresh-

water fish  is:  hexachloroethane  (highest toxicity),  1,1,2,2-

tetrachloroethane,  1,1,2-trichloroethane,  pentachloroethane,

and 1,2-dichloroethane  (U.S. EPA, 1979).

     B.   Chronic Toxicity

          The  only chronic  study  available  for  the  chlori-

nated  ethanes  is  for  pentachloroethane's   chronic  effects

on  the  marine  shrimp  (Mysidopsis   bahia),  which  produced

a chronic value of  580  ug/1  (U.S EPA, 1978).

     C.   Plant Effects

          Effective EC^Q  concentrations, based on chlorophyll

a  and  cell numbers   for  the  freshwater  algae  Selenastrum

capriconutum  ranges from 87,000  pg/1,  for  hexachloroethane

to  146,000  ug/1  for   1,1,2,2-tetrachloroethane,  with penta-

chloroethane  being intermediate  in  its phytotoxicity.    For

the  marine algae  Skeletonema costaturn,    a greater sensi-


                              *
                             -447-

-------
tivity was  indicated  by  effective EC<5Q_ concentrations based



on cell  numbers and  chlorophyll a  ranging  from  6,230 ug/1



for 1,1,2,2-tetrachloroethane and  7,750  ug/1 for hexachloro-



ethane to 58,200 ug/1 for pentachloroethane.



     D.   Residues



          The bioconcentration  value was greatest  for hexa-



chloroethane  with  a  value  of  139  ug/1  being  reported  for



bluegill.  Bioconcentration  values  of 2, 8, and 9  were obtained



for  1,2-dichloro,  1,1,2,2-tetrachloro,  and  1,1,1-trichloro-



ethane  for  bluegills.    1,1,2-Trichloroethane  and  1,1,1,2-



tetrachloroethane  used  the  octanol/water  coefficients  to



derive BCF's of 22 and 62, respectively.



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



          Based  on  the   NCI  carcinogenesis  bioassay  data,



and using  a  linear, non-threshold  model,  the  U.S.  EPA  (1979)



has estimated levels  of  four chloroethanes  in  ambient water



that will  result  in  an additional cancer risk of  10~ : 1,2-



dichloroethane,   7.0   ug/1;  1,1,2-trichloroethane,   2.7  ug/1;



1,1,2,2-tetrachloroethane,  1.8   ug/1;  hexachloroethane,  5.9



ug/1.   A  draft ambient  water  quality•criterion  to  protect



human  health has  been derived  by EPA  for  1,1,1-tr ichloro-



ethane  based on  mammalian  toxicity  data  at  the level  of



15.7 mg/1.

-------
          Insufficient mammalian toxicological data prevented




derivation  of  a water  criterion  for  monochloroethane,  1,1-



dichloroethane,  1,1,1,2-tetrachloroethane,  or  pentachloro-



ethane (U.S. EPA, 1979).



          The  following  compounds  have  had eight  hour, TWA



exposure  standards  established by OSHA:  monochloroethane,



1,000 ppm;  1,1-dichloroethane,  100 ppm; 1,2-dichloroethane,



50 ppm;  1,1,1-trichloroethane,  350  ppm; 1,1,2-trichloroethane,



10  ppm;  1,1,2,2-tetrachloroethane,  5  ppm;  hexachloroethane,



1 ppm.



     B.    Aquatic



          Criteria  for  protecting  freshwater  organisms have



been  dra  " 3 for  five  of  the chlorinated  hydrocarbons:  62



pg/1  (average  concentation)  not to exceed 140 ug/1 for  hexa-



chloroethane;  170  ug/1 not  to exceed 380 pg/1  for 1,1,2,2-



tetrachloroethane;  440  pg/1  not  to  exceed  1,000 ,ug/l for



pentachlo''"^ethane;  3,900  pg/1  not  to  exceed 8,800  ug/1 for



1,2-dichloroethane;  and  5,300  pg/1  not to  exceed  12,000



ug/1  for  x','l, 1-tr ichloroethane.  For  marine  organisms,  cri-



teria have  been drafted  as:  7  pg/1 (average concentration)



not  to  exceed  16  pg/1  for  hexachloroethane;  38 pg/1 not



to  exceed   87  pg/1  for  pentachloroethane;  70  pg/1   not  to



exceed  160  pg/1  for  1,1,2,2-tetrachloroethane;  240  pg/1



not  to  exceed  540  pg/1  for  1,1,1-trichloroethane;  and 880



pg/1 not to exceed 2,000 pg/1  for 1,2-dichloroethane.

-------
                     CHLORINATED ETHANES

                         REFERENCES

Brem, H., et al.  1974.  The mutagenicity and DNA-Modifying
effect of haloalkanes.  Cancer Res.  34: 2576.

Dickson,'A.O. , and J.P. Riley.  1976.  The distribution  of
short-chain halcgenated aliphatic hydrocarbons  in  some marine
organisms.  Mar. Pollut. Bull.  79: 167.

Fuller, G.C., et al.  1970.  Induction of hepatic  drug metab-
olism in rats bv methylchloroform inhalation.   Jour.  Pharma-
col. Ther.  175~: 311."

Holmberq, B., et al.  1977.  A study of the distribution  of
methylchloroform and n-octane in the mouse during  and after
inhalation. Scand. Jour. Work Environ. Health   3:  43.

Jakobson, I., et al.  1977.  Variations in the  blood  concen-
tration of 1,1,2-trichloroethane by percutaneous absorption
and other routes of administration in the guinea pig.  Acta.
Pharmacol. Toxicol.  41: 497.

Kirk, R., and D. Othmer.  1963.  Encyclopedia of chemical
technology.  2nd ed.  John Wiley and Sons, Inc., New  York.

Kiricheck, Y.F.  1974.  Effect of 1,2-dichloroethane  on  muta-
tions in peas.  Usp. Khim. Mutageneza Se.  232.

Klaassen, C.D., and G.L. Plaa.  1966.  Relative effects  of
various chlorinated hydrocarbons on liver and kidney  function
in mice.  Toxicol. Appl. Pharmacol.  9: 139.

Lange, N. (ed.)  1956.  Handbook of chemistry.  9th ed.
Handbook Publishers, Inc., Sandusky, Ohio.

Monster, A.C.  1979.  Difference in uptake, elimination,  and
metabolism in exposure  to trichloroethylene, 1,1,1-trichjloro-
ethane and tetrachloroethylene.  Int. Arch. Occup.  Environ.
Health  42: 311.

Monster, A.C., et al.   1979.  Kinetics of 1,1-trichloroethane
in volunteers; influence of exposure concentration  and work
load.  Int. Arch. Occup. Environ. Health  42: 293.

Morgan, A., et al.  1970.  The excretion in breath  of some
aliphatic halogenated hydrocarbons following administration
by  inhalation.  Ann. Occup. Hyg.  13: 219.

Morgan, A., et al.  1972.  Absorption of halogenated  hydro-
carbons and their excretion in breath using chlorine-38
tracer techniques.  Ann. Occup. Hyg.  15: 273.

-------
National Cancer Institute.   1977.   Bioassay  of  1,1-trichloro-
ethane foe possible  carcinogenicity..  Carcinog.   Tech.  Rep.
Ser. NCI-CG-TR-3.

National Cancer Institute.   1978a.   Bioassay of  1,2-dichloro-
ethane for possible  carcinogenicity.   Natl.  Inst.  Health,
Natl. Cancer Inst. Carcinogenesis Testing  Program.   DHEW
Publ. Mo. (NIH) 78-1305. Pub. Health Serv. U.S.  Dep.  Health
Edu. Welfare.

National Cancer Institute.   1978b.   Bioassay of  1,1,2-tri-
chloroethane for possible  carcinogenicity.   Natl. Inst.
Health, Natl. Cancer Inst.  DHEW  Publ.  No.  (NIH)  78-1324.  Pub.
Health Serv. U.S. Dep.  Health Edu.  Welfare.

National Cancer Institute.   1978c.   Bioassay of  1,1, 2 , 2-tetra-
chloroethane for possible  carcinogenicity.   Natl. Inst.
Health, Natl. Cancer Inst.  DHEW  Publ.  No.'- (NIH)  78-827.   Pub.
Health Serv. U.S. Dep.  Health Edu.  Welfare.

National Cancer Institute.   1978d.   Bioassay of  hexachloro-
ethane for possible  carcinogenicity.   Natl.  Inst. Health,
Natl. Cancer Inst. DHEW Publ. No.  (NIH)  78-1318.   Pub.  Health
Serv.  U.S. Dep. Health Edu. Welfare.

National Institute for  Occupational Safety and Health.  1978.
Ethylene dichloride  (1,2-dichloroethane).  Current Intelli-
gence Bull.  25.  DFEW  (NIOSH) Publ. No. 78-149.

Nylander, P.O., et al.   1978.  Mutagenic effects  of petrol  in
Drosoph ilia melanogaster.   I. Effects  of benzene  of and 1,2-
d ichloroethane.  Mutat.  Res.  57: 163.

Page, B.D., and B.P.C.  Kennedy. .  1975.   Determination of
mthylene chloride, ethylene  dichloride,  and  trichloroethylene
as  solvent residues  in  spice oleoresins, using  vacuum distil-
lation and electron-capture  gas  chromatography.   Jour.
Assoc. Off. Anal. Chen.  58: 1062.
                                                        »
Price, P.J., et al.  1978.  -Transforming activities of  tri-
chloroethylene and proposed  industrial alternatives.   In
vitro.  14: 290.

Rosenkranz, H.S.  1977.  Mutagenicity  of halogenated  alkanes
.and  their derivatives.   Environ.  Health  Perspect.  21:  79.

Schwetz, B.A., et al.   1974.  Embryo-  and  fetotoxicity  of  in-
haled carbon tetrachloride,  1,1,-dichloroethane,  and  methyl
ethyl ketone in rats.   Toxicol.  Appl.  Pharraacol.   28:  452.

Schwetz, B.A., et al.   1975.  Effect of  maternally  inhaled.
trichloroethylene, perchloroethylene,  methyl chloroform,  and
methylene chloride on embryonal  and fetal  development in  mice
and  rats.  Toxicol.  Appl.  Pharmacol.   32:  84.

-------
Snyth, K.F., Jr., et al.  1969.  Range-finding  toxicity  data:
list VII.  Am. Ind. Hyg. Assoc. Jour. 30: 470.

Stahl, C.J., et al.  1969.  Trichlcroethane poisoning:   ob-
servations on the pathology and toxicology  in six  fatal
cases.  Jour. Forensic Sci. 14: 393.

Traiger, G.J., and G.L. Plaa.  1974.  Chlorinated  hydrocarbon
toxicity.  Arch. Environ. Health 28: 276.

Truhaut, R.  1972.  Metabolic transformations of 1,1,1,2-
tetrachloroethane in aninals (rats, rabbits).   Chem.  Anal.
(Warsaw) 17: 1075.

Truhaut, R., et al.  1974.  Toxicological study of  1,1,1,2-
tetrachloroethane.  Arch. Mai. Prof. Med. Trav. Secur. Soc.
35: 593.

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.  1979.  Chlorinated Ethanes:  Ambient Water Quality
Criteria (Draft).

Van Dyke, R.A., and C.G. Wineman.  1971.  Enzymatic dechlori-
nation:  Dechlorination of chloroethanes and propanes _i_n
vitro.  Biochem. Pharniacol. 20: 463.

Vozovaya, M.A.  1974.  Development of progeny of two genera-
tions obtained from female rats subjected to the action  of
dichloroethane.  Gig. Sanit. 7: 25.

Walter, P., et al.  1976.  Chlorinated hydrocarbon  toxicity
(1,1,1-trichloroethane, trichloroethylene,  and  tetrachloro-
ethylene):  a monograph.  PE Rep. PB-257185.  Matl. Tech.
Inf. Serv., Springfield, Va.
                                                        -»
Weeks, M.H., et al.  1979.  The toxicity of hexachloroethane
in laboratory animals.  Am. Ind. Hyg. Assoc. Jour.  40: 187.

Yllner, S.  1971a.  Metabolism of 1,2-dichloroethane-14c
in the mouse.  Acta. Pharnacol. .Toxicol. 30: 257.

Yllner, S.  1971b.  Metabolism of 1,1,2-trichloroethane-l,2-
^4C in the mouse.  Acta. Pharmacol. Toxicol. 320:  248.

Yllner, S.  1971c.  Metabolism of 1,1,1,2-tetrachloroethane
in the mouse.  Acta. Pharmacol. Toxicol.. 29: 471.

Yllner, S.  1971d.  Metabolism of 1,1, 2 , 2-tetrachloroethane'-
14C in the mouse.  Acta. Pharmacol. Toxicol. 29: 499.

Yllner, S.  1971e.  Metabolism of pentachloroethane  in the
mouse.  Acta. Pharmacol. Toxicol. 2^: 481.

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                                      No. 38
      Chlorinated Naphthalenes


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

           APRIL 30, 1980

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

-------
                            CHLORINATED NAPTHALENE5
                                    Summary

     Chlorinated  naphthalenes  have  been used  in  a variety  of industries,
usually  as  .mixtures.   Chronic  toxicity  varies with  the  degree  of chlori-
nation,  with the  more  highly  chlorinated  species being  more  toxic.   The
clinical signs  o'f toxicity in humans  are damage to  liver,  heart, pancreas,
gall bladder, lungs, adrenal glands,  and kidney.   NO animal or human studies
have been presented  on the carcinogenicity,  mutagenicity,  or teratogenicity
of polychlorinated naphthalenes.
     Very  little  data  on aquatic  toxicity  are  available  for individual
chlorinated  naphthalenes.   48-Hour  and 96-hour  LC~  values  of octachloro-
naphthalene  over  500,000 pg/1  have been  reported for Daphnia maqna and the
bluegill, respectively.  A freshwater  alga  also  resulted in  a  96-hour LC50
value for octachloronaphtnalene of over 500,000 pg/l.
     Toxicity studies  with aquatic organisms  are confined  to  tests with 1-
chloronaphthalene  on one  freshwater  fish and  two  algal species  (one  fresh
and  one saltwater).   All   tests  have  reported 96-hour LC5n values of be-
tween 320 and 2,270  /jg/1.   Exposure of sheepshead minnow to 1-chloronaphtha-
                                                                  i
lene in an embryo-larval study resulted in a chronic value of 328 ug/1.
                                       I

-------
                           CHLORINATED NAPTHALENES
I.   INTRODUCTION
     This profile is based on the  draft  Ambient  Water Quality Criteria Docu-
ment for Chlorinated Naphthalenes (U.S.  EPA,  1979).
     Chlorinated naphthalenes consist  of two fused  six  carbon-membered aro-
matic  rings  where  any or  all  of  the  eight hydrogen  atoms can  be  replaced
with chlorine.   The physical properties of the  chlorinated naphthalenes are
generally  dependent on  the  degree  of  chlorination.   Melting points  range
from   17°C  for  1-chloronaphthalene   to  198°D   for  1,2,3,4-tetrachloro-
naphthalene.  As the degree  of chlorination increases,  the specific  gravity,
boiling point,  fire and  flash  points all increase,  while  the vapor  pressure
and water  solubility decrease.   Chlorinated naphthalenes  have been  used  as
the paper  impregnant in automobile  capacitors  (mixtures  of  tri- and tetra-
chloronaphthalenes), and as  oil  additives for engine cleaning, and in fabric
dyeing  (mixtures of mono- and  dichloronaphthalenes).   In  1956, the  total
U.S. production of  chlorinated  naphthalenes was approximately 3,175 metric
tons (Hardie, 1964).
II.  EXPOSURE
     A.  Water
         To  date,  polychlorinated naphthalenes  have not  been identified  in
drinking waters (U.S.  EPA,  1979).   However, these compounds  have been found
in  waters  or  sediments  adjacent to point  sources  or  areas  of  heavy  poly-
chlorinated biphenyl contamination.
     8.  Food
         Polychlorinated naphthalenes appear to  be  biomagnified in the aqua-
tic  ecosystem,  with  the degree of  biomagnification  being greater  for the
more  highly  chlorinated polychlorinated  compounds  (Walsh,  et   al.  1977).

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Erickson, at al.  (1978)  also noted a higher relative biomagnification of the
lowest chlorinated naphthalenes  by  the  fruit of apple trees grown on contam-
inated soil.  The  U.S.  EPA (1979)  has estimated the weighted average bicccn-
centration  factor  for Halowax 1014 (a  mixture  of chlorinated.naphthalenes)
to  be 4,300  for  the  edible portions  of  fish  and  shellfish  consumed  by
Americans.  This  estimate is  based on measured non-steady-state bioconcen-
tration studies in brown shrimp.
     C.  Inhalation
         Erickson,  et al.  (1978)  found ambient -air  concentrations  of poly-
chlorinated  naphthalenes  ranging   from  0.025  to  2.90  /jg/m   near  a  poly-
chlorinated naphthalene plant.  Concentrations  of trichloronaphthalene were
as  high  as  0.95 ug/m ,  while  hexachloronaphthalene  concentrations  never
exceeded 0.007 jug/m  .
III. PHARMACOKINETICS
     A.  Absorption
         Pertinent data could  not be located in  the available literature.
     8.  Distribution
         In the  rat  fed 1,2-dichloronaphthalene, the chemical and its metab-
olites were found primarily in  the  intestine,  kidney,   and  adipose tissue
                                                                  4
(Chu, et al. 1977).
     C.  Metabolism
         There  appears  to  be appreciable  metabolism  in mammals  of  poly-
chlorinated naphthalenes  containing four  chlorine atoms or  less (U.S. EPA,
1979).  Cornish  and  Block (1958)  investigated  the excretion of polychlori-
nated  naphthalenes in  rabbits and  found  79 percent  of   1-chloronaphthalene,
93  percent  of dichloronaphthalene,  and 45 percent of tetrachloronaphthalene

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were excreted  in the urine as  metabolites .of the parent  compounds.   Metab-
olism may  involve  hydroxylation alone or  hydroxylation in  combination  with
dechlorination.  In  some cases, an  arene oxide  intermediate may  be formed
(Ruzo,  et al. 1976).
     D.  Excretion
         In  rats fed  1,2-dichloronaphthalene,  initially more of the chemical
and  its  metabolites  were found in  the urine; however,  by the end of seven
days a greater proportion had been excreted  in the  feces (Chu, et al. 1977).
In the  first 24  hours,  62 percent of  the  dose was  excreted  in  the bile,  as
compared to  18.9 percent lost in the  feces.   This suggests  that there is an
appreciable  reabsorption and  enterohepatic recirculation of  this .particular
chlorinated  naphthalene.
IV.  EFFECTS
     No  animal or  human studies have  been reported on the  carcinogenicity,
mutagenicity, or teratogenicity of chlorinated  naphthalenes.  No.other  re-
productive effects were found in the available literature.
     A.  Chronic Toxicity
         Chronic dermal  exposure  to penta- and  hexachlorinated naphthalenes
causes a form of chloracne which, if persistent, can progress to fprm a cyst
or sterile abcess  (Jones,. 1941; Shelley  and  Kligman,  1957;  Kleinfeld, et al.
1972).    Workers  exposed to these two  isomers complained of  eye irritation,
headaches,   fatigue,   vertigo,   nausea,, loss  of  appetite,   and  weight  loss
(Kleinfeld,  et al. 1972).   More severe exposure to the fumes of polychlori-
nated naphthalenes has produced severe liver  damage,  together with  damage to
the  heart, pancreas,  gall bladder, lungs,  adrenal glands,  and. kidney tubules
(Greenburg,  et al. 1939).   Chronic  toxicity in animals appears to.be quali-
tatively the same  (U.S.  EPA,  1979).  Polychlorinatsd  naphthalenes containing

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three or  fewer  chlorine atoms were found  to be nontoxic, while tetrachloro-
naphthalene resulted in mild  liver  disease at levels as  high  as 0.7 mg/kg/-
day;  the  higher  chlorinated  naphthalenes  produce more  severe  disease  at
lower doses  (Bell,  1953).  Because of their insolubility,  hepta- and octa-
chloronaphthalene were  less toxic when  given in suspension than  when given
in solution.
     8.  Other Relevant Information
         Drinker, et al.  (1937)  showed enhancement  of hepatoxicity of a mix-
ture of  ethanol/carbon  tetrachloride  in  rats pretreated with  1.16 mg/m  of
a penta-/hexachloronaphthalene  mixture in air  for  six weeks.   In a similar
study trichloronaphthalene was inactive.
V.   AQUATIC TOXICITY                                  , '• ^
     A.  Acute Toxicity
         The  96-hour   L^cn  value   reported  for   the   bluegill,  Lepomis
macrochirus,'exposed to 1-chioronaphthalene is 2,270 jug/1  (U.S.  EPA, 1578).
With  saltwater  species,  exposure  of  the  sheepshear"'--,minnow,  Cyorinodon
varigatus,  and  mysid shrimp, Mysidopsis  bahia. to  1-chloronaphthalene  pro-
vided  96-hour LC5Q  values . of  1,290  and 370  jug/1,  respectively.   Daphnia
maqna and the bluegill,  Lepomis macrochirus,  have a slight  sensitivity  to
octachloronaphthalene, '  with  respective  48-hour  and  96-hour  LCcn  values
                                                                   5U
greater than 530,000pg/l (U.S. EPA, 1978).
     8.  Chronic Toxicity
         In  the only  chronic  study   reported  (embryo-larval), exposure  of
1-chloronaphthalene  to  the  sheepshead minnow resulted in a  chronic value  of
329 ug/1  (U.S. EPA, 1978).

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     C.  Plant Effects
         A freshwater alga, Selenastrum caoricornutum,  and  a saltwater alga,
Skeletonema costatum, when exposed to 1-chloronaphthalene,  both  produced 96-
hour EC5Q values ranging from 1,000 to 1,300 ug/1 based on cell numbers.
         Octachloronaphthalene  exposure  to  Selenastrum  capricornutum  re-
sulted in  a  96-hour EC5Q  value  of over  500,000  ug/1 based on  cell numbers
(U.S. EPA, 1978).
     0.  Residues
         Pertinent data could not be located in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.  Human
         The  only  standards  for  polychlorinated  naphthalenes are  the ACGIH
Threshold  Limit  Values  (TLV) .adopted by  the Occupational  Safety  and Health
Administration and are as follow:
                                                       ACGIH (1977)
                                                  Threshold Limit Values
     Trichloronaphthalene                         5       .  mg/m^
     Tetrachloronaphthalene                       2         mg/m^
     Pentachloronaphthalene                       0.5       mg/m^
     Hexachloronaphthalene                        0.2       mg/m^
     Octachloronaphthalene                        0.1   .    mg/m^

There  are  no  state  or  federal water  quality or ambient air quality standards
for chlorinated naphthalenes.
         The  U.S.  EPA  is  presently  evaluating  the  available  data  and has
recommended that a  single  acceptable daily intake  (ADI)  of 70 ;jg/man/day be
used  for  the  tri-,  tetra-,  penta-,  hexa-, and octa-chlorinated naphthalenes.
This  ADI  will be used  to  derive the human health criteria for  the chlori-
nated  naphthalenes.

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     8.  Aquatic
         For  1-chloronsphthalene,  the draft criterion  to protect freshwater
aquatic life  is  29 pg/1 as a  24-hour average,  not to exceed  67  ^ug/1 at any
time.  For  saltwater aquatic  species, the draft  criteron is 2.8 jug/1  as a
24-hour average, not to exceed 6.4 pg/1 at any time (U.S. EPA, 1979).

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                   CHLORINATED NAPHTHALENE

                         REFERENCES

American Conference of Governmental Industrial Hygienists.
1977.  TLVs Threshold Limit Value for chemical substances  and
physical agents in the workroom environment with  intended
changes.  Cincinnati, Ohio.

