DATE:


SUBJECT:




  FROM:



    TO:
December 2,  1980

Background Document:  Resource Conservation and Recovery Act
Subtitle C
VotAtt-t-, J/£lA-Vj.^/H X^-^
Angela'WTlkes, Publications  Officer
Office of Solid Waste  (WH-562)

EPA Regional and Headquarters Librarians
               Background Documents  1941.28 "Listing of Hazardous Wastes

          (Section 3001 Parts 261.31  and  261.32)" and 1941.29 "Appen-

          dix A-Health and Environmental  Effect  Profiles"  will  be sent

          in replacement of existing  documents of the same title. Please

          note this change. Thank you.
         WH-562: AWIlkesrjll:12-2-80
  FORM 1320-6 (REV. 3-76)

-------
                          Preface








     These health and environmental effect profiles have




been compiled to support the listing of approxmately 170




of the hazardous constituents identified on Appendix VIII




in the regulations (40 CFR, Part 261).  These profiles are



also being used to support the listing of hazardous wastes




in Subpart T) of Part 261, due to the presence in the



wastes, of these hazardous constituents. Many of these



profiles have been summarized from the water quality criteria



documents prepared in support of various programs under



the Clean Water Act.  In each case, however, the document



Is based on information and references available to the



Agency and which are referenced in each individual document.

-------
                            Table of Contents
Chemical  Substance(Document Number)                            Page




Acetaldehyde(l)                                                1-1




Acetonitrile(2)                                                2-1




Acetophenone(3)                                                3-1




Acetyl Chloride(4)                                             4-1




Acrolein(S)  '                                                  5-1



Acrylamide(Reserved)




Acrylonitrile(7)                                               7-1




Aldrin(8)                                                      8-1




Allyl Alcohol(9)                                               9-1




Aniline (172)                                                172-1




Antimony(lO)                                                  10-1




Arsenic(ll)                                                   11-1




Asbestos(12)                                                  12-5




Barium(13)                                                    13-1




Benzal Chloride(14)                                           14-1




Benzene(lS)                   .                                15-1




Benzidine(16)                                                 16-1




Benz(a)anthracene(17)          .                               17-1




Benzo(b)fluoranthene(lS)                                      18-1




Benzo(a)pyrene(19)                                            19-1




Benzotrichloride(20)                                          20-1




Benzyl Chloride(21)                                           21-1

-------
Chemical Substance(Document Number)                            Page


Beryllium(22)  .                                                22-1
     *


Bis(2-chloroethoxy) Methane(23)                                23-1


Bis(2-chloroethyl) Ether(24)                                   24-1



Bis(2-chloroisopropyl) Ether(25)                               25-1


Bis(chloromethyl) Ether(26)                                    26-1



Bis(2-ethylhexyl) Phthalate(27)                                27-1



Bromoform(28)                                                  28-1


Broraonethane(29)                                                29-1



4-Bronophenyl Phenyl Ether(30)                                 30-1


Cadmium(31)                                                    31-1


Carbon DisulfIde(32)                                           32-1


Carbon Tetrachloride (Tetrachloromethane)(33)                  33-1


Chloral(34)                                                    34-1



Chlordane(35)                                                  35-1


Chlorinated Benzenes(36)                                       36-1


Chlorinated Ethanes(37)                                        37-1


Chlorinated Naphthalenes(38)                                   38-1



Chlorinated Phenols(39).                                        39-1


Chloroacetaldehyde(40)                                         40-1


Chloroalkyl Ethers(41)                                         41-1


Chlorobenzene(42)                                            '  42-1


p-Chlorb-m-cresol(43)                                          43-1


Chloroethane(44)                                                44-1



Chloroethene(Vinyl Chloride)(45)                               45-1
                                  -iii-

-------
 Chemical Substance(Document Number)                            Page




 2-Chioroethyl Vinyl Ether(46)                                   46-1




 Chloroform (Carbon Trichlororaethane)