Bell, W.S.  1953.  The relative toxicity of the chlorinated
naphthalenes in experimentally produced bovine hyperkeratosis
(X-disease).  Vet. Met.  48: 135.

Chu, I., et al.  1977.  Metabolism and tissue distribution of
(1,4,5,-^4C)-l, 2-dichloronaphthaline in rats.  Bull.
Environ. Contain. Toxicol.  18: 177.

Cornish, H.H., and W.D. Block.  1958.  Metabolism  of  chlori-
nated naphthalenes.  Jour. Biol. Chem.  231: 583.

Drinker, C.K., et al.  1937.  The problem of possible  sys-
temic effects from certain chlorinated hydrocarbons.   Jour.
Ind. Hyg. Toxicol.  19: 283.

Erickson, M.D., et al.  1978.  Sampling and analysis  for
polychlorinated naphthalenes in the environment.   Jour.
Assoc. Off. Anal. Chem.  61: 1335.

Greenburg,  L., et al.  1939.  The systemic effects  resulting
from exposure to certain chlorinated hydrocarbons.  Jour.
Ind. Hyg. Toxicol.  21: 29.

Hardie, D.W.F.  1964.  Chlorocarbons and chlorohydrocarbons:
Chlorinated Naphthalenes.  pp. 297-303 In; Kirk-Othmer, En-
cyclo. of Chemical Technology.  2nd ed.  John Wiley and Sons,
Inc., New York.

Jones, A.T.  1941.  The etiology of acne with special ^refer-
ence to acne of occupational origin.  Jour. Ind. Hyg.  Toxi-
col.  23: 290.

Kleinfeld,  M. , et al.  1972.  Clinical effects of  chlorinated
naphthalene exposure.  Jour. Occup. Med.  14: 377.

Ruzo, L., et al.  1976.  Metabolism of chlorinated  naphtha-
lenes.  Jour. Agric.  Food Chem.  24: 581.

Shelley, W.B., and A.M. Kligman.  1957.  The experimental
production  of acne by penta- and hexa'chloronaphthalenes.
A.M.A. Arch. Derm.  75: 689.

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U.S. EPA.  1978.  In-depth studies  on  health  and  environmen-
tal impacts of selected water pollutants.   Contract No.   68-
01-4646.  U.S. Environ. Prot. Agency,  Washington,  D.C.

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

Walsh, G.E., et al.   1977.   Effects and  uptake  of  chlorinated
naphthalenes in marine unicellular  algae.   Bull.  Environ.
Contain. Toxicol.  18: 297.

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                                      No. 39
        Chlorinated Phenols


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

           APRIL 30, 1980

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

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                               SPECIAL NOTATION
    . The National Cancer Institute  (1979)  has  recently published the results
of  a  bioassay indicating  that  2,4,6-trichlorophenol induced  cancer in rats
and mice.  This study was  not included  in  the  Ambient .Water Quality Criteria
Document (U.S. EPA,  1979) and has not been reviewed for this hazard profile.

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                              CHLORINATED PHENOLS
                                    SUMMARY

     Mammalian data  supporting chronic  effects for most  of these compounds
is limited.  Insufficient data exist  to  indicate that any of the chlorinated
phenols  are  carcinogens.   In  skin   painting  studies,   3-chlorophenol  and
2,4,5-trichlorophenol  promoted  papillomas.   A  lifetime  feeding  study  with
2,4,6-trichlorophenol  was inconclusive  and  only provided  weak  suspicion of
carcinogenicity.    2,4,6-Trichlorophenol  gave  some  evidence  of  mutagenicity
in two  assays.   Tetrachlorophenol was not found to be fetotoxic in animals.
Chronic  exposure to  4-chlorophenol produced  myoneural disorders  in  humans
and animals.   Adverse health effects  in workers exposed to 2,4,5-trichloro-
phenol  may  have  been  due to  2,3,7,8-tetrachlorodibenzo-p-dioxin  contamina-
tion of the chlorophenol.
     Workers  chronically  exposed  to tetrachlorophenol,  pentachlorcphenol,
and small amounts of  chlorodibenzodioxins developed .severe skin irritations,
respiratory  difficulties, and  headaches.   Chlorophenols  are uncouplers  of
oxidative phosphorylation.   2,6-Oichlorophenol and trichlorocresol  are  con-
vulsants.   Chlorocresol  has  caused several  cases  of  local  and generalized
                                                                     4
reactions.
     In  acute  toxicity tests, 4-chloro-3-methylphenol  has  been  proven toxic
at concentrations as low  as  30 ug/1 in freshwater fish, whereas other fresh-
water  and  marine  organisms  appear to be more resistant.  The tainting  of
rainbow trout flesh has  been demonstrated at exposures of 15 to 84 ug/1 for
several of the chlorinated phenols.

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I.   INTRODUCTION
     This profile  is based  on  the Ambient  Water Quality  Criteria Document
for Chlorinated Phenols (U.S. EPA, 1979).
     The chlorinated phenols  represent  a group  of commercially produced sub-
stituted phenols and cresols  also  referred  to as chlorophenols or chlorocre-
sols.  The compounds  2-chlorophenol,  2,4-dichlorophenol,  2,4,6-trichlorophe-
nol, and pentachlorophenol are discussed in separate hazard profiles.
     Purified  chlorinated  phenols  are  colorless,  crystalline  solids  (with
the  exception of  2-chlorophenol  which is  a  liquid),  while  the  technical
grades may be light tan or  slightly  pink due  to impurities.  Chlorophenols
have pungent  odors.   In general,  the  volatility of chlorinated  phenols  de-
creases and the melting and  boiling points  increase  as the number of substi-
tuted chlorine atoms increases.  Although the solubility  of chlorinated phe-
nols in aqueous  solutions  is relatively low, it  increases  markedly when the
pH  of  the  solution exceeds  the  specific pKa.   The  solubilities of chlori-
nated  phenols and  chlorocresols  (with  the  exception of  2,4,6-trichloro-m-
cresol) range  from  soluble  to very soluble in  relatively  non-polar solvents
such as benzene and petroleum ether (U.S. EPA,  1979).
     The chlorinated  phenols that are  most  important  commercially *are  4-
chlorophenol,    2,4-dichlorophenol,   2,4,5-trichlorophenol,   2,3,4,6-tetra-
chlorophenol,  pentachlorophenol,  and 4-chloro-o-cresol.  Many  of  the chloro-
phenols have  no  commercial  application but are  produced  to  some  extent  as
byproducts of  the commercially important compounds.   The highly  toxic  poly-
chlorinated dibenzo-p-dioxins may  be formed during the chemical synthesis  of
some chlorophenols.  During  the  chlorination of  drinking  waters and waste-
water .effluents,  chlorophenols  may  be  inadvertently produced  (U.S.  EPA,
1979).

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     Chlorinated phenols are used  as  intermediates in the synthesis of dyes,
pigments, phenolic  resins, pesticides,  and herbicides.   Certain chlorophe-
nols are  used directly  as flea repellants,  fungicides,  wood preservatives,
mold  inhibitors,  antiseptics,   disinfectants,   and   antigumming  agents  for
gasoline.
     It is generally  accepted  that chlorinated phenols will undergo photoly-
sis  in  aqueous solutions  as  a  result of  ultraviolet irradiation  and that
photodegradation  leads  to the  substitution of  hydroxyl  groups  in  place of
the  chlorine  atoms  with subsequent polymerization (U.S.  EPA,  1979).  Micro-
bial degradation  of  chlorophenols has been reported by  numerous investiga-
tors (U.S. EPA, 1979).

                       3-CHLOROPHENOL  and 4-CHLORQPHENuL
II.  EXPOSURE
     Monochlorophenols  have been  found in  surface waters in the Netherlands
at concentrations of 2  to 20  pg/1 (Piet  and  DeGrunt, 1975).   Ingestion of
chlorobenzene can give  rise to  internal  exposure to  2-, 3-, and  4-chlorophe-
nols, as  chlorobenzene  is metabolized to  monochlorophenols (Lindsay-Smith,
et al.  1972).   No data were found demonstrating the presence of monochloro-
phenol in food.
     For 4-chlorophenol  the U.S. EPA  has estimated the weighted average bio-
concentration  factor  for  the edible  portions  of all  aquatic  organisms con-
sumed by  Americans  to  be 12.    This  estimate  is based on the octanol/water
partition coefficient.
     Data were  not   found  in  the  available literature  regarding inhalation
exposure.

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III. PHARMACOKINETICS
     Systematic studies  of the pharmacokinetics of  3-  or 4-chlorophenol are
not available.  Dogs  excreted 87  percent  of administered  4-chlorophenol  in
the urine as sulfuric and glucuronic conjugates (Karpow, 1893).
IV.  EFFECTS
     A.  Carcinogenicity
         Information is  not adequate  to  determine  whether 3- or 4-chlorophe-
nol possess carcinogenic properties.   A  20 percent  solution  of 3-chlorophe-
nol promoted  papillomas when repeatedly applied  to the  backs  of mice after
initiation with dimethylbenzanthrene (Boutwell and Bosch, 1959).
     B.  Mutagenicity,  Teratogenicity and Other Reproductive Effects
         Pertinent data  cannot be  located  in  the  available  literature  re-
garding mutagenicity, teratogenicity and  other reproductive effects.
     C.  Chronic Toxicity
         Rats  exposed  6 hrs/day  for  four months  to 2  mg  4-chlorophenol/m
showed a  temporary  weight loss and  increased myoneural  excitability.   Body
temperature and  hematological parameters  were not  altered  (Gurova,  1964).
In a  survey comparing  the health of workers,  4-chlorophenol  .exposed workers
had a significantly  higher incidence  of neurological disorders  compared to
unexposed workers in  the same plant.  Peripheral  nerve  stimulation studies
showed  increased  myoneural  excitability in  exposed workers.   The minimum
detection distance  in  a  two-point touch discrimination test  was  increased
(Gurova,  1964).
     0.  Other Relevant Information
         3- and 4-Chlorophenol are weak  uncouplers  of oxidative phosphoryla-
tion (Mitsuda, et  al.  1963; Weinback and  Garbus, 1965).
                                    -I-I7O-

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                    2.5-DICHLOROPHENOL.  2,6-OICHLOROPHENOL.
                3.4-OICHLOROPHENOL, and 3.5-OICHLOROPHENQL
II.  EXPOSURE
     Unspecified dichiorophenol  isomers have been detected in concentrations
of 0.01  to  1.5 pg/1 in Dutch  surface waters (Piet and  OeGrunt,  1975).  Oi-
chlorophenols  have  been found in flue  gas  condensates from municipal  incin-
erators  (Olie,  et  al.  1977).  No data  on  exposure from  foods  or the  dermal
route  were  found.   Exposure to  other  chemicals  can result in  exposure to
dichlorophenols  (i.e.,  dichlorobenzenes,  lindane, and  the alpha  and delta
isomers  of  1,2,3,4,5,6-hexachlorocyclohexane  are  metabolized by  mammals to
dichlorophenols) (Kohli, et al. 1976; Foster and Saha, 1978).
III. PHARMACOKINETICS
     Pharmacokinetic data  specific  to these dichiorophenol isomers could not
be located in  the available literature.
IV.  EFFECTS
     A.  Carcincgenicity
         Pertinent data cannot be located in the available literature.
     B.  Mutagenicity                 •
         2,3-,  2,4-, 2,5-, 2,6-,  3,4-,  and  3,5-Oichlorophenols  were found to
be  non-mutagenic  in  the   Ames  test  with  or  without microsomal  activation
(Rasaner and Hattula, 1977).
     C.  Teratogenicity, Other Reproductive Effects and Chronic Toxicity
         Pertinent data cannot be  located  in  the available literature  re-
garding teratogenicity,  other reproductive effects and chronic toxicity.
     D.  Other Relevant Information
         2,6-Oichlorophenol is a convulsant (Farquharson, et al.  1958). '
                                      i
                                    -H7/-

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                               TRICHLQROPHENOLS
II.  EXPOSURE
     Trichlorophenols  have been  detected  in  surface  waters in  Holland at
concentrations  ranging from  0.003  to  0.1  jjg/1 (Piet  and  DeGrunt,  1975).
2,4,5-Trichlorophenol can  be  formed  from  the chlorination of phenol in water
(Burttschell, et al. 1959).
     One  possible  source  of  trichlorophenol exposure for  humans  is through
the  food chain, as a  result of  the  ingestion  by grazing  animals  of  the
chlorophenoxy  acid  herbicides 2,4,5-T   (2,4,5-trichlorophenbxyacetic  acid)
and  silvex  (2-(2,4,5-trichlorophenoxy)-propionic  acid).   Residues  of   the
herbicides  on -sprayed  forage  are estimated to  be 100-300 ppm.   Studies in
which cattle and sheep were fed  these herbicides at  300, 1000 and  2000  ppm
(Clark, et  al.  1976)  showed  the presence  of 2,4,5-trichlorophenol in various
tissues.  In lactating cows fed 2,4,5-T at  100 ppm, an occasional residue of
0.06. ppm or less  of  trichlorophenol was detected in  milk  (Bjerke,  et  al.
1972).
     Exposure  to  other chemicals  such   as  trichlorobenzenes, lindane,   the
alpha  and  delta   isomers  of  1,2,3,4,5,6-hexachlorocyclohexane,   isomers  of
benzene  hexachloride,  and the insecticide  Ronnel can result  in  exposure to
trichlorophenols via metabolic degradation  of  the parent compound (tl.S.  EPA,
1979).
     The U.S. EPA  (1979)  has  estimated  the  weighted average bioconcentration
factors for the edible  portions of all aquatic  organisms  consumed by Ameri-
cans  to  be  130 for 2,4,5-trichlorophenol and  110 for 2,4,6-trichlorophenol.
These estimates  are based  on the  octanol/water partition coefficients  for
these chemicals.
                                    -473,-

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     Trichlorophenols are  found in  flue gas condensates  from municipal in-
cinerators  (Olie,  et al. 1977).   2,4,5-Trichlorophenol was  detected  in 1.7
percent of urine samples collected from the general population (Kutz, et al.
1978).
III. PHARMACOKINETICS
     A.  Absorption and Distribution
         Information  dealing with  tissue distribution  after administration
of trichlorophenols  could not be  located in the available literature.  Feed-
ing of 2,4,5-T and  silvex to sheep and cattle produced high  levels of 2,4,5-
trichlorophenol in liver and kidney  and low levels in muscle and fat (Clark,
et al. 1976). •
     B.  Metabolism
         Pertinent data could not be located in the available literature.
     C.  Excretion
         In  rats,  82 percent of an  administered  dose (1 ppm in the diet for
3 days) of  2,4,6-t-richlorophenol  was eliminated in the  urine and 22 percent
in the feces.  Radiolabelled trichlorophenol  was  not  detected in liver, lung
or 'fat obtained  5 days  after  the  last  dose  (Korte,  et al.-  1978).   The ap-
proximate blood  half-life  for 2,4,5-trichlorophenol  is  20 hours,  after dos-
ing of  sheep with  Erbon (an  herbicide which  is metabolized  to 2*,4,5-tri-
chlorophenol) (Wright, et al. 1970).
IV.  EFFECTS
     A.  Carcinogenicity
         A  21 percent solution of  2,4,5-trichlorophenol  in acetone promoted
papillomas but not  carcinomas  in  mice  after  initiation  with dimethylbenzan-
                                     -1-173-

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threne (Boutwell and  Bosch,  1959).  2,4,6-Trichlorophenol  showed no promot-
ing activity.
         Results from a  study  of mice  receiving 2,4,6-trichlorophenol in the
diet  throughout  their lifespans  (18 months)  were inconclusive.   The inci-
dence of  tumors, while  higher than  that  for compounds classified as noncar-
cinogens, was not significantly increased (Innes, et al. 1969).
     8.  Mutagenicity
         2,4,6-Trichlorophenol  (400  mg)  increased the  mutation rate but not
the rate of  intragenic recombination in  a strain of Saccharomyces cerevisiae
(Fahrig, et  al.  1978).   Two of the  340  offspring from mice injected with 50
mg/kg  of  2,4,6-trichlorophenol  during  gestation  were  reported  to  have
changes in hair  coat  color  (spots) of  genetic significance.  At  100 mg/kg, 1
out of  175  offspring  had a spot  (U.S.  EPA, 1979).  2,3,5-,  2,3,6-, 2,4,5-,
and  2,4,6-Trichlorophenol  were  found  to be nonmutagenic  in the  Ames  test
with and without microsomal activation (Rasanen and Hattula, 1977).
     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
         When  rats  were  fed  2,4,5-trichlorophenol  (99 percent  pure)  for 98
days  (McCollister,  et al.  1961),  levels  of 1000 mg trichlorophenol/kg  feed
(assumed  to  be  equivalent  to  100 mg/kg body  weight)  or  less  produced  no
adverse effects  as'judged  by  behavior, mortality, food consumption, growth,
terminal hematology, body.and .organ  weights,  and  gross or microscopic-patho-
logy.  At 10,000 mg/kg diet (1000 mg/kg  body  weight),  growth was  slowed  in
females.  Histopathologic  changes  were   noted  in liver  and kidney.   There

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were no  hematologic changes.   At 3000  mg/kg feed  (300  mg/kg body weight),


milder histopathologic  changes  in liver and  kidney  were  observed.  The his-


topathologic changes were considered to be reversible.


         Adverse health effects  including  chloracne, hyperpigmentation, hir-


sutism and  elevated uroporphyrins were  described in 29  workers involved in


the manufacture of  2,4-0  and  2,4,5-T (Bleiberg, et  al. 1964).  It is  likely


that  some  of  these  symptoms  represent 2,3,7,8-tetrachlorodibenzo-p-dioxin


toxicosis (U.S. EPA, 1979).


     E.  Other Relevant Information


         Trichlorophenols are uncouplers of oxidative phosphorylation  (Wein-


back and Garbus, 1965; Mitsuda, et al. 1963).





                               TETRACHLOROPHENOL


II.  EXPOSURE


     There  are three  isomers  of tetrachlorophenol:  -2,3,4,5-, 2,3,5,6-, and,


most  importantly,   2,3,4,6-tetrachlorophenol.   Commercial  pentachlorophenol


contains  three to  10  percent  tetrachlorophenol  (Goldstein,  et  al.  1977;


Schwetz,  et al.  1978).   Commercial  tetrachlorophenol  contains  pentachloro-


phenol (27  percent) and toxic nonphenolic impurities such as chlorodibenzo-
                                                                    4

furans and  chlorodioxin isomers  (Schwetz, et al.  1974).    There are reports


suggesting  the  presence of lower chlorophenols in  drinking  water,  but  the


presence,  of tetrachlorophenol  has  not  been  documented   (U.S.  EPA,  1979).


Exposure to other chemicals such as tetrachlorobenzenes  can  result in expo-


sure to tetrachlorophenols via degradation of the  parent  compound (Kohli,  et


al. 1976).
                                                                        »

     Data could not be  located  in the  available literature on ingestion from


foods.   The U.S.  EPA (1979)  has  estimated, a weighted  average bioconcentra-
                                     -W7S--

-------
tion factor  for 2,3,4,6-tetrachlorophenol of  320  for the  edible portion  of
aquatic  organisms consumed  by Americans.   This  estimate is  based  on the
octanol/water partition coefficient of 2,3,4,5-tetrachlorophenol.
     Tetrachlorophenols- have been  found  in  flue  gas condensates  from munici-
pal incinerators  (Olie, et al. 1977).
II.  PHARMACOKINETICS
     A.  Absorption and Distribution
         Pertinent  data  could  not  be  located  in the  available literature
regarding absorption and distribution.
     B.  Metabolism and Excretion
         In  rats,  over 98 percent of an  intraperitoneally administered dose
of  2,3,5,6-tetrachlorophenol was  recovered  in the urine  in 24 hours.  About
66  percent  was excreted as  the' unchanged compound and  35 percent as tetra-
chloro-p-hydroquinone.   About  94  percent  of the .intraperitoneal   dose   of
2,3,4,6-tetrachlorophenol was  recovered  in  the urine  in  24 hours, primarily
as  the unchanged  compound  with  trace  amounts of trichloro-p-hydroquinone.
Fifty-one percent of  the  intraperitoneal dose of 2,3,4,5-tetrachlorophenol'
was recovered in the urine in 24 hours,  followed by an additional seven per-
cent in  the  second 24 hours, primarily as  the unchanged compound with trace
                                                                     *
amounts  of  trichloro-p-hydroquinone.  In  these  experiments,  the urine was
boiled to split any conjugates (Alhborg and  Larsson, 1978).
IV.  EFFECTS
     A.  Carcinogenicity
         Pertinent data could not be located in the available literature.
     B.  Mutagenicity
         2,3,4,6-Tetrachlorophenol was  reported  to  be  nonmutagenic  in the
Ames test,  both  with and  without  microsomal activation  (Rasanen,  et  al.
1977).
                                    -476-

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     C.  Teratogenicity
         Tetrachlorophenol  did  not induce  teratogenic  effects  in  rats at
doses  of  10 or  30 mg/kg administered  on days  six through  15 of gestation
(Schwetz, et al. 1974).
     0.  Other Reproductive Effects
         Tetrachlorophenol  produced  fetotoxic  effects  (subcutaneous  edema
and delayed ossification of skull bones)  in  rats at doses of 10 and 30 mg/kg
administered on days six through 15 of gestation  (Schwetz, et al. 1974).
     E.  Chronic Toxicity
         Workers exposed  to wood dust  containing 100-800 ppm  2,3,4,6-tetra-
chlorophenol,  30-40 ppm  pentachlorophenol,  10-50  ppm chlorophenoxyphenols,
1-10  ppm  chlorodibenzofurans  and  less  than  0.5 ppm chlorodibenzo-p-dioxins
developed  severe skin  irritations, respiratory, difficulties  and  headaches
(Levin, et al. 1976).
         No toxicity  studies of 90 days  or longer  were  found  in the avail-
able literature.
     F.  Other Relevant Information
         2,3,4,6-Tetrachlorophenol  is a strong uncoupler  of oxidative phos-
phorylation (Mitsuda, et al. 1963; Weinback and Garbus, 1965).

                                 CHLOROCRESOLS
II.  EXPOSURE
     There are no  published  data available for  the  determination of current
human  exposure  to  chlorocresols  (U.S.  EPA,   1979).   p-Chloro-m-cresol  (4-
chloro-3-methylphenol)  has  been  detected  in chlorinated sewage  treatment
effluent (Jolley,  et  al.  1975).  Another potential source  of  chlorocresols
is the herbicide MCPA  (4-chloro-2-methylphenoxyacetate),  which  (in  its tech-

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nical grade)  is contaminated  with four  percent  4-chloro-o-cresol  (Rasanen,
et  al.  1977)  and which  can  be degraded  to  5-chloro-o-cresol  (Gaunt  and
Evans, 1971).
III. PHARMACOKINETICS
     A.  Absorption
         Chlorocresol (unspecified  isomer)  permeated human autopsy  skin more
readily than  either  2- or  4-chlorophenol,  but less  readily  than 2,4,6-tri-
chlorophenol (Roberts, et al. 1977).
     B.  Distribution and Metabolism
         Pertinent data could not be located in the available literature.
     C.  Excretion
         Fifteen  to  20 percent  of a subcutaneous  dose  of p-chloro-m-cresol
given to  a  rabbit was recovered in  the  urine.   The  same  compound given in-
tramuscularly was not recovered  in  the  urine  to any appreciable extent (Zon-
dek and Shapiro, 1943).
IV.  EFFECTS
     A.  Carcinogenicity
         Pertinent information could not  be located in the available litera-
ture.
     B.  Mutagenicity                                              *
         3-Chloro-o-cresol, 4-chloro-o-cresol and  5-chloro-o-cresol  were re-
ported to be nonmutagenic  in  the Ames  test, with  and without microsomal.ac-
tivation (Rasanen, et al.  1977).
     C. • Teratogenicity and Other Reproductive Effects
         Pertinent data  could not be  located in the  available  literature
regarding tertogenicity and other reproductive effects.

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     0.  Chronic Toxicity
         No information on  chronic  toxicity in humans or toxicity  studies  of
90  days or  longer in  experimental animals  were  presented in  the Ambient
Water  Quality  Criteria Document  (U.S. EPA,  1979).  p-Chloro-m-cresol  given
subcutaneously  to  young rats  for  14  days  (80 mg/kg/day)  produced mild in-
flammation  at  the  injection  site but  did  not affect growth  or produce le-
sions  in  kidney,  liver, or spleen (Wien,  1939).   Rabbits   (weighing 1.5-2.3
kg)  injected  subcutaneously with  12.5 mg  p-chloro-m-cresol/day suffered  no
obvious ill  effects (Wien,  1939).  Liver and kidney were normal histologic-
ally.
     E.  Other Relevant Information
         Chlorocresol,  a  preservative  in heparin  solutions,  caused several
cases  of  generalized and local  reactions (Hancock  and  Naysmith,  1975; Ain-
ley, et al. 1977).  Systemic  reactions included collapse,   pallor,  sweating,
hypotension, tachycardia  and  rashes.   Trichlorocresol is  also  a  convulsant
(Eichholz and Wigand, 1931).
                            .  CHLORINATED PHENOLS
I.   AQUATIC TOXICITY
     A.  Acute Toxicity
         The acute toxicity  of eight  chlorophenols was determined in nine
bioassays.   Acute  96-hour  LC5Q values  for  freshwater  fish ranged  from   30
jug/1 for  the  fathead minnow,   Pimephales  promelas,  for 4-chloro-3-methylphe-
nol  (U.S.  EPA, 1972)  to 9,040 ,ug/l  for the fathead minnow  for  2,4,6-tri-
chlorophenol  (Phipps,  et  al.   manuscript).   Among  the   freshwater inverte-
brates, Daohnia maqna  was  assayed with seven chlorophenols in eight 48-hour
static  bioassays.    Acute   LC5Q  values  ranged  from  290 ug/1  for 2,3,4,6-
tetrachlorophenol  and  4-chloro-2-methylphenol to  6,040  ug/1  for   2,4,6-tri-

-------
chlorophenol  (U.S.  EPA,  1978).   Acute 96-hour  static  LC50 values  in  the
sheepshead minnow  ranged  from 1,660 pg/1  for  2,4,5-trichlorophenol to  5,350
pg/1  for  4-chlorophenol.   The  only  marine   invertebrate  species  acutely
tested  has been  the  mysid  shrimp,  Mysidopsis  bahia  ,  with  acute  96-hour
static  LC5Q  values  reported  by  the  U.S.  EPA   (1978)  as:  3,830 ug/1  for
2,4,5-trichlorophenol; 21,900 ug/1 for 2,3,5,6-tetrachlorophenol,  and  29,700
pg/1  for 4-chlorophenol.
      8.  Chronic Toxicity
         No  data  other than  that presented  in  the  specific hazard  profile
for 2^chlorophenol, 2,4-dichloropnenol,  and pentachlorophenol were available
for  freshwater, organisms.  An embryo-larval study provided  a chronic  value
of  180 ,ug/r  for sheepshead minnows -t Cyprinodon  varieqatus j  exposed to  2,4-
dichloro-6-methylphenol (U.S.  EPA, 1978).
      C.  Effects on Plants
         Effective concentrations for 15 tests on four species of  freshwater
plants  ranged from  chlorosis LC5Q  of 603 pg/1  for 2,3,4,6-tetrachlorophe-
nol- to  598,584 /ug/1  for  2-chlofo-6-methylphenol in the duckweed, Lemna  minor
(Blackman,  et al.  1955).   The marine algae,  Skeletonema costatum7 has  been
used  to  assess the  relative toxicities of three  chlorinated  phenols.   Effec-
tive  concentrations,  based  on chlorophyll a content  and cell growth,  of 440
and 500  fjg/l were obtained for 2,3,5,6-tetrachlorophenol.   2,4,5-Trichloro-
phenol  and 4-chlorophenol  were  roughly two  and  seven  times as potent,  re-
spectively, as 2,3,5,6-tetrachlorophenol.
      0.  Residues
         Steady-state  bioconcentration factors have  not been calculated  for
the chlorinated phenols.   However, based  upon  octanol/water  partition  coef-.
ficients,  the  following  bioconcentration  factors have  been  estimated  for

-------
aquatic organisms  with a lipid  content of eight  percent:   41 for 4-chloro-
phenol; 440  for 2,4,5-trichlorophenol;  380  for 2,4,6-trichlorophenol;  1,100
for 2,3,4,6-tetrachlorophenol; and 470  for 4-chloro-3-methylphenol.
     E.  Miscellaneous
         The  tainting of  fish  flesh  by  exposure  of rainbow  trout;  .Salmo
qairdneri) to  various chlorinated phenols  has derived a  range of estimated
concentrations  not  impairing  the  flavor of  cooked  fish  from 15  yg/1  for
2-chlorophenol  to  84 ug/1  for 2,3-dichlorophenol (Schulze,  1961; Shumway  and
Palensky, 1973).
II.  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.  Draft criteria  recommended for chlorinated phenols by the U.S.  EPA
(1979) are given in  the following table:
                      Draft Ambient Water Quality Criteria
Compound
Criterion from
 Organoleptic
   Effects
Criterion from
Toxicological
    Data
Monochlorophenols
    3-chlorophenol
    4-chlorophenol
Dichlorophenols
    2,5-dichlorophenol
    2,6-diehlorophenol
Trichlorophenols
    2,4,5-trichlorophenol
    2,4,6-trichlorophenol
Tetrachloroohenol*
    2,3,4,6-tetrachlorophenol
   50 jug/1
   30 ug/1
   3.0 ug/1
   3.0 ug/1
   10 jug/1
   100 jjg/1
   915 jug/1
  none
  none
  none
  none
  1600 pg/1
  263 jjg/1

-------
Chlorocre_sol
    Insufficient data on which
      to base a criterion  .
*Tne criterion will be based on toxicological effects (U.S. EPA, 1979).
     8.  Aquatic
         The proposed  draft criterion for 2,4,6-trichlorophenol  is 52 pg/1,
not to exceed  150 /jg/1 in  freshwater environments.   No additional criterion
for other chlorinated  phenols can  presently  be  derived  for either freshwater
or marine organisms because of insufficient data (U.S. EPA, 1979).

-------
                              CHLORINATED PHENOLS

                                  REFERENCES


Ahlborg,  U.G.  and  K.  Larsson.   1978.   Metabolism of  tetrachlorophenols in
the rat.  Arch. Toxicol.  40: 63.

Ainley,  E.J.,   et  al.   1977.   Adverse  reaction  to  chlorocresol-preserved
heparin.  Lancet  1803: 705.

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

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

Bleiberg, J., -et  al.   1964.  Industrially  acquired porphyria.   Arch. Derma-
tol.  89: 793.

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

Burttschell,  R.H.,  et  al.   1959.   Chlorine  derivatives  of  phenol causing
taste and odor.  Jour. Am. Water Works Assoc.  51:  205.

Clark,  O.E.,  et al.   1976.   Residues  of chlorophenoxy acid  herbicides and
their  phenolic metabolites  in tissues  of sheep  and  cattle.   Jour.  Agric.
Food Chem.  23: 573.

Eichholz, F.  and R.  Wigand.  1931.  Uber die  wirkung  von darmdesinfektion
smilleln.  Eingegangen.  159: 81.

Fahrig, R. et  al.   1978.   Genetic activity of chlorophenols and chlorophenol
impurities.  Pages  325-338   In:  Pentachlorophenol: Chemistry,  pharmacology
and environmental toxicology.  K. Rango Rao, Plenum Press,  New York/

Farquharson, M.E.,  et  al.   1958.  The  biological action  of chlorophenols.
8r. Jour. Pharmacol.  13: 20.

Foster, T.S. and  J.G. Saha.   1978.   The in vitro metabolism .of lindane by an
enzyme preparation from chicken liver.  Jour. Environ.  Sci. Health  13: 25.

Gaunt,  J.K.  and W.C.  Evans.  1971.  Metabolism of 4-chlor-2-methylphenoxy-
acetate by a soil pseudomonad.  Biochem. Jour.  122: 519.

Goldstein,  J.A.,  et  al.   1977.   Effects of  pentachlorophenol on  hepatic
drug-metabolizing enzymes and  porphyria  related  to contamination with chlor-
inated dibenzo-p-dioxins and dibenzofurans.  Biochem.  Pharmacol.  26: 1549.

Gurova, A.I.   1964.   Hygienic characteristics of p-chlorophenol in  the ani-
line dye industry.  Hyg. Sanita.  29: 46.

-------
Hancock,  8.W.  and  A.  Naysmith.    1975.   Hypersensitivity  of  chlorocresol
preserved heparin.  Br. Med. Jour. 746.

Innes,  J.R.M., et al.  1969.   Bioassay  of pesticides  and  industrial chemi-
cals  for tumorigenicity  in mice:  A preliminary  note.  Jour.  Natl. Cancer
Inst.  42: 1101.

Jolley,  R.L.,  et  al.   1975.   Analysis  of  soluble  organic  constituents  in
natural  and  process  waters by high-pressure  liquid  chromatography.  Trace
Subs. Environ. Hlth.  9: 247.

Karpow,  G.   1893.  On  the antiseptic action  of three isomer chlorophenols
and of their salicylate esters  and  their  fate  in the metabolism.  Arch.  Sci.
Bid. St. Petersburg.  2: 304.  Cited by W.F.  von Oettingen, 1949.

Kohli, J., et  al.   1976.   The metabolism of higher  chlorinated benzene  iso-
mers.  Can. Jour. Biochem.  54: 203.

Korte,  I.,  et al.   1976.   Studies  on  the influences  of  some environmental
chemicals and  their  metabolites on the content  of  free adenine nucleotides,
intermediates  of glycolysis  and  on the  activities of  certain  enzymes  of
bovine lenses in vitro.  Chemosphere  5: 131.

Kutz,  F.W.,  et  al.   1978.  Survey  of  pesticide residues and their metabo-
lites in urine from the general population.  Pages  363-369  In: K.  Rango  Rao,
ed.   Pentachlorophenol: Chemistry,  pharmacology  and  environmental toxico-
logy, Plenum Press, New York.

Levin,  J.O., et  al.   1976.  Use of  chlorophenols  as fungicides in sawmills.
Scand. Jour. Work Environ. Health  2: 71.

Lindsay-Smith, Jr.,  et al.   1972.  Mechanisms  of  mammalian  hydroxylation:
Some novel metabolites of chlorobenzenes.  Xenobiotica  2: 215.

McCollister,  D.D.,   et al.   1961.   Toxicologic  information  on  2,4,5-tri-
chlorophenol.  Toxicol. Appl. Pharmacol.   3:  63.

Mitsuda, H.,  et  al.   1963.  Effect  of chlorophenol analogues on  tfte oxida-
tive phosphorylation in rat liver mitochondria.  Agric. Biol. Chem.  27:  366.

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

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

Piet, G.J.  and F. OeGrunt.  1975.   Organic  chloro  compounds  in surface and
drinking water of  the  Netherlands.   Pages 81-92 In: Problems raised  by the
contamination  of man  and  his environment.  Comm.  Eur. Communities,  Luxem-
bourg.

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

-------
Rasanen, L.,  et al.  1977.   The mutagenicity of  MCPA and  its  soil metabo-
lites,  chlorinated phenols,  catechols  and some  widely used  slimicides in
Finland.  Bull. Environ. Contam. Toxicol.   18: 565.

Roberts, M.S.,  et  al.   1977.   Permeability  of  human  epidermis  to phenolic
compounds.   Jour. Pharm. Pharmac.  29: 677.

Schulze, E.   1961.  The  effect of  phenol-containing  waste on  the taste of
fish.  Int. Revue Ges. Hydrobiol. 46, No. 1, p. 81.

Schwetz, 3.A.,  et  al.   1974.   Effect of purified and commercial grade tetra-
chlorophenol on  rat embryonal  and  fetal development.  Toxicol. Appl. Pharma-
col.  28: 146.

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

U.S. EPA.   1972.   The effect of chlorination  on selected organic chemicals.
Water Pollut. Control Res. Ser. 12020.

U.S.  EPA.   1978.   In-depth  studies on  health and  environmental  impacts on
selected *""•) pollutants.  Contract No. 68-01-4646.

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

Weinbach, E.C.  and J.  Garbus.  1965.  The  interaction of uncoupling phenols
with  mitochondria  and  with   mitochondrial   protein.    Jour.   Biol.   Chem.
210: 1811.
            •^
Wien, R.   1^39.  The toxicity  of parachlorometacresol  and of phenylmercuric
nitrate.  Quarterly Jour, and Yearbook of Pharmacy.  12: 212.
              /
Wright,  F.C.-,J et  al.   1970.   Metabolic and  residue studies  with 2-(2,4,5-
trichlorcphenoxy)-ethyl  2,2-dichloropropionate.    Jour.  Agric.  Food  Chem.
18: 845.                                                             »

Zondek,  8.  and 8.  Shapiro.   1943.   Fate  of  halogenated phenols  in  the  or-
ganism.  Biochem. Jour.   37: 592.

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                                      No. 40
         Chloroacetaldehyde
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

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                               CHLOROACETALDEHYDE



                                     Summary



     No carcinogenic effects v/ere observed in female ICR Ha Swiss mice follow-



ing administration of chloroacetaldehyde via dermal  application or subcutaneous



injection.   Mutagenic effects,  varying from weak to  strong, have been reported



in the yeasts Schizosaccharomyces pombe and Saccharomyces cerivisiae and in



certain Salmonella bacterial tester strains.   There  is  no evidence in the



available literature to indicate that chloroacetaldehyde produces teratogenic



effects.   Occupational exposure studies have shown chloroacetaldehyde to be a



severe irritant of the eyes, mucous membranes and skin.



     Data concerning the effects.of chloroacetaldehyde  on aquatic organisms



were not found in the available literature.

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                               CHLOROACETALDEHYDE



    INTRODUCTION



     Chloroacetaldehyde (C^rUClO) is a clear, colorless liquid with a pungent



odor.  Its physical properties include:  boiling point, 90.0-100.1°C (40 per-



cent sol.); freezing point, -16.3°C (40 percent sol.); and vapor pressure, 100



mm at 45°C (40 percent sol.).  Synonyms for Chloroacetaldehyde are:



monochloroacetaldehyde, 2-chloroacetaTdehyde and chloroaldehyde.   It is soluable



in water, acetone and methanol.  Primary uses of Chloroacetaldehyde include:



use as a fungicide, use in the manufacture of 2-aminothiazole, and use in the



removal of bark from tree trunks.



II.  EXPOSURE



     No monitoring data are available to indicate ambient air or water levels



of Chloroacetaldehyde, nor is any information available on possible exposure



from food.



     Occupational routes of human exposure to Chloroacetaldehyde are primarily



.through inhalation and skin absorption.



     Bioaccumulation data on Chloroacetaldehyde were not found in  the available



literature.  However, 2-chloroacetaldehyde is known to be a chemically reactive



compound and its half-life in aqueous solution has been reported as slightly



greater than 24 hours (Van Duuren et a!., 1972).



III. PHARMACOKINETICS



     A.  Absorption



          Exposure to Chloroacetaldehyde is primarily through inhalation and



skin absorption.



     Chloroacetaldehyde proved to be very lethal by inhalation.  In an iphalation



study conducted by Lawrence et al. (1972), mice were placed in a chloroacetaldehyde-



free chamber and air containing  Chloroacetaldehyde vapor was then  passed

-------
through the chamber.   The time of exposure required to kill 50% of the animals,



LT5Q)  was 2.57 min.  (the chamber atmosphere was calculated to have reached 45%



equilibrium within that time.)



     In comparison studies conducted on chloroacetaldehyde and 2-chloroethanol ,



chloroacetaldehyde was reported as exhibiting greater irritant activity, but



having lesser penetrant capacity (Lawrence et al.,  1972).



     B.  Distribution



          Information on the distribution of chloroacetaldehyde was not found



in the available literature.



     C.  Metaboli sm



          Chloroacetaldehyde appears to be a metabolite of a number of compounds



including 1,2-dichloroethane, chloroethanol and vinyl chloride (McCann et. al.',



1975).



     Johnson (1967) conducted i_n vitro studies on rat livers, the results of



which  indicated that S-carboxymethylglutathione was probably formed via



chloroacetaldehyde metabolic action.  Based upon these studies, Johnson suggested



that the same metabolic mechanism was operative in the i_n vivo conversion of



chloroethanol to S-carboxymethylglutathione.



     In recent studies, Watanabe et al. (1976a,b) reported .that chloro-



acetaldehyde would conjugate with glutathione and cysteine leading ultimately



to the types of urinary metabolites found in animals exposed to vinyl chloride.



The authors reported that as nonprotein free sulfhydral concentrations are



depleted, the alkylating metabolites, one of which is chloroacetaldehyde, are



likely to react with protein, DNA and RNA, eliciting proportionally greater



toxicity.  This is in agreement with other studies conducted on vinyl ch.loride



metabolism (Hefner et al., 1975; Bolt et al., 1977).

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     Chloroacetaldehyde was shown to cause the destruction of lung hemoprotein,



cytochrome P450, as well as liver microsomal cytochrome P450, with no requirement



for NADPH (Harper and Patel,  1978).   The results suggested that the aldehydes



tested, one of which was chloroacetaldehyde, were the toxic intermediates



which inactivated pulmonary enzymes following exposure to some environmental



agents.



     D.  Excretion



          Information specifically on the rates and routes of chloroacetaldehyde



elimination was not found in the available literature.  Studies on vinyl



chloride and ethylene dichloride, however, indicate that chloroacetaldehyde,



as an intermediate metabolite, may ultimately convert to a number of urinary



metabolites — including chloroacetic acid, S-carboxymethylcysteine and thiodiacetic



acid—depending on the particular metabolic pathway involved in the biotransforma-



tion of the parent compound (Johnson, 1967; Yllner, 1971; Watanabe, 1976a,b).



IV.  EFFECTS



     A.  Careinogenicity



          In a study on the carcinogenic activity of alkylating agents, Van



Duuren et al.  (1974) exposed female ICR Ha Swiss mice to 2-chloroacetaldehyde



(assayed as diethylacetal).  The routes of administration were via skin and



subcutaneous injection.  The authors reported no significant tumor induction.



Later studies confirmed these findings (Goldschmidt, personal communication,



1977). However, in a report by McCann et al. (1975), the authors stated that



previous reports of changes of respiratory epithelium in lungs of rats exposed



to chloroacetaldehyde were suggestive of premalignant conditions.



     B.  Mutagenicity



          Many studies have been reported which show that chloroacetaldehyde



exhibits varying degrees of mutagenic activity (Huberman et al., 1975; Border

-------
and Webster, 1976; Elmore et al., 1976; Rosenkranz, 1977).   Loprieno et al.
(1977) reported that 2-chloroacetaldehyde showed only feeble genetic activity
when tested in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae.
However, McCann et al.  (1975) reported that chloroacetaldehyde was quite
effective in reverting Salmonella bacterial tester strain TA 100, but did not
revert TA 1535.  In a later study, Rosenkranz (1977) found that
2-chloroacetaldehyde did display some mutagenic activity towards TA 1535.
     In a study conducted by Elmore et al. (1976) the authors reported that
the chloroacetaldehyde monomer and monomer hydrate were more mutagenically
active that the dimer hydrate and the trimer.
     Rannug et al. (1976) reported that the mutagenic effectiveness of
                              4
chloroacetaldehyde is about 10  times higher than expected from kinetic data.
     C.  Teratogenicity and Other Reproductive Effects
          Pertinent information could not be found.in the available literature.
     0.  Chronic Toxicity
          No chronic information could be found in the available literature.
However, extensive toxicity studies conducted by Lawrence et al.  (1972) revealed
some subacute effects of chloroacetaldehyde on Sprague-Dawley and Black Bethesda
rats.  Groups of rats received .001879 and .003758 ml/kg of chloroacetaldehyde
(representing 0.3 .and 0.6 of the acute LD5Q dose, respectively) daily for 30
consecutive days.  Hematologic tests at the end of 30 days showed that there
was a  significant decrease in hemoglobin, hematocrit, and erthrocytes in the
high dose group; the low dose group showed an increase in monocytes accompanied
by a decrease in lymphocytes.  The animals were sacrificed and organ-to-body
weight  ratios were calculated.  Ratios for both brain and lungs were significantly
                                                                        «
greater in  the low dose group, while the  high dose group showed a significant
increase in the brain, gonads, heart, kidneys, liver, lungs and spleen.

-------
Histological  examination did not reveal any abnormalities attributable to



chloroacetaldehyde except for the lungs which showed more severe bronchitis,



bronchiolitis and bronchopneumonia than were seen in controls.



     In another subacute (subchronic) study, chloroacetaldehyde was administered



to rats in doses of .00032, .00080, .00160 and .00320 ml/kg, three times a



week for 12 weeks.  Hematologic determinations showed no significant differences



between controls and the two lower dose groups, while animals administered



.0016 ml/kg showed a decrease in red cell count and lymphocytes and an increase



in segmented neutrophiles; the highest dose group showed a significant decrease



in red blood cells and hemoglobin with an increase in clotting time and segmented



neutrophiles.  Organ-to-body weight ratios were determined for several organs



and, although there were some significant differences from controls, there



were no apparent dose-related responses.



     D.  Acute Toxicity



          Lawrence et al.  (1972) conducted a series of acute toxicity tests on



ICR mice, Sprague-Dawley and Black Bethesda rats, New Zealand albino rabbits



and Hartlez strain guinea pigs.  .The results were reported as follows:  the



LDqnS (ml/kg) for chloroacetaldehyde administered intraperitoneally ranged



from .00598 in mice to .00464 in rabbits; the LD50s (ml/kg) for chloroacetaldehyde



administered intragastrically were reported as .06918 in male mice, .07507  in



female rats and .08665 in male rats; the dermal ID™ (ml/kg) in rabbits was



reported as .2243; and the inhalation LTrQ in mice was reported as 2.57 min.



     E.  Other Relevent Information



          Case studies show that contact with a strong solution of chloroacetaldehyde



in the human eye will likely result in permanent impairment of vision and skin



contact with a potent solution will result in burns (Proctor and .Hughes,



1978).

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V.    AQUATIC TOXICITY



     Data concerning the effects of chloroacetaldehyde on aquatic organisms



were not found in the available literature.



VI.  EXISTING GUIDELINES



     The 8-hour, TWA occupational  exposure limit established .for chloroacetaldehyde



is 1 ppm.  This TLV of 1 ppm was set to prevent irritation (ACGIH,  1976).
                                     i

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                               CHLOROACETALDEHYDE

References

1.    American Industrial Hygiene Association.   1976.   Threshold  limit values
     for substances in workroom air.  3rd ed.   p.  48.   Cincinnati.   Cited in
     Proctor and Hughes, 1978.

2.    Bolt, H. M. et al. 1977.  Pharmacokinetics  of vinyl  chloride  in the  rat.
     Toxicology.  1_:11^.

3.    Border, E. A., and I. Webster.  1977.   The  effect of vinyl  chloride
     monomer, chloroethylene oxide and chloroacetaldehyde on  DNA synthesis in
     regenerating rat  liver.  Chem. Biol. Interact.••  17:239.

4.    Elmore, J. 0. et  al. 1976.  Vinyl chloride  mutagenicity  via the metabolites
     chlorooxirane and chloroacetaldehyde monomer  hydrate.  Biochim.   Biophys.
     Acta.  442:405.

5.    Harper, C., and J. M. Patel.  1978.  Inactivation of pulmonary  cytochrome
     P 450 by aldehydes.  Fed. Proc.  37:767.           •:  ''• j

6.    Hefner, R. E. , Jr. et al. 1975.  Preliminary  studies of  the fate of  inhaled
     vinyl chloride monomer in rats.  Ann. N.Y.  Acad.  Sci.  246:135.

7.    Huberman,  E. et al. 1975.  Mutation  induction in  Chinese hamster V79
     cells by two vinyl chloride metabolites,  chloroethylene  oxide and
     2-chloroacetaldehyde. Int. J. Cancer.   16:639.
                                                         •'-.
8.    Johnson, M. K.  1967.  Metabolism of chloroethanol  in the rat.   Biochem.
     Pharmacol.  16:185.

9.    Lawrence W. H. et al. 1972.  Toxicity profile of  chloroacetaldehyde.  J.
     Pharm. Sci.  61:19.

10.  Loprieno,  N. et al. 1977.  Induction of gene  mutations and  gene conversions
     by vinyl chloride metabolites in yeast.   Cancer  Res.   36:253.

11.  McCann, J. et al.  1975.  Mutagenicity of  chloroacetaldehyde,  a  possible
     metabolic  product of 1,2-dichloroethane (ethylene dichloride),  chloroethanol
     (ethylene  chlorohydrin), vinyl chloride,  and  cyclophosphamide.   Proc.
     Nat. Acad. Sci.   72:3190.

12.  Proctor, N. H., and J. P. Hughes.  1978.   Chemical  hazards  of the workplace.
     p. 160.  Lippincott Co., Philadelphia.

13.  Rannug, U. et al.  1976.  Mutagenicity of  chloroethylene  oxide,
     chloroacetaldehyde, 2-chloroethanol and chloroacetic acid,  conceivable
     metabolites of vinyl chloride.  Chem. Biol. Interact.  12:251.

14.  Rosenkranz, H. S.   1977.  Mutagenicity  of halogenated alkanes and their
     derivatives.  Environ. Health Perspect.   21:79.

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15.   Van Duuren, B. L. et al.  1972.  Carcinogenicity of  halo-ethers.   II.
     Structure-activity relationships of analogs of bis- (chloromethyl) ether.
     J.  Nat. Cancer Inst.   48:1431.

16.   Van Duuren, B. L. et al.  1974.  Carcinogenic activity  of  alkylating
     agents. J. Nat. Cancer Inst.  53:695

17.   Watanabe, P. G. et al.  1976a.  Fate of 14C vinyl chloride after  single
     oral administration in rats.  Toxicol. Appl. Pharmacol.   36:339.

18.   Watanabe, P. G. et al.  1976b.  Fate of   C vinyl chloride following
     inhalation exposure in rats.  Toxicol. App. Pharmacol.  37:49.
                                                       14
19.   Yllner, S.  1970.  Metabolism of chloroacetate -1-  C  in  the mouse.   Acta
     Pharmacol. Toxicol.  30:69.

     Yllner, S.  -1971.  Metaboli:
     Pharmacol. Toxicol.  30:257.
                                                         14
20.   Yllner, S.  -1971.  Metabolism of 1,2-dichloroethane-  C in the mouse.   Acta

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                                      No. 41
         Chloroalkyl Ethers
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

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                       SPECIAL NOTATION

 »
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
chloroalkyl ethers and has found sufficient evidence to
indicate that this .compound is carcinogenic.

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                     CHLOROALKYL ETHERS

                           SUMMARY

     Bis(chloromethyl)ether  (BCME), chloromethyl  methyl  ether

(CMME), and bis(2-chloroethyl)ether (BCEE) have shown  carcin-

ogenic effects in animal studies following administration  by

various routes.  Epidemiological studies  in  the United States,

Germany, and Japan have indicated that workers exposed to

BCME and CMME developed an increased  incidence of  respiratory

tract tumors.

     Testing of BCME, CMME,  BCEE, and bis(2-chloroisopropyl)-

ether (BCIE) in the Ames Salmonella assay and in _E.  coli have

indicated that these compounds have mutagenic activity.  Cy-

togenetic studies of lymphocytes from workers exposed  to BCME

and CMME have reported an  increased frequency of  aberrations,

which appear to be reversible.

     There is no available evidence to indicate chloroalkyl

ethers produce adverse reproductive or teratogenic effects.

     The information base  for freshwater  organisms and chloro-

alkyl ethers is limited to a  few toxicity tests of 2-chloro-

ethyl vinyl ether and bis(2-chloroethyl)ether.  The.repbrted

96-hour LCjQ value for bis(2-chloroethyl)ether in  the

bluegill is greater than 600,000 ug/l«  A "no effect"  value

of 19,000 ug/1 was observed  using the fathead minnow in  an

embryo-larval test.  Bis(2-chloroethyl)ether has a reported

bioconcentration factor of 11 in a 14-day exposure to  blue-

gills.  The half-life is from four to seven days.  The re-»

ported 96-hour LC5Q value  for the bluegill and 2-chloro-

ethyl vinyl ether is 194,000 ug/1.
                            -S'OO-
                              /

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                     CHLOROALKYL  ETHERS



I.   INTRODUCTION



     This profile is based on the Ambient Water  Quality



Criteria Document for chloroalkyl ethers  (U.S. EPA,  1979).



     The chloroalkyl ethers are compounds with a hydrogen



atom in one or both of the aliphatic ether chains  substituted



by a chlorine atom.  The chemical reactivity  of  these  com-



pounds varies greatly, depending  on the nature of  the  ali-



phatic groups and the placement of  the chlorine  atoms.   The



most reactive compounds are those with short  aliphatic groups



and those in which chlorine substitution  is closest  to the



ether oxygen (alpha-chloro) (U.S. EPA, 1979).



     As an indication of their high reactivity,  chloromethyl



methyl ether (CMME), bis(chloromethyl)ether (BCME),  1-chloro-



ethyl ethyl ester, and. 1-chloroethyl methyl ether  decompose



rapidly in water.  The beta-chloroethers, bis(2-chloroethyl)-



ether (BCEE) and bis(2-chloroisopropyl)ether  (BCIE)  are more



stable in aqueous systems; they are practically  insoluble  in



water  but miscible with most organic solvents (U.S. EPA,



1979).



     The chloroalkyl ethers have  a wide variety  of industrial



and laboratory uses in organic synthesis, textile  treatment,



the manufacture of polymers and insecticides, in  the prepara-



tion of ion exchange resins, and  as degreasing agents  (U.S.



EPA, 1979).



     While the short chain alpha-chloroalkyl  ethers  (BCME,.



CMME) are very unstable in aqueous systems, they appear  to be



relatively stable in the atmosphere (Tou and  Kallos, 1974).



Bis(chloromethyl)ether will form  spontaneously in  the pres-

-------
ence of both hydrogen chloride and  formaldehyde  (Frankel,  et



al. 1974).



II.  EXPOSURE



     The beta-chloroalkyl ethers have been monitored  in



water.  Industrial effluents from chemical plants  involved  in



the manufacture of glycol products, rubber, and  insecticides



may contain high levels of these ethers  (U.S. EPA,  1979).



The highest concentrations in drinking water of  bis(2-chloro-



ethyl)ether, bis(2-chloroisopropyl)ether, and bis-l,2-(2-



chloroethoxy)ethane (BCEXE) reported by  the U.S. EPA  (1975)



are 0.5, 1.'58, and 0.03 ug/lr respectively.  The average con-



centration of these compounds in drinking water  is  in  the



nanogram range (U.S. EPA, 1979).  Chloroalkyl ethers  have



been detected in the. atmosphere, and human inhalation  expo-



sure appears to be limited to occupational settings.



     The chloroalkyi ethers have not been monitored in food



(U.S. EPA, 1979).  The betachloroalkyl ethers, because of



their relative stability and low water solubility, may have a



tendency to be bioaccumulated.  The U.S. EPA (1979) has esti-



mated the weighted biocohcentration factor to be 25 for' the



edible portions of fish and shellfish consumed by Americans.



This is based on the measured' steady-state bioconcentration



studies in bluegills.  Bioconcentration  factors  for BCME (31)



and BCIE (106) have been derived using a proportionality con-



stant related to octanol/water partition coefficients  (U.S.



EPA, 1979).  Dermal exposure for the chloroalkyi ethers has



not been determined (U.S. EPA, 1979).
                             -SOZ-

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III. PHARMACOKINETICS



     A.   Absorption



          Experiments with  radio-labelled  BCIE and  BCEE in



female rats and monkeys have  indicated  that  both  compounds



are readily absorbed  in the blood  following  oral  administra-



tion (Smith, et al.,  1977;  Lingg,  et  al.,  1978).  Pertinent



data could not be located  in  the available literature  re-



trieved on dermal or  inhalation absorption of  the alkyl



ethers.



     B.   Distribution



          Species differences  in the  distribution of radio-



labelled BCIE have been reported by Smith, et  al.  (1977).



Monkeys, as compared  to rats,  retain  higher  amounts of radio-



activity in the liver, muscle, and brain.  Urine  and expired



air from the rat contained  higher  levels of  radioactivity



than those found in the monkey.  Blood  levels  of  BCIE  in  mon-



keys reached a peak within  two hours  following oral adminis-



tration and then declined  in  a biphasic manner (^1/2's



= 5 hours and 2 days  for the  first and  second  phases,  respec-



tively) .



C.   Metabolism



          The biotransformation of BCEE in rats following



oral administration appears to involve  cleavage of  the ether



linkage and subsequent conjugation (Lingg, et  al.,  1978).



Thiodiglycolic acid and chloroethanol-D-glucuronide were



identified as urinary metabolites  of  BCEE.   Metabolites of



BCIS identified in the rat  included l-chloro-2-propanol,  pro-



pylene oxide, 2-(l-methyl-2-chloroethoxy)-propionic acid, and



carbon dioxide (Smith, et al., 1977).

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     D.   Excretion



          BCEE administered orally  to rats was  excreted



rapidly, with more than 60 percent  of the compound  excreted



within 24 hours.  Virtually all of  this elimination was  via



the urine (Lingg, et al., 1978).



IV.  EFFECTS



     A.   Carcinogenicity



          There are several studies with bis(chloromethyl)-



ether  (BCME), chloromethyl methyl ether (CMME), and bis(2-



chloroethyl)ether (BCEE) that show  carcinogenic effects.



BCME induced malignant tumors of the male rat respiratory



tract  following  inhalation exposure (Kuschner, et  al.,



1975).  Application of BCME and BCEXE to the skin of mice



produced skin tumors (Van Duuren, et al., 1968), while subcu-



taneous injection of BCME to newborn mice induced pulmonary



tumors (Gargus, et al., 1969).



     Oral administration of bis(2-chloroethyl)ether (BCEE) to



mice has been shown to increase the incidence of hepatocellu-



lar carcinomas in males (Innes, et  al., 1969).



     Epidemiological studies of workers in the  United States,



Germany, and Japan who were occupationally exposed  to BCME



and CMME have indicated these compounds are human respiratory



carcinogens (U.S. EPA, 1979).



     Both BCME and CMME have been:shown to accelerate the



rate of lung tumor formation in Strain^A mice following  inha-



lation exposure (Leong, et al., 1971).  BCME and BCEE have*



shown  tumor initiating activity for mouse skin, while CMME



showed only weak initiating activity (U.S. EPA, 1979).
                              X

-------
          Preliminary results of  a National Cancer  Institute



study indicate that oral administration of BCIE  does  not  pro-



duce an increase in tumor  incidence  (U.S.  EPA, 1979).



     B.   Mutagenicity



          Testing of the chloroalkyl ethers in the  Ames Sal-



monella assay on _E. coli have indicated that  BCME,  CMME,



BCIE, and BCEE all produced mutagenic  effects  (U.S. EPA,



1979).  BCEE has also been reported  to induce mutations in



Saccharomyces cerevisiae (U.S. EPA,  1979).  Neither BCEE  nor



BCIE showed mutagenic effects in  the heritable translocation



test in mice (Jorganson, et al.   1977).  An increase  in cyto-



genetic aberrations in  the lymphocytes of workers exposed  to



BCME and CMME was reported by Zudova and Landa (1977);  the



frequency of aberrations decreased following  the removal  of



workers from exposure.



     C.   Teratogenicity and Other Reproductive  Effects



          Pertinent data could not be  located  in the  avail-



able literature.



     D.   Chronic Toxicity



          Chronic occupational exposure to CMME  contaminated



with BCME has produced  bronchitis in workers  (U.S.  EPA,



1979).  Cigarette smoking has been found to act  synergisti-



cally with CMME exposure to-produce  bronchitis (Weiss,  1976,



1977).



          Animal studies have indicated that  chronic  exposure



to BCIE produces liver  necrosis in mice.  Exposure  in  rats'



causes major effects on the lungs, including  congestion and



pneumonia (U.S. EPA, 1979).

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     E.   Other Relevant Information



          The initiating activity of several chloroalkyl



ethers indicates that these compounds may  interact  with other



agents to produce skin papillomas (Van Duuren, et al., 1969,



1972).



V.   AQUATIC TOXICITY



     A.   Acute Toxicity



          The reported static 96^hour LC5Q value for  the



bluegill (Lepomis macrochirus) with 2-chloroethyl vinyl ether



(concentration unmeasured) is 194,000 ug/1 (U.S. EPA, 1978).



The 96-hour LCgQ values for the bluegill could not  be de-



termined in a static test for bis(2-chloroethyl)ether with



exposure concentrations as high as 600,000 ug/1.  The concen-



tration of the ether was not monitored during the bioassay.



Pertinent data could not be located in the available  litera-



ture on saltwater species.



     B.   Chronic Toxicity



          An embryo-larval test was conducted with  bis(2-



chloroethyl)ether and the fathead minnow,  (Pimephales prome-



las).   Adverse effects were not observed at test concentra-



tions  as high as 19,000 ug/1-



     C.   Plant Effects



          Pertinent data could not be located in the  avail-



able literature.



     D.   Residues



          Using bis(2-chloroethyl)ether, a bioconcentratiofi



factor of 11 was determined during a 14-day exposure of blue-



gills  (U.S. EPA, 1979).  The half-life was observed to be



between four and seven days.

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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

          Based on animal carcinogenesis bioassays,  and  using

a linear, nonthreshold model, the U.S.  EPA (1979) has esti-

mated the following ambient water levels of  chloroalkyl

ethers which will produce an increased  cancer risk  of

10~5: BCIE,' 11.5ug/l; BCEE, 0.42 ug/1;  and BCME  0.02

ng/1.

          Eight-hour TWA exposure values (TLV) for  the  fol-

lowing chloroalkyl ethers have been  recommended  by  the  Ameri-

can Conference of Governmental and Industrial Hygienists

(ACGIH, 1978): BCME, 1 ppb; BCEE, 5  ppm.

     B.   Aquatic

          Freshwater and saltwater drafted criteria  have  not

been derived for any chloroalkyl ethers because  of  insuffi-
                                                        j
cient data (U.S. EPA, 1979).
                             -5-07-

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                     CHLOROALKYL ETHERS

                         REFERENCES

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.

Frankel, L.S., et al.  1974.  Formation of bis (chloromethyl)
ether from formaldehyde and hydrogen chloride.  Environ. Sci.
Technol.  8: 356.

Gargus, J.L., et al.  1969.  Induction of lung adenomas  in
newborn mice by bis(chloromethyl) ether.  Toxicol. Appl.
Pharmacol.  15: 92.

Irines, J.R.M., et al.  1969.  Bioassay of pesticides and in-
dustrial chemicals for tumorigenicity in mice: A  preliminary
note.  Jour. Natl. Cancer Inst.  42: 1101.

Jorgenson, T.A., et al.  1977.  Study of the mutagenic poten-
tial of bis(2-chloroethyl) and bis  (2-chloroisopropyl) ethers
in mice by the heritable translocation test.  Toxicol.  Appl.
Pharmacol.  41: 196.

Kuschner, M., et al.  1975.  Inhalation carcinogenicity of
alpha halo esthers.  III. Lifetime  and limited period  inhala-
tion studies with bis(chloromethyl)ether at 0.1 ppm.   Arch
Environ. Health  30: 73.

Leong, B.K.J., et al.  1971.  Induction of lung adenomas by
chronic inhalation of bis(chloromethyl)ether.  Arch. Environ.
Health  22: 663.

Lingg, R.D., et al.  1978.  Fate of bis(2-chloroethyl)ether
in rats after acute oral administration.  Toxicol. Appl.
Pharmacol.  45: 248.

Smith, C.C., et al.  1977.  Comparative metabolism of  halo-
ethers.  Ann. M.Y. Acad. Sci.  298: 111.

Tou, J.C., and G.J. Kallos.  1974.  Kinetic study of the sta-
bilities of chloromethyl methyl ether and bis(chloromethyl)-
ether in humid air.  Anal. Chem.  46: 1866.

U.S. EPA.  1975.  Preliminary assessment of suspected  carcin-
ogens in drinking water.  Rep. Cong. U.S. Environ. Prot.
Agency, Washington, D.C.
                                                          »
U.S. EPA.  1978.  In-depth studies  on health and  environmen-
tal impacts of selected water pollutants.  U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
                              a

-------
U.S. EPA.  1979.  Chloroalkyl Ethers: Ambient Water Quality
Criteria. (Draft).

Van Duuren, B.L., et al.  1968.  Alpha-haloethers: A new  type
of alkylating carcinogen.  Arch. Environ. Health  16: 472.

Van Duuren, B.L., et al.  1969.  Carcinogenicity of halo-
ethers.  Jour. Natl. Cancer Inst.  43: 481.

Van Duuren> B.L. , et al.  1972.  Carcinogenicity of halo-
ethers.  II. Structure-activity relationships of analogs  of
bis(chloromethyl)ether.  Jour. Natl. Cancer Inst.  48: 1431.

Weiss, W. 1976.  Chloromethyl ethers, cigarettes,, cough and
cancer.  Jour. Occup. Med.  18: 194.

Weiss, W.  1977.  The forced end-expiratory flow rate in
Chloromethyl ether workers.  Jour. Occup. Med.  19: 611.

Zudova, Z., and K. Landa.  1977.  Genetic risk of occupation-
al exposures to haloethers.  Mutat. Res.  46: 242.

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                                      No. 42
           Chlorobenzene


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

           APRIL 30, 1980
                 -SVO-

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and  environmental  impacts  presented by  the
subject chemical.   This document  has undergone  scrutiny to
ensure its technical acc-uracy.
                             -5JI-

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                                .CHLOROBENZENE
                                    Summary

     There  is  little data  on  the quantities of  chlorobenzene in air, water
and food, although  this compound  has  been identified in these media.  Chron-
ic exposure to chlorobenzene appears  to  cause a variety of pathologies under
different experimental regimens;  however,  the liver and kidney  appear to be
affected  in  a number  of  species.  There  have  been no studies  conducted to
evaluate  the  mutagenic,   teratogenic,  or  carcinogenic  potential  of chloro-
benzene.
     Four species  of freshwater  fish  have 96-hour LC50 values  ranging  from
24,000  to 51,620 ug/1.  Hardness does not significantly affect  the values.
In saltwater,  a  fish and shrimp  had  reported 96-hour l_C50 values of 10,500
ug/1 and 6,400 jug/1,  respectively.   No chronic data involving chlorobenzene
are available.   Algae, both fresh and saltwater, are considerably less  sen-
sitive to chlorobenzene toxicity than fish and invertebrates.

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 I.   INTRODUCTION
     This  profile  is based  on the  Ambient Water  Quality  Criteria Document
 for Chlorinated Benzenes (U.S. EPA, 1979).
     Chlorobenzene,  most  often   referred  to  as  monochlcrobenzene  (fC3;
CgHjCl;  molecular  weight  112.56),  is  a  colorless liquid  with .a  pleasant
aroma.    Monochlorobenzene  has a  melting  point  of -45.6°c,  a  boiling  point
of  131-132°C,  a water   solubility of  488 mg/1  at '25°C, and  a density  of
1.107 g/ml.  Monochlorobenzene  has been used as  a synthetic intermediate  in
the production of phenol, DDT,  and aniline.  It is also used as a solvent  in
the  manufacture  of  adhesives,   paints,   polishes,  waxes,  diisocyanates,
Pharmaceuticals and natural rubber (U.S. EPA, 1979).
     Data  on current  production derived  from  U.S.  International Trade  Com-
mission  reports show  that  between 1969 and  1975,  the  U.S.  annual production
of monochlorobenzene decreased by  50  percent,  from approximately 600 million
pounds to approximately 300 million pounds (U.S. EPA, 1977).
II.  EXPOSURE
     A.  Water
         Based on the vapor pressure, water solubility,  and  molecular weight
of  Chlorobenzene,  Mackay  and Leinonen  (1975)  estimated the  half-life  of
evaporation from water to be  5.8  hours.   Monochlorobenzene has  been  detected
in ground  water,  "uncontaminated" upland water,  and in  waters  contaminated
either  by  industrial, .municipal  or  agricultural waste.  The  concentrations
ranged  from 0.1 to 27 pg/1, with  raw waters having  the  lowest  concentration
and municipal  waste the  highest   (U.S.  EPA, 1975,  1977).   These  estimates
should  be  considered  as gross  estimates  of  exposure,  due  to  the  volatile
nature  of monochlorobenzene.
                                    -SV3-

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      8.  Food
          The U.S.  EPA (1979) has  estimated the weighted  average  bioconcen-
 tration factor of monochlorobenzene to be 13 for the edible  portions  of fish
 and shellfish consumed by Americans.  This estimate  was based on  octanol/-
 water partition coefficients.
      C.  Inhalation
          Data have  not  been  found in  the  available  literature  which  deal
 with exposure to chlorobenzene outside of the industrial  working environment.
 III. PHARMACOKINETICS
      A.  Absorption
          There   is  little  question,   based  on  human  effects  and  mammalian
 toxicity  studies, that chlorobenzene  is  absorbed through the lungs and  from
 the gastrointestinal tract (U.S. EPA,  1977).
      B.  Distribution
          Because chlorobenzene  is  highly  lipophilic  and  hydrophobia,   it
 would  be  expected that it would  be distributed throughout  total  body water
 space,  with  body lipid providing a  deposition site (U.S.  EPA, 1979).
      C.  Metabolism
          Chlorobenzene is  metabolised via an  NADPH-cytochrome  P-448 depen-
dent microsomal enzyme system..  The  first product,  and  rate limiting step,
 is  a epoxidation;  this is followed by  formation of diphenolic and monophe-
 nolic   compounds  (U.S. EPA,  1979).   Various  conjugates  of these  phenolic
 derivatives  are  the primary excretory products  (l_u, et  al.  1974).  Evidence
 indicates that  the  metabolism of monochlorobenzene  results  in  the  formation
 of  toxic  intermediates (Kohli, et al.  1976).   Brodie,. et. al. (1971) induced
 microsomal  enzymes   with  phenobarbital and  showed   a  potentiationin  in  'the
 toxicity   of    monochlorobenzene.     However,   -the   use  of   3-methylcho-

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lanthrene  to  induce microsomai enzymes provided  protection  for  rats (Oesch,
et  al.  1973).  The metabolism of chiorobenzene may also  lead  to the forma-
tion of carcinogenic active intermediates (Kohli, et al. 1976).
     0.  Excretion
         The  predominant route  of elimination  is  through the  formation  of
conjugates of the  metabolites of monochlorobenzene and  elimination  of  these
conjugates by the  urine  (U.S. EPA,  1979).   The types  of conjugates formed
vary with  species  (Williams,  et  al.  1975).   In the rabbit, 27 percent  of  an
administered dose appeared unchanged in the expired air (Williams, 1959).
IV.  EFFECTS
     Pertinent data could  not be located in the  available literature on  the
carcinogenicity, mutagenicity, teratogenicity, or other  reproductive effects
of chiorobenzene.
     A.  Chronic Toxicity
         Data on  the  chronic  toxicity of  chiorobenzene  is sparse and  some-
what contradictory.   "Histopathological  changes" have been  noted in lungs,
liver  and  kidneys  following  inhalation  of monochlorobenzene (200,  475, and
1,000 ppm) in rats, rabbits and  guinea pigs  (Irish,  1963).  Oral administra-
tion of doses of 12.5, 50  and 250 mg/kg/day  to rats produced little  patholo-
gical change,  except for growth retardation in males (Knapp,  et  al. 1971).
     B.  Other Relevant Information
         Chiorobenzene appears to  increase the activity  of microsomai NADPH-
cytochrome P-450 dependent  enzyme systems.   Induction  of microsomai enzyme
activity  has  been  shown to  enhance the  metabolism of  a  wide variety  of
drugs,  pesticides and other xenobiotics  (U.S.  EPA,  1979).
                                   - 5J5--

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V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         Pickering  and  Henderson  (1966)  reported  observed  96-hour  LC5Q
values  for goldfish,  Carassius  auratus,  guppy,  Poecilia  reticulatus,  and
bluegill,  Lepomis  macrochirus, to  be 51,620,  45,530,  and  24,000  jug/1,  re-
spectively,  for  chlorobenzene.   Two  96-hour  LC^ values  for chlorobenzene
and fathead minnows, .Pimephales promelas,  are 33,930 ug/1  in soft water (20
mg/1)  and 29,120 Aig/1 in  hard water  (360  mg/1), indicating  that hardness
does not  significantly  affect  the acute toxicity -of chlorobenzene  (U.S. EPA,
1978).   With  Daphnia maqna,  an observed  48-hour  EC5g value  of  86,000 pg/1
was  reported.   In saltwater  studies, sheepshead  minnow  had  a  reported  un-
adjusted  LC5g  (96-hour)  value  of  10,500  jug/1,   with  a  96-hour EC5Q  of
16,400 jug/1 for mysid shrimp (U.S. EPA, 1978).
     8.   Chronic Toxicity
         NO  chronic  toxicity  studies  have  been  reported  on  the  chronic
toxicity  of chlorobenzene and any salt or  freshwater species.
     C.   Plant Effects
         The  freshwater alga Selenastrum  capricornutum  is considerably less
sensitive  than fish  and Daphnia  magna.   Based on  cell numbers,  the species
has  a  reported  96-hour  EC5Q  value  of 224,000 /jg/1.   The  saltwater  alga,
Skeletonema costatum,  had a  96-hour  EC50, based  on  cell  numbers of 341,000
jug/1.
     0.   Residues
          A bioconcentration  factor of 44  was  obtained  assuming  an 8 percent
lipid content of fish.
                                     -SV6-

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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  American  Conference   of   Governmental  Industrial  Hygienists
(ACGIH,  1971)  threshold  limit  value for  chlorobenzene is 350  mg/m3.   The
acceptable daily  intake  (ADI)  was  calculated  to  be-.1.008  mg/day.   The  U.S.
EPA  (1979)  draft  water  criterion  for  chlorobenzene  is 20  pg/1,   based  on
threshold concentration for odor and taste.
     B.  Aquatic
         For  chlorobenzene,  the  drafted   criterion to  protect  freshwater
aquatic  life  is  1,500 ;jg/l as  a 24-hour  average;  the concentration  should
not  exceed  3,500 ;jg/l  at any  time.   To protect  saltwater aquatic life,  a
draft criterion  of  120 jjg/1 as  a  24-hour average  with a  concentration  not
exceeding 280 pg/1 at any time has been recommended (U.S.  EPA, 1979).
                                     -sn-

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                         CHLOROBENZENE

                          REFERENCES

American Conference  of Governmental  Industrial Hygienists.
1971.  Documentation of  the  threshold  limit  values  for sub-
stances in workroom  air.   3rd.  Ed.

Brodie, B.B.,  et  al.  1971.   Possible  mechanism of  liver ne-
crosis caused  by  aromatic organic  compounds.   Proc.  Natl.
Acad. Sci.   68: 160.

Irish, D.D.  1963.   Halogenated  hydrocarbons:   II.  Cyclic.
TniIndustrial  Hygiene and Toxicology,  Vol. II, 2nd  Ed.,  ed.
F.A. Patty  , Interscience, New  York. p.  1333.

Knapp, W.K., Jr.,  et al.   1971.  Subacute  oral toxicity of
monochlorobenzene in dogs and rats.  Topxicol. Appl.  Pharma-
col,  19: 393.

Kohli, I., et  al.  1976.   The- metabolism of  higher  chlori-
nated benzene  isomers.   Can.  Jour. Biochem.   54:  203.

.Lu, A.Y.H.,  et al.   1974. Liver microsomal  electron trans-
port systems.   III.   Involvement of  cytochrome b5 in the
NADH-supported cytochrome p^-450 dependent hydroxylation of
chlorobenzene.  Biochem.  Biphys. Res.  Comm.   61:  1348.

Mackay, D.,  and P.J.  Leinonen.   1975.   Rate  of evaporation  of
•low-solubility contaminants  from water bodies  to atmosphere.
Environ. Sci.  Technol.   9: 1178.

Oesch, F., et  al.  1973.   Induction  activation and  inhibition
of epoxide hydrase.   Anomalous  prevention  of chlorobenzene-
induced hepatotoxicity by an  inhibitor of  epoxide hydrase.
Chem. Biol.  Interact. 6: 189.

Pickering, Q.H.,  and C.  Henderson.   1966.  Acute toxicity of
some important petrochemicals to fish.  Jour.  Water Pollut.
Control" Fed.   38:  1419.

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

U.S. EPA.  1977.   Investigation of selected  potential  envi-
ronmental  contaminants:  Halogenated  benzenes.   EPA  560/2-77-
004.

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

-------
U.S. EPA.  1979.  Chlorinated Benzenes: Ambient Water Quality
Criteria  (Draft).

Williams, R.T.  1959.  The metabolism of halogenated aromatic
hydrocarbons.  Page 237 in Detoxication mechanisms.  2nd ed.
John Wiley and Sons, New York.

Williams, R.T., et al.  1975.  Species variation  in the meta-
bolism of some organic halogen compounds.  Page 91 Tn'A.D.
Mclntyre and C.F. Mills, eds.  Ecological and toxicological
research.  Plenum Press, New York.

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                                      No.  43
         p—Chloro-m-cresol


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

           APRIL 30,  1980
                 -s-ao-

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

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                               p-CHLORO-m-CRESOL

SUMMARY
         f
     p-Chloro-m—cresol has been found to be susceptible to biodegradation
under aerobic conditions in a synthetic sewage sludge.  It has been  found
to be formed by the chlorination of waters receiving effluents from  electric
power-generating plants and by the chlorination of the effluent from a
domestic sewage treatment facility.
     Very little information on the health effects of p-chloro-m-cresol
was located.  p-Chloro-m-cresol has been characterized as very toxic
in humans, although support for this statement is 'limited.  In rats, a
subcutaneous LI>5Q of 400 mg/kg and an oral LDL  of 500 mg/kg have been
reported.

I.  INTRODUCTION

    p-Chloro-m-cresol (4-chlor/ -7rmethylphenol; C^E^CIO; molecular
weight 142.58) is a solid (dimorphous crystals) at room temperature.  The
pure compound is odorless, but it has a phenolic odor in its most common,  impure
form.  Its melting point is 55.5 C and its boiling point is 235°C.
It is soluble in water and many organic solvents (Windholz 1976).
     A review of the production,range (includes importation) statistics
for p-chloro-m-cresol (CAS No. ^j-50-7) as listed in the initial TSCA
Inventory (U.S. EPA 1979) shows that between 10,000 and 90,000 pounds of
                                "l           *
this chemical were produced/imported in 1977.
     p-Chloro-m-cresol' is used as an external germicide and as a preserva-
tive for glues, gums, paints, inks, textiles and leather goods (Hawley 1971).
It is also used as a preservative in cosmetics (Wilson 1975, Liem 1977).
EPA (1973) indicates that p-chloro-m-cresol is "cleared for use in adhesives
used in food packaging."
*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  Con-
fidential Business Information.  The data submitted for the TSCA Inventory,
including production range information, are subject to the limitations  con-
tained  in the Inventory Reporting Regulations (40 CFR 710).

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II.  EXPOSURE
     A.  Environmental Face
     Voets et al.  (1976) reported  that p-chloro-m-cresol was quite susceptible
to microbial breakdown under aerobic  conditions  in  an organic medium
(synthetic sewage  sludge), while degradation under  aerobic conditions in a
mineral solution (simulating oligotrophic  aquatic systems) was relatively
difficult.  No degradation was observed  in either system under anaerobic
conditions.

     B.  Bioconcentration

     No studies on the bioconcentration  potential of this compound were
found.  Based on its solubility, p-chloro-m-cresol  would not be expected
to have a high bioconcentration potential.

     C.  Exposure

     Human exposure to p-chloro-m-cresol occurs  through its presence in
certain cosmetics  and in a variety of other consumer products in which
it is used as a preservative  (Wilson  1975,  Liem  1977).
     p-Chloro-m-cresol has been found to be formed  by the chlorination
of water from a lake and a river receiving cooling  waters from electric
power-generating plants, at concentrations of  0.2 ug/1 and 0.7 ug/1, res-
pectively.  It has also been found to be formed  by  the chlorination of the
effluent from a domestic sewage treatment  facility  at a concentration of
                                                                 :
1.5 ug/1 (Jolley et al. 1975).

III.   PHARMACOKINETICS

     No information was found.

IV.  HEALTH EFFECTS

     Very little toxicological data for p-chloro-m-cresol  was  available.   The
subcutaneous LD-Q for p-chloro-m-cresol  in rats is 400  mg/kg (NIOSH 1975).
The oral LD   for p-chloro-m-cresol in rats is 500 mg/kg.   In  mice  the
           L*O
intraperitoneal LD   is 30 mg/kg and  the subcutaneous LD   is  200 ing/kg

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(U.S. DHEW 1978).  One author has rated p-chloro-m-cresol as very  toxic,
with a probable lethal dose to humans of 50-500 mg/kg.  (Von Oettingen
as quoted in Gosselin et al. 1976) .  p-Chloro-m—cresol was also reported
as non-irritating to skin in concentrations of 0.5 to' 1.0% in  alcohol.

V.  AQUATIC TOXICITY

    A.  Acute

    The only information available is that for Daphnia pulex.  The
96-hour LC5Q for p-chloro-m-cresol exposure is 3.1 mg/L (Jolley et al. 1977)

VI.  GUIDELINES
     No guidelines for exposure to p-chloro-m-cresol  were located.

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                               References


Gosselin RE et al. 1976.  Clinical Toxicology of Commercial Products.
Fourth Edition.

Hawley GG (Ed.) 1971.  Condensed Chemical Dictionary, 8th Edition.  Van
Nostrand Reinhold Co.

Jolley RL., Jones G, Pitt WW, and Thompson JE. 1975.  Chlorination of
Organics in Cooling Waters and Process Effluents.  In  Proceedings of the
Conference on the Environmental Impact of Water Chlorination, Oak Ridge,
Tennessee, Oct. 22-24, 1975, published July 1976.

Jolley RL, Gorchev H, Hamilton DH.  1978.  Water Chlorination Environmental
Impact and Health Effects In Proceedings of the Second Conference on the
Environmental Impact of Water Chlorination, Gatlinburg, Tenn. 1977.

Liem DH. 1977.  Analysis of antimicrobial compounds in cosmetics, Cosmetics
and Toiletries, 92: 59-72.

National Institute of Occupational Safety and Health.  1975.  Registry of
Toxic Effects of Chemcial Substances.  1978 Edition.  DHEW  (NIOSH) Publication
79-100, Rockville, MD.

U.S. EPA.  1973.  EPA Compendium of Registered Pesticides, Vol. II, Part I,
Page P-01-00.01.

U.S. EPA.  1979.  Toxic Substances Control Act Chemical Substance Inventory,
Production Statistics for Chemicals on the Non-Confidential TSCA Inventory.

Voets JP, Pipyn P, Van Lancker P, and Verstraete W.  1976.  Degradation of
microbicides under different environmental conditions.  J. Appl. Bact.
40:67-72.

Wilson, CH.  1975.  Identification of preservatives in cosmetic products by
thin layer chromatography.  J. Soc. Cosmet. Chem., 26:75-81.

Windholz M. ed. 1976.  The Merck Index, Merck & Co., Inc., Rahway, Mew Jersey.

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                                      No. 44
            Chloroethane
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

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                        CHLOROETHANE



                           SUMMARY



     There is no available evidence which  indicates  that



monochloroethane produces carcinogenic, mutagenic, or  terato-



genic effects.  Symptoms produced by  human  poisoning with



monochloroethane include central nervous system  depression,



respiratory failure, and cardiac arrhythmias.  The results  of



animal studies indicate that liver, kidney,  and  cardiac  tox i-



city may be produced by monochloroethane.



     Data examining the toxic effects of chloroethane  on



aquatic organisms were not available.

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                        CHLOROETHANE




I.   INTRODUCTION



     This profile is based on the Ambient Water Quality  Cri-



teria Document for Chlorinated  Ethanes  (U.S.  EPA,  1979a).



     The chloroethanes are hydrocarbons  in  which one  or  more




of the hydrogen atoms have been replaced by  chlorine  atoms.



Water solubility and vapor pressure decrease  with  increasing



chlorination, while density and melting  point increase.




Monochloroethane (chloroethane, M.W. 64.52)  is a gas  at  room



temperature.  The compound has  a boiling point of  13.1°C,  a



melting point of -138.7°C, a specific gravity of 0.9214,  and



a solubility of 5.74 g/1  in water (U.S.  EPA,  1979a).



     The chloroethanes are used as solvents,  cleaning and  de-



greasing agents, and in the chemical synthesis of  a number of




compounds.



     The 1976 production  of mdnochloroethane  was 335  x 10^




tons/year (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 present  in raw and finished waters  are



due primarily to industrial discharges.  Small amounts of  the



chloroethanes may be formed by  chlorination  of drinking  water

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or treatment of sewage.  Air levels of chloroethanes  are




produced by evaporation of these volatile compounds widely



used as degreasing agents and  in dry cleaning  operations




(U.S. EPA, 1979a).




     Sources of human exposure to chloroethanes  include



water, air/ contaminated foods and fish, and dermal absorp-



tion.  Fish and shellfish have shown levels of chloroethanes



in the nanogram range (Dickson and Riley, 1976).   Data on  the



levels of monochloroethanes in foods is not available.



     An average bioconcentration factor for monochloroethane



in fish and shellfish has not  been derived by  the'EPA.



III. PHARMACOKINETICS



     Pertinent data could not  be located in the  available



literature on monochloroethane 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



following oral or inhalation exposure; widespread  distribu-



tion of the chloroethanes throughout the body; enzymatic de-



chlorination and oxidation to  the alcohol and  ester forms;



and excretion of the chloromethanes primarily  in  the  urine



and expired air.  Specifically for monochloroethane,  absorp-



tion following dermal application is minor; and  excretion




appears to be rapid, with the  major portion of the  injected



compound excreted in the first 24 hours (U.S.  EPA,  1979a).

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IV.  EFFECTS




     Pertinent data could  not  be  located  in  the  available



literature on monochloroethane  for  carcinogenicity,  mutageni-



city, teratogenicity and other  reproductive  effects.



     A.   Chronic Toxicity



          Hunan symptons of monochloroethane poisoning  indi-



cate central nervous system depression,  respiratory  failure,



and cardiyascular symptoms, including  cardiac arrhythmias



(U.S. EPA, 1979a).  Animal toxicity has  indicated  kidney  dam-



age and fatty infiltration of  the liver,  kidney,  and  heart



(U.S. EPA, 1979a).



V.   AQUATIC TOXICITY



     Pertinent data could  not  be  located  in  the  available



1iterature.



VI.  EXISTING GUIDLINES AMD STANDARDS



     A.   Human



          The eight-hour TWA standard  prepared' by  OSHA  for



monochloroethane  is 1,000  ppm.               .• -j '



          Sufficient data  are  not available  to derive a cri-



terion to protect hunan health  from exposure to  nonochloro-



ethane in ambient water.



     B.   Aquatic



          There are not sufficient  toxicological  data to  cal-



culate exposure criteria.

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                                 CHLOROETHANE

                                  REFERENCES
Dickson, A.G., and J.P. Riley.   1976.   The  distribution of short-chain halo-
genated  aliphatic  hydrocarbons   in  some  marine  organisms.   Mar.  Pollut.
Bull.  79: 167.

Kirk, R.,  and Othmer, 0.   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.

U.S.  EPA.   1979a.   Chlorinated  Ethanes:   Ambient  Water Quality  Criteria.
(Draft).

U.S.  EPA.   1979b.   Environmental Criteria and  Assessment Office.   Chlori-
nated Ethanes:. Hazard Profile.  (Draft).

Van  Dyke,  R.A.,  and  C.G.F.  Wineman.   1971.    Enzymatic  dechlorination:
Dechlorination   of   chloroethanes  and   propanes   in_   vitro.    Biochem.
Pharmacol.  20: 463.

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                                      No. 45
            Chloroethene
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

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                           CHLOROETHENE



                         (VINYL CHLORIDE)



                             Summary








     Vinyl chloride has been used for over 40 years in the produc-



tion of  polyvinyl chloride.   Animal studies  indicate  that vinyl



chloride is not teratogenic, but it has been found to be mutagenic



in several biologic test systems.  Vinyl chlor.ide  has been found to



be carcinogenic in laboratory animals and  has jaeen positively asso-



ciated with angiosarcoma of  the  liver  in  humans.   Recently "vinyl



chloride disease",  a  multisystem disorder,  has  been  described in



workers exposed to vinyl chloride.



     Data  are  lacking  concerning  the  effects of  vinyl chloride



in freshwater and saltwater aquatic life.
                                X

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                           CHLOROETHENE



                         (VINYL  CHLORIDE)



I.    INTRODUCTION



     Vinyl chloride  (CH2CHC1;  molecular weight 62.5)  is a highly



flammable  chloro-olefinic  hydrocarbon   which  emits  a  sweet  or



pleasant odor,  and has a  vapor density slightly  more  than twice



that of  air.    Its physical properties  include:    melting point,



-153.8°C;  and  solubility  in  water,  O.llg/100 g  at 28°C.   It is



soluble  in alcohol and  very  soluble in  ether and  carbon tetra-



chloride  (Weast,  1972).  -Many  salts :of  metals (including silver,



copper,  iron,"  platinum,   iridium)  have  the  ability  to  complex



with  vinyl chloride  resulting  in  its  increased solubility  in



water.   Conversely, alkali metal salts, such  as  sodium  or potas-



sium  chloride,   may  decrease  the  solubility of   vinyl  chloride



in aqueous solutions (Fox, 1978).



     Vinyl chloride has been used for over 40 years in the produc-



tion of polyvinyl chloride (PVC), which in turn is the most widely



used material in the manufacture of plastics.  Production of vinyl



chloride in the  U.S. reached slightly over 5 billion pounds in 1977



(U.S. Int. Trade Comm, 1978).



     Vinyl chloride and polyvinyl. chloride are  used in the manufac-



ture of numerous products  in building and construction, the automo-



tive industry,  for  electrical  wire insulation and cables, piping,



industrial and  household  equipment,  packaging for  food  products,



medical  supplies,  and  are depended upon  heavily  by  the rubber,



paper and  glass  industries (Maltoni, 1976a).



     In  the U.S.  about  1500 workers  were employed in monomer syn-



thesis and an additional 5000  in polymerization  operations (Falk,

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et al. 1974).   As many as 350,000 workers were estimated to be asso-



ciated with fabricating plants  (U.S.  EPA,  1974).   By 1976, it was



estimated that worldwide nearly one million persons were associated



with, manufacturing  goods  derived   from   PVC  (Maltoni,  1976a).



Potential  sources  of population exposure  to vinyl  chloride  are



emissions  from PVC fabricating  plants,  release of  monomers  from



various plastic products,  and emissions from the  incineration of



PVC products  (U.S. EPA,  1975).



II.  EXPOSURE



     A.   Water



          Small amounts of vinyl chloride may be present  in public



water  supplies  as  a  result of  industrial  waste  water discharges.



The  levels  of vinyl chloride  in effluents  vary  considerably  de-



pending on the extent of in-plant treatment of waste water.  Vinyl



chloride  in  samples  of waste  water  from  seven areas ranged  from



0.05 ppm to 20 ppm, typical levels being 2-3 ppm (U.S. EPA, 1974).



The  low  solubility and  high volatility of  vinyl  chloride tend to



limit the amounts found in water; however,   the presence of certain



salts may increase the  solubility and  therefore could create situa-



tions of concern (U.S.  EPA, 1975).



          Polyvinyl chloride pipe.used  in  water  distribution sys-



tems provides  another  source of  low  levels of vinyl  chloride  in



drinking water.  In a study by  the U.S. EPA  of five water distribu-



tion systems which used PVC  pipes,  water from the  newest, longest



pipe system had the highest vinyl chloride concentration (1.4 ug/1)



while the two oldest  systems only had  traces of vinyl chloride • (0.3



     and  0.6  ug/1) (Dressman and  McFarren, 1978).    The  National
                              -537-

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Science Foundation (NSF)  has adopted a voluntary standard of 10 ppm

or less of residual monomer  in  finished pipe and fittings.  Three

times  a  year NSF  samples water  supplies  in several  cities.    In

1977, more than  95  percent of the  samples  conformed  to the stan-

dard/ however, levels of  5.6 ug/1 and 0.27 pg/1  vinyl chloride have

been detected in at least two cities.

     B.   Food

          Small quantities of vinyl chloride are ingested by humans

when  the  entrained monomer  migrates  into  foods packaged  in  PVC

wrappings  and containers.   The  solubility of  vinyl  chloride  in

foods packaged in water is low (0.11 percent); however,  the  monomer

is soluble in alcohols and mineral oil.  In  1973,  the U.S. Treasury

Department banned the use of vinyl  chloride polymers for packaging

alcoholic beverages (Int. Agency Res. Cancer,  1974)..  The FDA anal-

yzed a number of  PVC packaged products in 1974.   The concentrations

ranged from  "not detectable" to  9,000  ppb.

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

bioconcentration factor  of vinyl chloride to be  1.9 for  the  edible

portions of  fresh and shellfish  consumed by Americans.   This esti-

mate was based on the octanol/water  coefficient  of vinyl chloride.

     C.   Inhalation

          Inhalation  of  vinyl chloride  is  the  principal route  of

exposure to  people working  in or living  near vinyl chloride  indus-

tries.  After 1960,  Dow Chemical Co. was successful  in  reducing ex-

posures to workers  to about 25  ppm level,  though levels up  to 500
                                             '                  »
ppm still occurred.   Inhalation exposures drastically dropped after

appropriate. controls  were  instituted  following case  reports   of

vinyl chloride induced angiosarcoma of the  liver in  workers  and .ex-

perimental animals  .(U.S.   EPA, 1979) .

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III. PHARMACOKINETICS



     A.   Absorption



          Vinyl chloride is rapidly absorbed through the lungs and



enters the blood stream  (Duprat, et al. 1977).



     B.   Distribution



          The  liver  of  rats  accumulates  the  greatest percentage



of  vinyl  chloride  and/or metabolites  of  vinyl  chloride  72 hours



after  a  single oral  dose   (Watanabe,  et  al.  1976).   Ten minutes



after  a 5-minute inhalation exposure  to  vinyl  chloride at 10,000



ppm,  the  compound  was   found  in the  liver,  bile  duct,  stomach,



and  kidney of •• rats  (Duprat,  et  al.  1977).    Immediately  after


                             14
exposure  by  inhalation  to    C-vinyl  chloride  at  50  ppm  for  5


                                       14
hours,  the percent  incorporated  as    C/radioactivity per  gram



of  tissue  was  highest  for  kidney (2.13),  liver  (1.86), and spleen



(0.73).  Forty-eight hours after  the beginning of exposure, labeled



material could still.be detected in these  tissues.



     G.   Metabolism



          Detoxification of vinyl chloride takes place primarily in



the liver  by oxidation to polar  compounds which can be conjugated



to glutathione and/or cysteine (Hefner, et al. 1975).  These cova-



lently bond metabolites are then excreted  in the urine.



          Vinyl chloride is metabolized extensively by  rats in vivo



and the metabolic pathways appear to be saturable.  The postulated



primary metabolic pathway  involves  alcohol dehydrogenase and, for



rats,  appears  to be  saturated by exposures  to  concentrations ex-



ceeding 220 to 250 ppm.  In rats exposed  to higher concentrations,



metabolism of vinyl  chloride is postulated to occur via a secondary

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pathway involving  epoxidation and/or peroxidation.   Present data



indicates that vinyl chloride  is metabolized  to an activated car-



cinogen  electrophile and  is  capable of  covalent  reaction with



nucleophilic groups or cellular macromolecules  (U.S. EPA, 1979).



          There is ample  evidence  that  the mixed function oxidase



(MFO) system may be  involved  in  the  metabolism of vinyl chloride.



Rat liver microsomes catalyze the covalent binding of vinyl chlor-



ide  metabolites  to   protein   and  nucleic  acids;  chloroethylene



oxide is  thought  to  be the primary  microsomal metabolite capable



of alkylating  these  cellular  macromolecules  (Kappus,  et al. 1975;



1976;  Laib  and  Bolt,  1977).    Hathway   (1977)  reports  _in  vitro



depurination of  calf thymus  DNA by  chloroacetaldehyde identical



to  that  observed  in  hepatocyte  DNA  following  the administration



of vinyl chloride  to rats i_n vitro.



     D.   Excretion



          Watanabe,  et  al.  (1976)   monitored  the  elimination  of



vinyl chloride for 72 hours following a  single oral dose adminis-



tered to rats.   The total  14c-activity recovered  at  each dose level



ranged from 82-92  percent.  At a dose level  of 1 mg/kg, 2 percent



was  exhaled  as vinyl chloride,  13  percent was  exhaled as carbon



dioxide, 59  percent  was eliminated  in the urine  and  2  percent in



the feces.  Excretion of vinyl chloride at a dose level of 100 mg/kg



was  66  percent exhaled  as vinyl  chloride, 2.5  percent  as carbon



dioxide, 11 percent in the urine  and  0.5  percent  in  the  feces.  Ad-



ministration by inhalation produced almost the same results.

                                                              •

          Green and Hathway (1975)  found that more than 96 percent


          14
of 250 ug   C-vinyl chloride administered via intragastric,  intra-

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venous or intraperitoneal routes was excreted within 24  hours.  The
rats given  vinyl chloride  by  the  intragastric -route  exhaled 3.7
percent  as  vinyl  chloride,  12.6  percent   as  C02; 71.5  percent
of  the  labeled  material was in  the urine and  2.8  percent in the
feces.   Intravenous  injections  resulted  in 9.9  percent  exhaled
as vinyl chloride, 10.3  percent  as  CC^;  41.5 percent in the urine
and 1.6 percent in the feces.
IV.  EFFECTS
     A.   Carcinogenicity
          The carcinogenicity  of vinyl chloride has been  investi-
gated in several animal studies.   Viola,  et al.  (1971) induced skin
epidermoid carcinomas,  lung carcinomas or bone steochrondromas in
24/25 male rats  exposed to  30,000 ppm vinyl chloride intermittently
for 12 months.  Tumors appeared  between  10 and 11 months.  Caputo,
et  al.  (1974)  observed carcinomas  and sarcomas in  all groups of
male  and female  rats  inhaling  various concentrations of  vinyl
chloride except those exposed  to 50 ppm.
          Maltoni  and  Lefemine  (1974a,b;   1975)   reported  on  a
series  of  experiments concerning the  effects on  rats,  mice,  and
hamsters  of  inhalation  exposure to vinyl chloride  at  concentra-
tions ranging from  50 to 10,000 ppm for varying  periods  of time.
The animals  were observed  for their   entire  lifetime.   Angiosar-
comas  of the liver  occurred  in all  three   species,  as  well  as
tumors  at  several other sites.   A differential  response  between
the sexes was not reported.
          Maltoni  (1976b)   observed  four subcutaneous  angiosar-
comas,  four  zymbal  gland   carcinomas,  and   one  nephroblastoma  in

                                 t
                               -SH)-

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66 offspring  of  rats exposed by  inhalation  4 hours/day to 10,000
or 6,000  ppm  vinyl chloride  from the 12th to  18th  day of gesta-
tion.  Liver angiosarcomas were also observed in rats administered
vinyl chloride via stomach tube for 52 weeks.
          Recent  experiments  by   Lee,  et  al.   (1977)   with  rats
and  mice  confirm  the  carcinogenicity  of vinyl  chloride.   Each
species was  exposed to  50,250 or  1000  ppm vinyl chloride  or 55
ppm  vinylene  chloride  6  hr/day,  5  days/week  for   1-12  months.
After 12  months,  bronchioalveolar adenomas,  .mammary gland tumors,
and  angiosarcomas  in  the  liver and other  sites  developed  in mice
exposed to all•three dose  levels  of vinyl chloride.   Rats exposed
to 250  ppm or  100 ppm vinyl chloride developed  angiosarcoma in
the  liver, lung and other sites (Lee, et al. 1978).
          The primary effect  associated  with  vinyl chloride expo-
sure  in man  is  an increased  risk  of  cancer  in  several organs  in-
cluding angiosarcoma of  the  liver.  Liver angiosarcoma is an  ex-
tremely rare liver cancer  in humans, with  26 cases  reported annual-
ly in the U.S.  (Natl. Cancer.Inst., 1975).  Human  data  on  the car-
cinogenic  effects  of vinyl chloride  have  been  obtained primarily
from cases of  occupational  exposures of workers.  The  latent period
has  been  estimated to be .15-20 years; however, recent case reports
indicate  a longer  average  latent  period (Spirtas  and Kaminski,
1978).
          A  number of  epidemiological  studies of  vinyl chloride
have  been  reported (U.S. EPA,  1979).   Tabershaw/Cooper  Associates
(1974)  found  no  increase  in  the  overall  mortality rate for v'inyl
chloride  workers  nor significant  increases  in  standard mortality

                                X

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rates  (SMR's)   for  malignant  neoplasms.   Reexamination  of  this



data by Ott,  et al.  (1975)  including more  clearly defined expo-



sure levels  confirmed  the previous  findings:    no increase  over



that expected  for  malignant  neoplasms  in the  low exposure group



(TWA 10-100  ppm vinyl  chloride)  and a  non-significant   increase



in deaths  due  to malignant  neoplasms in the  high exposure group



(TWA, greater than 200 ppm).



          However, liver  cancer  death were twelve-fold, and brain



cancer  deaths   were  five-fold  greater  than, that  expected  in  a



study by  Wagoner (1974).   Likewise, Monson,  et  al.   (1974) found



death due to  cancer  to  be   50  percent  higher   than  expected  in



vinyl chloride  workers who  died  from 1947-1973,  including a  900



percent increase in cancers of the  liver  and biliary tract.



           In the most recent  update  of the NIOSH  register,  a total



of 64 cases of  hepatic angiosarcoma  have  been identified, worldwide



among vinyl chloride exposed industrial workers (Spirtas and Kamin-



ski,  1978).    Twenty-three of  these cases  were   reported  in  the



United States.  Six cases  were documented since 1975.



     B.    Mutagenicity



          Vinyl chloride has been found to be mutagenic in  a number



of biological systems  including:   metabolically  activated  systems



using   Salmonella   typhimurium;   back   mutation  systems  using



Escherichia coli; forward mutation and gene coversion in yeast;  and



germ cells of  Drosophila and Chinese hamster V79 cells  (U.S.  EPA,



1979) .



          The dominant  lethal assay  was  used to test the mutag'eni-



city of inhaled vinyl  chloride  in mice.   Levels  as high as  30,000

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ppm (6 hours/day for 5 days)  yielded  negative results  (Anderson, et



al.  1976).



          Several   investigators  have  observed  a  significantly



higher incidence of  chromosomal  aberrations  in the lymphocytes of



workers  chronically  exposed to  high  levels  of  vinyl  chloride



(Ducatman, et al. 1975;  Purchase,  et al.  1975; Funes-Crav'ioto, et



al. 1975).



     C.   Teratogenicity



          Animal  studies using  mice,  rats  and  rabbits,  indicate



that inhalation of vinyl  chloride does  not  induce  gross teratogenic



abnormalities in offspring of mothers exposed 7 hours  daily  to con-



centrations ranging  from 50  to 2,500 ppm (John, et al. 1977); how-



ever,  excess  occurrences  of  minor  skeletal  abnormalities  were



noted.   Increased  fetal  death  was  noted  at  the higher  exposure



levels.   These  findings  were confirmed by Radike,  et al.  (1977a)



who exposed rats to  600-6,000 ppm vinyl chloride, 4 hours daily on



the 9th  to the 21st  day of gestation.



          Further examination  is needed  of reported high rates of



congenital defects in three small communities in which vinyl chlor-



ide polymerization  plants are located  (U.S.  EPA,  1979).



     D.   Other Reproductive Effects



          No  effect on fertility in mice  was noted in a dominant



lethal assay conducted by Anderson,  et al.  (1976).



     E.   Chronic Toxicity



          There  are  numerous  clinical  indications  that chronic



exposure  to  vinyl chloride  is  toxic to humans  (U.S.  EPA,  1979) .



Hepatitis-like  changes,  angioneurosis, Raynaud's syndrome,  derma-

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titis,  acroosteolysis,   thyroid  insufficiency,   and  hepatomegaly



have  been  reported  around the  world.    Other long  term effects



include  functional  disturbances of  the  central  nervous  system



with adrenergic sensory  polyneuritis  (Smirnova and Granik,  1970);



thrombocytopenia,  splenomegaly,  liver malfunction  with  fibrosis,



pulmonary changes  (Lange,  et  al. 1974);  and  alterations in serum



enzyme levels (Makk, et al. 1976).



     F.   Other Relevant Information



          Pretrea.tment of  rats  with pyrazole'-  (an alcohol dehydro-



genose  inhibitor)  and  ethanol   inhibits  the   metabolism  of vinyl



chloride  (Hefner,  et al.  1975).   This  indicates the  involvement



of alcohol dehydrogenose in the metabolism of  vinyl chloride.



          The chronic • ingestion of alcohol was  found to increase



the  incidence  of  liver  tumors  and tumors  in  other  sites  in  in-



dividuals exposed  to vinyl chloride (Radike, 1977b) .



          Jaeger   (1975)  conducted  experiments  to determine  the



interaction between vinylidene chloride (1,1-DCE) and vinyl chlor ide.



In  this  experiment,  the effects of  4-hour  exposures  to 200  ppm



of  1,1-DCE  and 1,000  ppm  vinyl  chloride were less  than if 1,1-



DCE was given alone.



V.   AQUATIC TOXICITY



     A.   Pertinent information relevant to acute  and  chronic toxi-



city, plant effects and residues  for vinyl chloride were  not found



in the available literature.

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VI.  EXISTING GUIDELINES AND STANDARDS



     A.   Human



          The current federal OSHA standard for  vinyl chloride is  1



ppm (TWA)  with a maximum of 5 ppm  for a period of no  longer than 15



minutes in 1 day.  (39 FR  35890 (Oct. 4, 1979)).



          In  1974, a notice to cancel  registrations of pesticide



spray products containing vinyl chloride as a propellant was  issued



(39 FR  14753  (April  26, 1974)).   Other aerosol productsx such as



hair spray,  utilizing  vinyl chloride as  a propellant were  banned



from the market in the U.S. and other countries (Int.  Agency Res.



Cancer, 1974). 'The U.S. EPA proposed in 1975 and 1976 an emission



standard of 10 ppm vinyl chloride at the stack for industry.



          The  draft   ambient  water  quality  criterion for  vinyl



chloride  has  been set  to  reduce  the  human lifetime  cancer risk



level  to  10~5,  10"6  and  10~7 (U.S.  EPA,  1979).   The corresponding



criteria are 517 pg/1, 51.7 ;jg/l and 5.17 pg/1, respectively.  The



data base  from  which this  criterion has been  derived is currently



being  reviewed,  therefore, this criteria  to protect human  health



may change.



     B.   Aquatic



          Fresh or salt water criteria  could not be derived because



of insufficient data (U.S. EPA, 1979).
                              - ff

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                                 CHLOROETHENE
                               (VINYL CHLORIDE)

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Caputo, A.,  et  al.   1974.   Oncogenicity  of  vinyl  chloride at low concentra-
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occupational  poisoning by certain hydrocarbons and their  derivatives.   Gig.
Tr.  Prof.  Zabol.  14:  50.

Spirtas,  R.  and R.  Kaminski.   1978.   Angiosarcojia  of the  liver  in  vinyl
chloride/polyvinyl chloride  workers.   Update of  the  NIOSH Register.   Jour.
Occup. Med.   20: 427.

Tabershaw/Cooper Assoc.,  Inc.   1974.   Epidemiologic  study of vinyl  chloride
workers.   Final  report submitted  to  Manufacturing Chemists Assoc.,  Washing-
ton, D.C.  Berkeley, Calif.

U.S. EPA.   1974.   Preliminary assessment of the  environmental problems  asso-
ciated with  vinyl  chloride and polyvinyl chloride.  EPA 560/4-74-001.   Natl.
Tech. Inf. Serv., Springfield,  Va.

U.S.  EPA.   1975.   A  scientific  and technical  assessment  report  on  vinyl
chloride  and  polyvinyl  chloride.   EPA-600/6-75-004.   Off.  Res.  Dev.,  U.S.
Environ. Prot. Agency, Washington, D.C.

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

U.S.  International  Trade Commission.   1978.  Synthetic  organic chemicals.
U.S. Production  and  Sales,  1977.   Publ. 920.  U.S.  Government Printing Of-
fice, Washington, O.C.

.Viola, P.L.,  et  al.   1971.   Oncogenic  response of rat skin, lungs, bones  to
vinyl chloride.  Cancer  Res.   31:  516.

Wagoner, J.E.  1974.   NIOSH presented before the  environment. Commerce  Comm.
U.S. Senate, Washington,  D.C.

Watanabe,  P.G.,  et  al.    1976.   Fate  of  (14C)   vinyl  chloride  after single
oral administration in rats.   Toxicol. Appl. Pharmacol.  36:  339.

Weast,  R.C.   (ed.)   1972.  Handbook  of chemistry and physics.   CRC Press,
Cleveland, Ohio.

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                                      No.  46
     2-Chloroethyl Vinyl Ether


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

           APRIL 30, 1980

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                          DISCLAIMER
     This report represents  a  survey of the potential health
and environmental hazards from exposure to  the subject chemi-
cal.  The information contained in the report is  drawn chiefly
from secondary  sources  and  available  reference  documents.
Because of the limitations of such sources,  this  '-u ~>rt 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.
                             - S'SJ-

-------
                        2-CHLOROETHYL  VINYL  ETHER

SUMMARY

     Very little information is available for 2-chloroethyl vinyl ether.  It
appears to be relatively stable except, under acidic conditions.  There is some
potential for bioconcentration of the compound in exposed organisms.  No expo-
sure data were available, although 2-chloroethyl vinyl ether has been identified
in industrial effluent discharges.
     The acute toxicity of 2-chloroethyl vinyl ether is relatively low:  oral
LD  :  250 mg/kg; dermal LD   3.2 mL/kg; LC  :  250 ppm (4 hrs).  Eye irrita-
tion has been reported following exposure to 2-chloroethyl vinyl ether.  No
other data on health effects were available.

I.  INTRODUCTION

     2-Chloroethyl vinyl ether (CICH^CH OCH=CH •  molecular weight 106.55) is a
liquid having the following physical/chemical properties (Windholz,  1976; Weast,
1972; U.S. EPA, 1979c):
               Boiling point (760 mm Hg):            109°C
               Melting point:                        -70°C
               Density:                            1.047520
               Solubility:                         Soluble in water  to the extent
                                                   of 6g/L; very soluble in
                                                   alcohol and ether

The compound finds use in the manufacture of anesthetics,  sedatives, and
cellulose ethers (Windholz, 1976).
     A review of the production range (includes importation) statistics for 2-
chloroethyl vinyl ether (CAS No. 110-75-8) which is listed in the initial TSCA
inventory (1979a) has shown that none of this chemical was produced  or imported
in 1977*.
*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 (40CFR710).

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II.  EXPOSURE

     A.  Environmental Rate

     The 0-chloroalkyl ethers have been shown to be quite stable to hydrolysis
and to persist for extended periods without biodegradation (U.S. EPA, 1979b).
2-Chloroethyl ethyl ether (a 8-chloroalkyl other) is stable to sodium hydroxide
solutions but will undergo hydrolysis in the presence of dilute acids to acet-
aldehyde and 2-chloroethanol (Windholz 1976).  Conventional treatment systems
may be inadequate to sufficiently remove the g-chloroalkyl ethers once present
in water supplies (U.S. EPA 1979b; U.S. EPA 1975).

     B.  Bioconcentration

     A calculated faioconcentration factor of 34.2 (U.S. EPA,  1979b) points to
some potential for 2-chloroethyl vinyl ether accumulation in exposed organisms.

     C.  Environmental Occurrence

     There is no specific information available on general population exposure
to 2-chloroethyl vinyl ether.   The compound has been identified three times in
the water of Louisville,  Kentucky (3/74):   twice in effluent
facturing plants and once in the effluent  from a latex plant  (U.S.  EPA 1976). No
concentration levels were given.
     NIOSH, utilizing data from the National Occupational Hazards Survey
(NOHS 1977) has compiled a listing summarizing occupational exposure to 2-
chloroethyl vinyl ether (Table 1).  As shown, NIOSH estimates 23,473 people
are exposed annually to the compound.  The number of potentially exposed indi-
viduals is greatest for the following areas:  fabricated metal products; whole-
sale trade; leather, rubber and plastic,  and chemical products.

III.  PHARMACOKINETICS
                                                                        »
     Vinyl ethers readily undergo acid catalysed hydrolysis to give alcohols and
aldehydes, e.g., 2-chloroethyl vinyl ether is hydrolyzed to 2-chloroethanol and
acetaldehyde (Salomaa et al. 1966).

-------
                                                   TABLE 1
PROJECTED NUMBERS BY INDUSTRY
SIC
CODE

25
28
30
31
34
35
36
37
38
39
50
73
                     HAZARD         DESCRIPTION

                     84673 Chloroethyl Vinyl Ether, 2-
DESCRIPTION
Furniture and fixtures
Chemicals and allied products
Rubber and plastic  products
Leather and leather products
Fabricated metal products
Machinery, except electrical
Electrical equipment and supplies
Transportation equipment
Instruments and related products
Miscellaneous manufacturing industries
Wholesale trade
Miscellaneous business services
ESTIMATED
 PLANTS
ESTIMATED
 PEOPLE
ESTIMATED
EXPOSURES
                                   920
                                   683
                                   669
                                   279
                                   149
                                    35
                                   432
                                   553
                                   299
                                   240
                                 6,194
                                    20
                                  i
                                 T
                                 V1
                                 Vi
                                  i
TOTAL
                                                           2,059
               23,473
                 23,473

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IV.  HEALTH EFFECTS

     A.  Mutagenicity

     Although no information on the mutagenicity of 2-chloroethyl vinyl ether was
available, its hydrolysis product, 2-chloroethanol, has been shown to be muta-
genic in Salmonella typhimurium TA 1535 (Rannug et al. 1976), TA100 and TA98
(McCann et al. 1976), as well as Klebsiella pneumonia (Voogd et al. 1972).

     B.  Other Toxicity

     Very little toxicological data for 2-chloroethyl vinyl ether is available.
The oral LD_Q for 2-chloroethyl vinyl ether in rats is 250 rag/kg (U.S. EPA,  1975,
Patty 1963).  Dermal exposure to the shaven skin of rabbits for 24 hours resulted
in an LD5_ of 3.2 mL/kg (U.S. EPA, 1976).  The acute inhalation toxicity of
2-chloroethyl vinyl ether in rats was determined following single four-hour
exposures.  The lowest lethal concentration was 250 ppm (U.S. EPA, 1975).  In a
similar inhalation study, 1/6 rats exposed by inhalation to 500 ppm died during
the 14-day observation period (U.S. EPA, 1975).
     Primary skin irritation and eye irritation studies have also been conducted
for 2-chloroethyl vinyl ether.  Dermal exposure to undiluted 2-chloroethyl vinyl
ether did not cause even slight erythema.  Application of 0.5 mL undiluted 2-
chloroethyl vinyl ether to the eyes of rabbits resulted in severe eye injury
(U.S. EPA, 1975).

V.  AQUATIC TOXICITY

     A.  Acute

     The adjusted 96-hour LC,.-. for blue gill exposure to 2-chloroethyl vinyl
ether is 194,000 ug/L (U.S. EPA, 1979b).  Dividing by the species sensitivity
factor (3.9), a Final Fish Acute Value of 50,000 ug/L is obtained (Table 1).
                                                                        »
There is no data on invertebrate or plant exposure.

VI.  EXISTING GUIDELINES

     No guidelines were located.

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           Table 2 .   Freshwater fish acute values  (U.S.  EPA,  1979b)


                                                                        Adjusted
                       Bioassay Test      Chemical       Time     LC5o     LC5Q
Organism               Method   Cone.**   Description    (hrs)    (ug/L)    (ug/L)

Bluegill,                 S      U       2-chloroethyl    96    354,000   194,000
Lepomis macrochirus                       vinyl  ether
*   S = static
**  U = unmeasured

    Geometric mean of adjusted values:   2-chloroethyl vinyl  ether =  194,000 ug/L

             = 50,000 ug/L

-------
                                References


Lange NA (ed.).  1967.  Lange's Handbook, of Chemistry, rev. 10th ed.,  New York:
McGraw-Hill Book Co.

McCahn J, Simmon V.,  Streitwieser D, Ames BN.  1975.  Mutagenicity of chloro-
acetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene
dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride and cyclo-
phosphamide.  Proc. Nat. Acad. Sci.  72:3190-3193.

National Occupational Hazard Survey (NOHS) 1977 Vol. Ill, U.S. DREW,  NIOSH,
Cincinnati, Ohio (Special request for computer printout:  2-chloroethyl vinyl
ether Dec. 1979)

Rannug U., Gothe R. Wachtmeister CA.  1976.  The mutagenicity of chloroethylene
oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable
metabolites of vinyl chloride,  Chem-Biol. Interactions 12:251-263.

Salomaa P, Kankaanpera A. Lajunen M.  1966.  Protolytic cleavage of vinyl
ethers, general acid catalysis, structural effects and deuterium solvent isotope
effects.  Acta Chemica Scand.  20:1790-1801.

U.S. EPA, 1975.  Investigation of selected potential environmental
contaminants:  Haloethers.       EPA 560/2-75-006.

U.S. EPA, 1976.  Frequency of organic compounds identified in water.   EPA 600/4-
76-062. .

U.S. EPA, 1979a.  Toxic Substance Control Act, Chemical Substance Inventory,
Production Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.

U.S. EPA, 1979b.  Ambient Water Quality Criteria Document on Chloroalkyl Ethers.
PB 297-921.

U.S. EPA, 1979c.  Ambient Water Quality Criteria Document on Haloethers.  PB  296-796.

Voogd CE, Jacobs JJJAA, van der Stel JJ.  1972.  On the mutagenic action of
dichlorvos.  Mutat. Res. 16:413^16.

Weast RC (ed.).  1972.  Handbook of Chemistry and Physics, 53rd ed.  The Chemical
Rubber Co., Cleveland, OH.

Windholz M.  (ed.).  1976.  The Merck Index, 9th ed.  Merck & Co. Inc., Rahway, NJ.
                                  -5" 5-7-

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                                      No. 47
Chloroform (Carbon Trichlororaethane)


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

           APRIL 30, 1980
               -55**-

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

-------
                       SPECIAL NOTATION










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



chloroform and has found sufficient evidence to indicate



that this compound is carcinogenic.
                              -560-

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                          CHLOROFORM



                           SUMMARY






     Chloroform has been  found  to  induce  hepatocellular




carcinomas in mice and kidney epithelial  tumors  in  rats.



Hepatomas have also been  induced in mice,  but  necrosis may



be a prerequisite to tumor formation.   Bacterial assays



involving chloroform have yielded  no mutagenic effects.



Chloroform has produced  teratogenic effects  when administered




to pregnant .rats.



     Reported y6-hour LCcQ values  for  two common freshwater



fish range from 43,800 to 115,000  ug/1  in static tests.



A 48-hour static test with Daphnia magna  yielded an LC(-n



of 28,900 jjg/1.  The observed 96-hour  LC5Q for the  saltwater



pink shrimp is 81,500 jjg/1.  In a  life  cycle chronic test,



the chronic value was 2,546 ug/1 for Uaphnia_ magna_.   Per-



tinent information on chloroform toxicity to plants could



not be located in the available literature.  In  the only



residue study reported,  the bluegill concentrated chloroform



six times after a 14-day  exposure.  The tissue half-life



was less than one day suggesting that  residues of chloroform



would not be an environmental hazard to aquatic  life.
                            -5-4,1-

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                          CHLOROFORM

I.    INTRODUCTION

     This profile is based on the Ambient Water Quality

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

     Chloroform  (CHCl^; molecular weight 119.39}  is a clear,

colorless liquid with a pleasant, etheric, non-irritating

odor and taste  (Hardie, 1964; Windholz, 1976).  It has the

following physical/chemical properties (Hardie, 1964; Irish,

1972; Windholz,  1976}:

     Boiling Point:      61-62°C
     Melting Point:      -63.5°C
     Flash Point:        none (none-flammable)
     Solubility:         Water - 7.42 x 10° pg/1  at 25°C
                         Miscible with alcohol, benzene,
                              ether, petroleum ether, carbon
                              tetrachloride, carbon disulfide,
                              and oils.
     Vapor Pressure:     200 mm Hg at 25 C


     Current Production:  1.2 x 10  metric tons/year  (U.S.

EPA, 1978a).

     Chloroform  is currently used either as a solvent or

as an intermediate in the production of refrigerants  (prin-

cipleus) , plastics, and Pharmaceuticals (U.S. EPA, 1975)<.

     Chloroform  is relatively stable under normal environ-

mental conditions.  When exposed to sunlight, it .decomposes

slowly in air but is relatively stable in water.  The mea-

sured half-life  for hydrolyis was found to be 15  months

 (Natl. Acad. Sci., 1978a).  Degradation in water  can occur

in the presence  of metals and is accelerated by aeration

 (Hardie, 1964).

-------
     For additional information regarding halomethanes as



a class the reader is referred to the Hazard Profile on



halomethanes (U.S.  EPA, 1979b).



II.  EXPOSURE



     Chloroform appears to be ubiquitous in the environment.



A major source of chloroform contamination is from the chlor-



ination of water and wastewater (U.S. EPA, 1975; Bellar,



et al. , 1974).  Industrial spills may occasionally be a



pulse source of transient high level contamination (Nat.



Acad. Sci., 1978a; Neely, et al., 1976; Brass and Thomas,



1978).



     Based on available monitoring data including informa-



tion from the National Organics Monitoring Survey (NOMS),



the U.S. EPA (1978b) has estimated the uptake of chloroform



by adult humans from air, water,  and food:
Source
Atmosphere
Water
Food Supply
Total
Atmosphere
Water
Food Supply
Total
Atmosphere
Water
Food Supply
Total
Adult
mg/yr
Maximum Conditions
204
343
16
563
Minimum Conditions
0.41
0.73
2.00
3. 14
Mean Conditions
20.0
64.0
9.00
93
Percent
uptake
36
61
3
100. 00
13
23
64
100.. 00
22
69
10
100.00

-------
A similar estimate, not using MOMS data, has been made by

the National Academy of Sciences  (Nat. Acad. Sci., 1978a).

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

factor for chloroform to be 14 for the edible portions of

fish and shellfish consumed by Americans.  This estimate-

is based on measured steady-state bioconcentration studies

in bluegills.

III. PHARMACOKINETICS

     A.   Absorption

          The efficiency of chloroform absorption by the

gastrointestinal tract is virtually 100 percent in humans

(Fry, et al., 1972).  The.corresponding value by inhalation

is 49 to 77 percent (Lehmann and Hassegawa, 1910).  Quantita-

tive estimates of dermal absorption efficiency were not

encountered.  Since chloroform was used as an anesthetic

via dermal administration,  some dermal absorption by humans

can be assumed (U.S. EPA,  1979a).

     B.   Distribution

          Chloroform is transported to all mammalian body

organs and is also transported across the placenta.  Strain

differences for chloroform distribution in mice have been

documented by Vessell, et al.,  (1976).

     C.   Metabolism

          Most absorbed chloroform is not metabolized by

mammals.  Toxication, rather than detoxication, appears
                                                            »
to be the major consequence of metabolism and probably involves

mixed-function oxidase (MFO) enzyme systems.  This observa-

-------
tion is based on enhancement of chloroform  toxicity by MFO



inducers and the diminution of toxicity by MFO  inhibitors



(Ilett, et al., 1973, McLean, 1970).  At least  in  the liver,



covalent binding of a metabolite to  tissue  is associated



with tissue damage (Lavigne and Marchand, 1974).   Limited



human data (two people) suggest that about  50 percent of



absorbed chloroform is metabolized to C02 (Fry, et al.,



1972; Chiou, 1975).



     D.   Excretion



          In humans, the half-life of chloroform in the



blood and expired air is 1.5 hours  (Chiou,  1975) .  Most



unchanged chloroform and C02 generated from chloroform are



eliminated via the lungs.  Chlorine generated from chloroform



metabolism is eliminated via the urine (Taylor, et al.,



1974; Fry, et al., 1972).



IV.  EFFECTS



     A.   Carcinogenicity



          Eschenbrenner and Miller  (1945) demonstrated that



oral doses of chloroform administered over a 16-month period



induced hepatomas in strain A mice.  Based on variations



in dosing schedules, these researchers concluded that necro-



sis was prerequisite to tumor induction.



          In the National Cancer Institute bioassay of chloro-



form (NCI, 1976), hepatocellular carcinomas were induced



in mice (Table 1) and kidney epithelial tumors  were induced



in male rats (Table 2), following oral doses over  extended



periods of time.

-------
          Ten epidemiologic studies have been conducted



on the association of human exposure to chloroform and/or



other trihalomethanes with cancer.  A review of these studies



by the National Academy of Sciences (NAS, 1978b) indicated



that these studies suggest that higher concentrations of



trihalomethanes in drinking water may be associated with



an increased frequency of cancer of the bladder.  One of



these studies (McCabe, 1975)  claimed to demonstrate a statis-



tically significant correlation between age, sex, race,



adjusted death rate for total cancer, and chloroform levels.



     B.   Mutagenicity



          Chloroform yielded negative results in the Ames



assay  (Simmon, et al. 1977).



     C.   Teratogenicity



          At oral dose levels causing signs of maternal



toxicity, chloroform had fetotoxic effects on rabbits (100



mg/kg/day) and rats  (316 mg/kg/day) (Thompson, et al., 1974).



Fetal abnormalities  (acaudia, imperforate anus, subcutaneous



edema, missing ribs, and delayed ossification) were induced



when pregnant rats were exposed to airborne chloroform at



489 and 1,466 mg/m , 7 hrs/day, on days 6 to 15 of gestation.



At 147 mg/m  , the only effects were significant increases



in delayed skull ossification and wavy ribs (Schwetz, et



al. , 1974) .

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    Table 1.   Hepatocellular Carcinoma Incidence in Mice'
Male
     Controls
Colony    Matched
57TT~^    1718
                                   Low
                                   Dose
                             138 mg/kg  1850
     High
	Dose	
277 mg/kg  4VTB"

Female

(6%)
1/80
(1%)
(6%)
0/20
(0%)
(30%)
238 mg/kg 36/45
(80%)
(98%)
477 mg/kg 39/41
(95%)
Table  2.   Statistically  Significant Tumor  Incidence in Rats'
               Controls
          Colony    Matched

Kidney    0/99      0/19

epithelial

tumors/animals

P value   0.0000    0.0016
                         Males

                         Low
                         Dose
                                                       High
                                                       Dose
                   90 mg/kg

                          (8%)
                                           4/50   180/mg/kg   12/50

                                                        (24%)
 Source:  National Cancer Institute, 1976.

     D.   Other Reproductive Effects

          Pertinent data could not be located in the avail-

able literature.

     E.   Chronic Toxicity

          The NIOSH Criteria Document (1974) tabulates data

on the effect of chronic chloroform exposure in humans.

The primary target organs appear to be the  liver and kidneys,

with some signs of neurological disorders.  These effects

have been documented only with occupational exposures.
                             -5-47-

-------
With the exception of the possible relationship  to  cancer
(Section IV.A), chronic toxic effects in humans, attribut-
able to ambient levels of chloroform, have not been documented,
          The chronic effects of chloroform  in experimental
mammals is similar to the effects seen  in humans:   liver
necrosis and kidney degeneration  (Torkelson, et  al.,  1976;
U.S. EPA, 1979a).
     F.   Other Relevant Information
          Ethanol pretreatment of mice  reportedly enhances
the toxic effects of chloroform on the  liver (Kutob and
Plaa,  1961), as does high fat and low protein diets (Van
Oettingen, 1964; McLean, 1970).  These  data  were generated
using  experimental mammals.
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          Bentley, et al.  (1975) observed the 96-hour  LC5Q
values for rainbow trout,  (Salmo gairdner i), of  43,800 and
66,800 Jjg/l and for bluegills  (Lepomis  macrochirus) ,  100,000
to 115,000 jjg/1, all in static tests.   A 48-hour static
test with Daphnia magna resulted  in an  LC5Q  of 28,900  pg/1
(U.S.  EPA 1979a).  The observed 96-hour LC5Q for the  pink
shrimp (Panaeus duorarum) is 81,500 jjg/1.  (Bentley,  et
al. , .1975) .
     B.   Chronic Toxicity
          The chronic effects of chloroform  on Daphnia magna
were determined using flow-through methods with  measured
concentrations.  The chronic effect level was 2,546 pg/1
(U.S.  EPA, 1979a).  No other chronic data were available.
                              /
                             -5-4, s-

-------
     C.   Plant Effects

          Pertinent information could not be located  in

the available literature concerning acute chronic toxicity

of chloroform to plants.

     D.   Residues

          In the only residue study reported, the bluegill

(Lepomis macrochirus)  bioconcentrated chloroform six  times

after a 14-day exposure  (U.S. EPA, 1979a).  The tissue half-

life was less than one day.

VI.  EXISTING GUIDELINES AND STANDARDS

     Both the human health and aquatic criteria derived

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

reviewed; therefore, there is a possibility that these crite-

ria may be changed.

     A.   Human

          Based on the NCI mice data, and using the "one-

hit" model,  the EPA (1979a) has estimated levels of chloro-

form in ambient water which will result  in specified  risk

levels of human cancer:
Exposure Assumption      Risk Levels and Corresponding Criteria
     (per" day)              .         _?
                         0         10 '      10 °          10 5
2 liters of drinking     0    0.021 ug/1  0.21 ug/1     2.1 ug/1
water and consumption
of 18.7 grams fish and
shellfish.
                                                           »
Consumption of fish      0    0.175 fig/1  1.75 ug/1    17.5
shellfish only.
                              Sf
                            -sv*-

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     The  above  risks  assume  that  drinking  water  treatment



 and distribution  will have no  impact  on  the  chloroform con-



 centration.



     "The  NIOSH  time-weighted average  exposure  criterion



 for chloroform  is 2 ppm  or 9.8  mg/m .



     The  FDA  prohibits the use  of chloroform in  drugs, cos-



 metics, or  food contact  material  (14  FR  15026,  15029 April



 9, 1976).



     Refer  to the Halomethane  Hazard  Profile for discussion



 of criterion  derivation  (U.S.  EPA,  1979b).



     B.   Aquatic



          For chloroform,  the  draft cr't-~rion  to protect
                                         /


 freshwater  aquatic life,  based  on chronic  invertebrate toxi-



 city,  is  500  ^ig/1 as  a .24-hour  average and the concentration



 should  not  (based on  acute effects)  exceed 1,200 pg/l at



 any  time  (U.S.  EPA,  1979a).  To protect saltwater aquatic

                                       .)'

 life,  the concentration  of chloroform should not exceed



 620 jjg/1  as a 24-hour average  and the concentration should



.not  exceed  1,400  ^jg/1 at anytime  (U.S. EPA,  1979a) .   These



 were calculated from  an  experiment on a  marine invertebrate.
                               Sf

                             -sio-

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                                  CHLOROFORM
                                  REFERENCES
Bellar, T.A., et  al.   1974.  The occurrence of  organohalides in chlorinated
drinking water.   Jour. Am. Water Works Assoc.  66: 703.

Bentley,  R.E.,  et  al.   1975.    Acute  toxicity  of  chloroform  to  bluegill
(Lepomis  macrochirus),  rainbow  trout,  (Salmo  qairdneri),  and  pink  shrimp
(Penaeus  duorarum)T  Contract  No.  WA-6-99-1414-B.   U.S.  Environ.  Prot.
Agency.

Brass, H.J.  and R.F.  Thomas.  1978.  Correspondence  with  Region III.  Tech.
Support Oiv., U.S. Environ. Prot. Agency,  Washington, D.C.

Chiou, W.L.   1975.   Quantitation of hepatic and  pulmonary first-pass, effect
and  its  implications  in  pharmacokinetic   study.    I.  Pharmacokinetics  of
chloroform in man.  Jour.  Pharmacokin. Biopharmaceu.  3: 193.

Eschenbrenner, A.B. and E.  Miller.   1945.   Induction of hepatomas in mice by
repeated  oral administration of chloroform, with  observations  on  sex  dif-
ferences.  Jour. Natl. Cancer Inst.  5: 251.

Fry,  B.J.,  et al.   1972.   Pulmonary elimination  of  chloroform and its meta-
bolites in man.  Arch. Int. Pharmacodyn.  196: 98.

Hardie,  DJV.F.    1964.   Chlorocarbons  and  chlorohydrocarbons:  chloroform.
_In:  Kirk-Othmer  encyclopedia of chemical technology.   2nd ed.   John Wiley
and Sons, Inc.,  New York.

Ilett,  K.F.,  et  al.   1973.  Chloroform  toxicity  in mice:   Correlation  of
renal  and hepatic necrosis  with covalent binding  of metabolites  to tissue
macromolecules.   Exp. Mol. Pathol.  19: 215.

Irish,  D.O.   1972.    Aliphatic   halogenated  hydrocarbons.   Ln:  Industrial
hygiene and toxicology.  2nd ed.  John Wiley and Sons, Inc., New York.

Kutob, S.D. and G.L.  Plaa.   1961.  The effect of acute ethanol intoxication
on chloroform-induced liver damage.  Jour. Pharmacol. Exp. Ther.  135: 245.

Lavigne,  J.G. and C.  Marchand.   1974.   The role  of  metabolism in chloroform
hepatotoxicity.   Toxicol.  Appl.  Pharmacol.  29: 312.

Lehmann,  K.B.  and Hassegawa.   1910.   Studies of the absorption  of chlori-
nated hyrocarbons in animals and humans.  Archiv. fuer Hygiene.  72: 327.

McCabe, L.J.   1975.   Association between  trihalomethanes  in  drinking water
(NORS data) and mortality.  Draft report.   U.S. Environ. Prot. Agency.
                                                                       »
McLean, A.E.M.  1970.   The effect  of  protein deficiency  and  microsomal en-
zyme  induction by DDT  and phenobarbitone  on  the  acute toxicity of chloroform
and pyrrolizidine alkaloid retrorsine.  Brit. Jour.  Exp. Pathol.  51: 317.

-------
National  Academy  of  Sciences.   1978a.  Nonfluorinated  halomethanes  in the
environment.  Environ. Studies Board, Natl. Res. Council, Washington, O.C.

National Academy of  Sciences/National  Research  Council.   1978b.  Epidemiolo-
gical studies of cancer  frequency and  certain organic  constituents of drink-
ing water - A review of recent literature for U.S. Environ. Prot. Agency.

National  Cancer Institute.   1976.    Report on  carcinogenesis bioassay  of
chloroform.  Natl.  Tech. Inf. Serv.  P8-264018.   Springfield, Va.

National Institute for  Occupational  Safety and Health.  1974.   Criteria for
a  recommended  standard...Occupational-exposure  to chloroform.   NIOSH Publ.
No. 75-114.  Dept.  Health Educ. Welfare, Washington,  O.C.

Neely,  W.8.,  et al.   1976.   Mathematical   models predict  concentration-time
profiles  resulting  from chemical  spill in river.  Environ.   Sci.  Technol.
10: 72.

Schwetz, B.A.,  et  al.  1974.  Embryo and  fetotoxicity of  inhaled chloroform
in rats.  Toxicol.  Appl. Pharmacol.   28: 442.

Simmon,  J.M.,  et  al.  1977.   Mutagenic activity of chemicals  identified in
drinking water.  In:  0. Scott,  et  al., (ed.)   Progress in genetic toxico-
logy.  Elsevier/North Holland Biomedical Press,  New York.

Taylor, D.C., et al.  1974.   Metabolism of  chloroform.   II.  A  sex difference
in the metabolism of  (l^C)-chloroform in mice.   Xenobiotica  4: 165.

Thompson,  D.J.,  et  al.   1974.  Teratology studies on  orally .administered
chloroform in the rat and rabbit.  Toxicol. Appl. Pharmacol.  29: 348.

Torkelson, T.R., et al.  1976.   The  toxicity of  chloroform  as  determined by
single  and  repeated   exposure  of laboratory animals.  Am.  Ind.  Hyg.  Assoc.
Jour.  37: 697.

U.S.  EPA.   1975.   Development  document for interim  final  effluent limita-
tions  guidelines and new  source performance standards  for the significant
organic  products segment of the organic chemical  manufacturing point source
category.  EPA-440/1-75/045.  U.S.  Environ. Prot. Agency, Washington, D.C.

U.S.  EPA.   1978a.   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.   1978b.   Office  of Water  Supply.  Statement  of  basis and purpose
for an  amendment to  the national interim primary  drinking  water regulations
on trihalomethanes.  Washington, D.C.

U.S.  EPA.    1979a.    Chloroform:  Ambient  Water  Quality Criteria. Document.
(Draft)
                                                                       »

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

-------
Van Oettingen, w.F.  1964.  The  hydrocarbons  of industrial  and toxicological
importance.  Elsevier Publishing Co., New York.

Vessell, E.S.,  et al.   1976.   Environmental and genetic  factors  affecting
the response of laboratory animals to drugs.  Fed. Am.  Soc.  Exp.  Biol.  Proc.
35: 1125.

Windholz,  M.,  ed.   1976.  The  Merck Index.  9th  ed.   Merck and Co.,  Inc.,
Rahway, N.J.
                                   -5-73-

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                                      No. 48
           Chloromethane
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.   20460

           APRIL 30,  1980
                 -S7H-

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

-------
                        CHLOROMETHANE



                           SUMMARY



     Chloromethane is toxic to humans by its action on the



central nervous system.  In acute toxicity, symptoms consist



of blurring vision, headache, vertigo, loss of coordination,



slurring of speech, staggering, mental confusion, nausea,



and vomiting.  Information is not available on chronic toxicity,



teratogenicity, or carcinogenicity.  Chloromethane is highly



mutagenic to the bacteria, Salmonella typhimurium.



     Only three toxicity tests have been conducted on three



species of fish yielding acute values ranging from 147,000



to 300,000 ^ag/1.  Tests on aquatic invertebrates or plants



have not been conducted.

-------
                        CHLOROMETHANE


I .    INTRODUCTION


     This profile is based on the Ambient  Water  Quality


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


     Chloromethane  (CH.,C1; methyl chloride; molecular  weight


50.49) is a colorless, flammable, almost odorless  gas  at

room temperature and pressure (Windholz, 1976).  Chloromethane


has a melting point of -97.7°C, a boiling  point  of -24.2°C,


a specific gravity of 0.973 g/ml at -10°C, and a water solubi-


lity of  5.38 x 10  >ig/l.  It is used as a refrigerant,


a methylating agent, a dewaxing agent,  and catalytic solvent

in synthetic rubber production  (MacDonald, 1964).   However,


its primary' use is as a chemical intermediate  (Natl.   Acad.


Sci., 1978).  Chloromethane is  released to the environment

by manufacturing and use emissions, by  synthesis during


chlorination of drinking water  and municipal sewage, and
          \-
by natural-'synthesis, with the  oceans as the primary site


(Lovelock  -1975) .  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 Chloromethane


qualitatively in finished drinking waters  in the U.S.  How-

ever, there are no data on its  concentration in  drinking


water, raw water, or waste-water (U.S.  EPA, 1979a) ,  probably'

because it is more reactive than other  chlorinated methanes

(Natl. Acad. Sci. , 1978) .
                            -577-

-------
     B .    Food

          There is no information on the presence of chloro-


methane in food.  There is no bioconcentration factor  for

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


     C.    Inhalation


          Saltwater atmospheric background concentrations

of chloromethane averaging about 0.0025 mg/m  have been


reported  (Grimsrud and Rasmussen, 1975; Singh, et al.  1977).


This is higher than reported average continental background


and urban levels and suggests that the oceans are a major


source of global chloromethane (National Acad. Sci., 1978).


Localized sources, such as burning of tobacco or other com-


bustion processes, may produce high indoor-air concentra-


tions of chloromethane  (up to 0.04 mg/m )  (Natl. Acad. Sci.,


1978).  Chloromethane is the predominant halomethane in

indoor air, and is generally in concentrations two to  ten


times ambient  background levels.


III. PHARMACOKINETICS

     A.    Absorption


          Chloromethane is absorbed readily via' the lungs,


and to a less  significant extent via the skin.  Poisonings

involving gastrointestinal absorption have not been reported


(Natl. Acad. Sci., 1977; Davis, et al. , 1977).


     B.    Distribution '


          Uptake of chloromethane by the blood is rapid
                                                            i
but results in only moderate blood levels with continued


exposure.  Signs and pathology of intoxications suggest
                            -S7S-

-------
wide tissue (blood, nervous tissue, liver, and kidney) distri-



bution of absorbed chloromethane  (Natl. Acad. Sci., 1978).



     C.   Metabolism



          Decomposition and sequestration of chloromethane



result primarily by reaction with sulfhydryl groups in intra-



cellular enzymes and proteins  (Natl. Acad. Sci., 1977).



IV.  EFFECTS



     A.   Carcinogenicity



          Pertinent information could not be located  in



the available literature.



     B.   Mutagenicity



          Simmon and coworkers  (1977) reported that chloro-



methane was mutagenic to Salmonella tryphimurium strain



TA 100 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.  Also, Andrews, et al. (1976) have demonstrated



that chloromethane was mutagenic to S_._ typhimur ium strain



TA1535 in the presence and absence of added liver homogenate



preparations .



     C.   Teratogenicity and Other Reproductive Effects



          Information on positive evidence of teratogenisis



or other reproductive effects was not available in the literature,



     D.   Chronic Toxicity



          Under prolonged exposures to chloromethane  (dura-
                                                            »


tion not specified) increased mucous flow and reduced mucosta-
                            -579-

-------
tic effect of other agents  (e.g., nitrogen oxides) were



noted in cats (Weissbecker, et al. , 1971).



     E.    Other Relevant Information



          In acute human intoxication, chloromethane pro-



duces central nervous system depression, and systemic poison-



ing cases have also involved hepatic and renal injury  (Hansen,



er al.,  1953; Spevac, et al., 1976).



V.   AQUATIC TOXICITY



     A.    Acute Toxic ity



          A single 96-hour  static renewal test serves as



the only acute study for freshwater providing an adjusted



LC5Q value of 550,000 ug/1  for the bluegill sunfish  (Lepomis



macrochirus) .  (Dawson, et  al., 1977).  Studies on fresh-



water invertebrates were not found.  For the marine  fish,



the tidewater silversides  (Menidia beryllina) , a 96-hour



static renewal assayed provided an LC5Q value of 270,000



ug/1 (Dawson, et al. , 1977).  Acute studies on marine inverte-



brates were not found.



     B.    Chronic Toxicity



          In a review of the available literature, chronic



testing with chloromethane  has not been reported.



     C.    Plant Effects



          Pertinent information could not be located in the



available literature.



VI.  EXISTING GUIDELINES AND STANDARDS



     Neither the human nor  the aquatic criteria derived



by U.S.  EPA, 1979a, which are . summarized below, have gone
                            -580-

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



a possibly that these criteria may be changed.



     A.   Human



          OSHA (1976) has established the maximum acceptable



time-weighted average air concentrations for daily eight-



hour occupational exposure at 210 mg/m .  The U.S. EPA  (1979a)



Draft Water Quality Criteria for Chloromethane is 2 ug/1.



Refer to the Halomethanes Hazard Profile for discussion



of criteria derivation (U.S. EPA, 1979b) . *-



     B.   Aquatic



          Criterion recommended to protect freshwater or-



ganisms have been drafted as 7,000 ug/1, not to exceed 16,000



ug/1 for a 24-hour average concentration.  For marine life,



the criterion has been drafted as 3,700 pg/I, not to exceed



8,400 pg/1 as a 24-hour average concentration.
                            -SSJ-

-------
                        CHLOROMETHANE
                          REFERENCES

Andrews, A.W.,  et al.  1976.  A comparison of the mutagenic
properties of vinyl chloride and methyl chloride.  Mutat.
Res. 40: 273.

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, of Contract
No.  68-01-4315.  Off. Toxic Subst.,  U.S. Environ. Prot.
Agency, Washington, D.C.

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

Grimsrud, E.P., and R.A. Rasmussen.  1975.  Survey and an-
alysis of halocarbons in the atmosphere by gas chromatography-
mass spectrometry.  Atmos. Environ. 9: 1014.

Hansen, H., et al.  1953.  Methyl chloride intoxification:
Report of 15 cases.  AMA Arch. Ind. Hyg. Occup. Med. 8:
328.

Lovelock, J.E.   1975.  Natural halocarbons in the air and
in the sea.  Nature 256: 193.

MacDonald, J.D.C.  1964.  Methyl chloride intoxication.
Jour. Occup. Med. 6: 81.

National Academny of Sciences.  1977.  Drinking water and
health.  Washington, D.C.

Nation-al Academy of Sciences.  1978.   Nonfluorinated halo-
methanes in the environment.  Washington, D.C.

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

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, N2o and other atmospheric constituents.'
Atmos. Environ. 11: 819.

-------
Spevac, L., et al.  1976.  Methyl chloride poisoning in
four members of a family.  Br.  Jour. Ind. Med. 33: 272.

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.  1979a.  Halomethanes:  Ambient Water Quality Cri-
teria  (Draft).

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

Weissbecker, L., et al.  1971.   Cigarette smoke and tracheal
mucus  transport rate:  Isolation of effect of components
of smoke.  Am. Rev. Resp. Dis.  104: 182.

Windholz, M.,   (ed.)  1976.  The Merck Index.  Merck and Co.,
Rahway, N.J.
                            -533-

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                                      No. 49
        2-Chlo ronaphthalene


  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.
                          -SSS*-

-------
                       2-CHLORONAPHTHALENE




SUMMARY


     Monochlorinated naphthalenes are relatively insoluble  in


water.  They can be slowly degraded by bacteria and are subject


to photochemical decomposition.  Monochlorinated naphthalenes


appear to bioconcentrate in plants and animals exposed to the


substances.  2-Chloronaphthalene has been identified as a pol-


lutant in a variety of industries.


     No information was located on the carcinogenicity, mutagen-


icity, or teratogenicity of 2-chloronaphthalene or other mono-


chlorinated naphthalenes.  The metabolism of some chlorinated


naphthalenes, however, proceeds through an epoxide mechanism.  If


an epoxide is formed as an intermediate in the metabolism of 2-


chloronaphthalene, it could react with cellular macromolecules


possibly resulting in cytotoxicity, mutagenicity, oncogenicity,


or other effects.




I.  INTRODUCTION


     This profile is based on the Ambient Water Quality Criteria


Document for Chlorinated Naphthalenes (U.S. EPA, 1979b).


     2-Chloronaphthalene (C,QH-C1; molecular weight 162) is a


crystalline solid with a melting point of 61°C and a boiling


point of 256°C.  Its density at 16°C is 1.27.  It is insoluble in
                                                            »

water and soluble in many organic solvents (Weast; 1972 and


Hardie, 1964).

-------
     A review of the production  range  (includes  importation)

statistics for 2-chloronaphthalene  (CAS. No.  91-58-7) which  is

listed in the inital TSCA  Inventory  (1979a) has  shown that

between 1,000 and 9,000 pounds of this  chemical  were

produced/imported in 1977.jV

     Monochloronaphthalenes and  mixtures of mono- and dichloro-

naphthalenes have been used for  chemical-resistant gauge  fluids

and instrument seals, as heat exchange  fluids, high-boiling

specialty solvents  (e.g.,  for solution  polymerization), color

dispersions, engine crankcase additives to dissolve sludges  and

'gums, and as ingredients in motor tuneup compounds.  Monochloro-

naphthalene was formerly used as a wood preservative  (Dressier,

1979).



II. EXPOSURE
                                                 1
     A.  Environmental Fate

     Polychlorinated naphthalenes do not occur •'  jturally  in  the

environment.  Potential environmental accumulation can occur

around points of manufacture of  the compounds or products

containing them, near sites of disposal of polychorinated

naphthalene-containing wastes, and, because polychlorinated
   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).

-------
biphenyls (PCBs) are to some extent contaminated by polychlori-



nated naphthalenes (Vos _et_ _al_. 1970; Bowes et al. 1975) near



sites of heavy PCB contamination.



     Because polychlorinated naphthalenes are relatively insol-



uble in water, they are not expected to migrate  far from their



point of disposition. The use of mono- and dichlorinated naphtha-



lenes as an engine oil additive and as a polymerization solvent



in the fabric industry suggests possible contamination of  soil or



water.



     Walker and Wiltshire (1955) found that soil bacteria  when



first grown on naphthalene could also grow on 1-chloronaph-



thalene, producing a diol and chlorosalicylic acid.  Canonica et



al. (1957) found similar results for 2-chloronaphthalene.  Okey



and Bogan (1965) studied the utilization of chlorinated sub-



strates by activated sludge and found that naphthalene was



degraded at a fairly rapid rate, while 1-and 2-chloronaphthalenes



were handled more slowly.



     Ruzo ^t_ _al^. (1975) studied the photodegradatiori of 2-chloro-



naphthalene in methanol.  The major reaction pathways seen were



dechlorination and dimerization.  Jaffe and Orchin (1966)  indi-



cated that any 2-chloronaphthalene present at the surface  of



water could be degraded by sunlight to naphthalene.  In the



aquatic environment, 2-chloronaphthalene can exist as a surface



film, be adsorbed by sediments, or accumulated by biota.

-------
     B.  Bioconcentration



     Monochlorinated naphthalenes appear to bioconcentrate  in the



aquatic environment.  Adult grass shrimp (Palaemonetes pugio)



were exposed to a mixture of mono- and dichloro naphthalenes for



15 days.  The concentration of chloronaphthalenes detected  in the



shrimp was 63 times that of the experimental environment.   When



removed from the contaminated environment, however, the concen-



tration in the shrimp returned to virtually zero within 5 days



(Green and Neff, 1977).



     Erickson £t_\al_- (1978a) reported a higher relative biocon-



centration of the lower chlorinated naphthalenes in the fruit of



apple trees grown on contaminated soil.  The soil was found to



have a polychlorinated naphthalene level of 190 ug/kg of which



1.6 ug/kg consisted of monochloronaphthalenes.  While the apples



grown on this soil had only 90 ug/kg of polychlorinated naphtha-



lenes, the level of monochloronaphthalene was 62 ug/kg.



     C.  Environmental Occurrence



     2-Chloronaphthalene has been identified as a pollutant in a



variety of industries,  e.g. organic chemical, rubber, power



generation, and foundries (U.S. EPA, 1979c).



     Chlorinated naphthalenes have been found more consistently



in air and soil samples than in associated rivers and streams



(Erickson _et_ _al_.,   1978b).  The air samples contained mainly the



mono-, di- and trichlorinated naphthalenes, while soil contained
                                                            #


mostly the tri-, tetra- and pentachlorinated derivatives.



     To date polychlorinated naphthalenes have not been identi-



fied in either drinking water or market basket food.  The Food



and Drug Administration has had polychlorinated naphthalene

-------
monitoring capability for  foods  since  1970, but has  not reported


their occurrence in food  (U.S. EPA,  1975).




III. PHARMACOKINETICS


     Ruzo et al. (1976b)  reported  the  presence of  2-chloronaph-


thalene in the brain, kidney, and  liver of pigs six  hours  after


injection.  Small concentrations of  3-chloro-2-naphthol,  a


metabolite , were seen in  the kidney and  liver with  large  amounts


occurring in the urine and bile.   The  metabolism of  some  chlori-


nated napthalenes proceeds through an  epoxide mechanism (Ruzo et


al. 1975, 1976ab; Chu _et_ _al_. , 1977ab) .




IV.  HEALTH EFFECTS


     A.  Teratogenicity,  Mutagenicity, and Carcinogenicity


     No information was  located  on the carcinogenicity, muta-


genicity, or teratogenicity  of polychlorinated naphthalenes.


     If an epoxide is formed as  an intermediate in the  metabolism


of 2-chloronaphthalene,  it could react with cellular macromole-


cules.  Binding might occur  with.protein, RNA, and DMA  resulting


in possible cytotoxicity,  mutagenicity, oncogenicity, or  other


effects (Garner, 1976; Heidelberger, 1973;.Wyndham and  Safe,


1978).


     B.  Other Toxity


     In man, the first disease recognized as being associated
                                                            0

with occupational exposure to higher polychlorinated naphthalenes


was chloracne.  Occurrence of this disease was associated  with


the manufacture or use of  polychloronaphthalene-treated electri-


cal cables.  Kleinfeld _et_ ^1_. (1972) noted that workers at

                               -590-

-------
an electric coil manufacturing plant had no cases of chloracne
while using a mono- and dichloronaphthalene mixture.  When a
tetra-/pentachlorinated naphthalene mixture was  substituted for
the original mixture, 56 of the 59 potentially exposed workers
developed chloracne within a "short" time.
     The lower chlorinated naphthalenes appear to have low acute
toxicity.  Mixtures of mono-/dichloronaphthalenes and tri-/tetra-
chloronaphthalenes at 500 mg/g in a mineral oil  suspension
applied to the skin of the human ear caused no response over a
30-day period.  A mixture of penta-/hexachloronaphthalenes given
under the same conditions caused chloroacne (Shelley and Kligman,
1957).
     The oral LD50 for rats and mice is 2078 mg/kg and 886 mg/kg
respectively  (NIOSH, 1978).  No mortality or illness was reported
in rabbits given 500 mg/kg orally (Cornish and Block, 1958).

V.   AQUATIC EFFECTS
     The LC50 (ppb) of a mixture of 60% mono- and 40% dichloro-
naphthalenes in grass shrimp (Palaemonetes pugio)is as follows:
                                       72-hr     96-hr
                   post larval stage     -        449
                   adult                370       325
                                       (Green and Neff, 1977)
VI.  EXISTING GUIDELINES
                                                            »
     There are no existing guidelines for 2-chloronaphthalene.

-------
                           BIBLIOGRAPHY
Bowes, G. W. j5t_ _a_l_.  1975.  Identification of  chlorinated  diben-
zofurans in American polychlorinated biphenyls.  Nature  256,  305.
(as cited in U.S. EPA, 1979b).

Canonica, L. _et_ _al_. 1957.  Products of microbial oxidation of
some substituted naphthalenes. Rend. 1st. Lombardo  Sci.  91,  119-
129 (Abstract).

Cornish H.H., and W.D. Block. 1958.  Metabolism  of  chlorinated
naphthalenes. J. Biol. Chem. 231, 583.   (as cited in  U.S.  EPA,
1979b).

Chu, I., et _al_.  1977a.  Metabolism and  tissue distribution of
(1, 4, 5,8-^C)-l, 2-dichloronaphthalene in rats. Bull.  Environ.
Contain. Toxicol. 18, 177.  (as cited in U.S. EPA, 1979b).

Chu, I., et al.  1977b.  Metabolism of chloronaphthalenes.  J.
Agric. Food Chem. 25, 881.  (as  ' jted in U.S.  EPA,  1979b).

Dressier, H.  1979.  Chlorocarbons and chlorohydrocarbons:
chlorinated naphthalenes.  In. Standen A. ed.  Kirk-Othmer
Encyclopedia of Chemical Technology, 3rd ed. New York:  John  Wiley
and Sons, Inc.

Erickson, M.D., et al.  1978a.   Sampling and analysis for
polychlorinated naphthalenes in'he environment  J.  Assoc.  Off.
Anal. Chem. 61, 1335.  (as cited-'in U.S. EPA,  1979b).

Erickson, M.D., et_ _al_.  1978b.   "^velopment of methods  for
sampling and analysis of polychlorinated naphthalenes in ambient
air. Environ. Sci. Tech. 12(8),  927-931.

Garner, R.C.  1976.  The role of epoxides in bioactivation and
carcinogenesis.  In;  Bridges, J.  W. and L. F.  Chasseaud,  eds.
Progress in drug metabolism, Vol. 1. New York: John Wiley  and
Sons. pp. 77-128.

Green, F. A., Jr. and J. M. Neff.  1977.  Toxicity, accumulation,
and release of three polychlorinated naphthalenes (Halowax 1000,
1013, and 1099) in postlarval and adult grass  shrimp,
Palaemonetes pugio. Bull. Environ. Contam. Toxicol. 14,  399.

Hardie, D.W.F.  1964.  Chlorocarbons and chlorohydrocarbons:
chlorinated naphthalenes.  In: Kirk-Othmer Encyclopedia of
Chemical Technology. 2nd ed. John Wiley and Sons. Inc., New  York.

Heidelberger, C.  1973.  Current trends in carcinogenesis.  Proc.
Fed. Am. Soc. Exp. Biol.  32,2154-2161.

Jaffe, H. H. and M. Orchin.  1966.  Theory and aplication  of
ultraviolet spectroscopy.  Wiley Pub. New York>  624pp.

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Kleinfeld, M. ,  et al_-  1972.  Clinical  effects  of  chlorinated
naphthalene exposure. J. Occup. Med. _14_, 377-379.   (as cited  in
U.S. EPA, 1979b).

National Institute of Occupational Safety  and Health.   1978.
Registry of Toxic Effects of Chemical Substances.   DHEW Publ. No.
79-100.

Okey, R. W. and R. H. Bogan.  1965.  Apparent involvement  of
electronic mechanisms in limiting microbial metabolism  of
pesticides. J.  Water Pollution Contr. Fedr. 37, 692.

Ruzo, L.O., _et_ _al_.  1975.  Hydroxylated metabolites of  chlo-
rinated naphthalenes (Halowax 1031)  in  pig urine.  Chemosphere 3,
121-123.

Ruzo, L. O. , _et_ al_.  1976a.  Metabolism of chlorinated
naphthalenes. . J. Agric. Food Chem. 24, 581-583.

Ruzo, L.O., et al. 1976b.  Uptake and distribution of
chloronaphthalenes and their metabolities  in pigs.  Bull.
Environ. Contam. Toxicol. 16(2), 233-239.

Shelley, W. B., and A. M. Kligman.   1957.  The  experimental
production of acne by penta-and hexachloronaphthalenes.  A.M.A.
Arch'. Derma to 1. 7j, 689-695.  (as cited in U.S. EPA, 1979b) .

U.S. EPA.  1975.  Environmental Hazard Assessment  Report:
Chlorinated Naphthalenes. (EPA 560/8-75-001).

U.S. EPA.  1979a.  Toxic Substances  Control Act Chemical
Substance Inventory, Production Statistics for  Chemicals on  the
Non-Confidential Initial TSCA Inventory, .

U.S. EPA.-  1979b.  Ambient Water Quality Criteria:  Chlorinated
Naphthalenes.  PB-292-426.

U.S. EPA. Unpublished data obtained  from the U.S.  EPA
Environmental Research Laboratory, Athens, Georgia, February 22,
1979c.

Vos, J.G., et al.  1970.  Identification and toxicological evalu-
ation of chlorinated dibenzofurans and chlorinated  naphthalenes
in two commercial polychlorinated biphenyls.  Food  Cosmet.
Toxicol.  _§_, 625.  (as cited in U.S. EPA,'  1979b)

Walker, N. and G.H. Wiltshire.  1955.  The decomposition of  1-
chloro- and 1-bromonaphthalene.by soil bacteria. J. Gen.
Microbiol. 12,  478-483.

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Weast, R.C., ed.  1972.  CRC Handbook  of Chemistry  and Physics
CRC Press, Inc., Cleveland, Ohio.

Wyndham, D., and S. Safe.  1978.   In vitro metabolism  of 4-
                                ss

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                                      No. 50
           2-Chloropheno1


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

           APRIL 30, 1980

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

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                       2-CHLOROPHENOL



                           SUMMARY



     Insufficient data exist  to  indicate  that  2-chlorophenol



is a carcinogenic agent.  2-Chlorophenol  appears  to act as  a



nonspecific irritant in promoting tumors  in  skin  painting



studies.  No information  is available  on  mutagenicity,  tera-



togenicity, or subacute and chronic  toxicity.   2-Chlorophenol



is a weak uncoupler of oxidative phosphorylation  and a  con-



vulsant.



     2-Chlorophenol is acutely toxic to  freshwater fish at



concentrations ranging from 6,590 to 20,170  ug/1.   No marine



studies are available.  Concentrations greater than 60  ug/1



have been reported to taint cooked rainbow trout  flesh  in



flavor  impairment studies.

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I.   INTRODUCTION

     This profile is based primarily on the Ambient Water

Quality Criteria Document for 2-Chlorophenol  (U.S. EPA,

1979) .

     2-Chlorophenol (ortho-chlorophenol) is a  liquid  having

the empirical formula CgH^Cl (molecular weight: 128.56).

It has  the following physical/chemical properties  (Rodd,

1954; Judson and Kilpatrick, 1949; Sax, 1975;  Stecher, 1968;

Henshaw, 1971):
          Melting Point:        8.7°C
          Boiling Point Range:  175-176°C
          Vapor Pressure:       1 mm Hg at 12.1°C
          Solubility:           Slightly soluble  (lg/1)
                                   in water at 25°C and
                                   neutral pH

     2-Chlorophenol is a commercially produced chemical used

as an intermediate in the production of higher chlorophenols

and phenolic resins and has been utilized in a process for

extracting sulfur and nitrogen compounds from  coal (U.S. EPA,

1979).

     2-Chlorophenol undergoes photolysis in aqueous solutions

as a result of UV irradiaton (Omura and Matsuura,  1971;

Joschek and Miller, 1966).  Laboratory studies suggest that

microbial oxidation could be a degradation route for  2-chlo-

rophenol (Loos, et al., 1966; Sidwell, 1971; Nachtigall and

Butler, 1974).  However, studies performed by  Ettinger and

Ruchhoft (1950) on the persistency of 2-chlorophenol  in sew-

age and polluted river water indicated that the removal of
                                                          «
monochlorophenols requires the presence of an  adapted micro-

flora.

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II.   EXPOSURE




     A.   Water



          The generation of waste  from  the  commercial  produc-



tion and use of 2-chlorophenol  (U.S. EPA, 1979)  and  the  inad-



vertent synthesis of 2-chlorophenol due  to  chlorination  of



water contaminated with phenol  (Aly, 1968:  Barnhart  and  Camp-



bell, 1972; Jolley, 1973; Jolley,  et al., 1975)  are  potential



sources of contamination of water  with  2-chlorophenol.   How-



ever, no data regarding 2-chlorophenol  concentrations  in fin-




ished drinking water are available (U.S.  EPA,  1979).



     B.   Food



          Information on levels of 2-chlorophenol  in foods  is



not available.  Any contamination  of foods  is probably  indi-



rect as a result of use and subsequent  metabolism  of phenoxy-



alkanoic herbicides (U.S. EPA, 1979).   Although  residues of



2,4-dichlorophenol were found in tissues of animals  fed  2,4-D



and nemacide containing food  (Clark, et  al.  1975);  Sherman,



et al. 1972), no evidences were cited to indicate  the  pres-



ence of 2-chlorophenol; moreover,  there was  no  contamination



of 2-chlorophenol in milk and cream obtained from  cows  fed



2,4-D treated food (Bjerke, et al.  1972).



          The potential for airborne exposure to 2-chloro-



phenol in the general environment,  excluding occupational ex-



posure, has not been reported (U.S. EPA, 1979).



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



average bioconcentration factor for 2-chlorophenol and  the*



edible portion of fish and shellfish consumed by Americans at

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490.  This estimate is based on measured steady  state biocon-


centration studies in bluegills.


     C.   Inhalation


          Pertinent data regarding concentrations  of  2-chloro-


phenol in ambient air could not be found in  the  available


literature.


III. PHARMACOKINETICS


     A.   Absorption


          Data dealing directly with the absorption of 2-


chlorophenol by humans and experimental animals  has not been


found.  Chlorophenol compounds are generally  considered to be


readily absorbed, as would be expected from  their  high lipid


solubility and low degree of ionization at physiological pH


(Doedens, 1963; Farquharson, et. al. , 1958 ) .   Toxicity studies


indicate that 2-chlorophenol is absorbed through the  skin.


     B.   Distribution


          Pertinent data regarding tissue distribution of 2-


chlorophenol was not located in the available  literature.


     C.   Metabolism


          Data regarding the metabolism of 2-chlorophenol in


humans was not available (U.S. EPA, 1979).   Based  on  experi-


mental work in two species, it appears that  the  metabolism of


2-chlorophenol in mammals is similar to that  of  phenol in


regard to the formation and excretion of sulfate and  glucur-


onide conjugates (Von Oettingen, 1949;  Lindsay-Smith,  et al.
                                                           *

1972)  Conversion of chlorobenzene to monochlorophenols,


including 2-chlorophenol, has been shown in  vitro  with rat
                               If

                             -6,00-

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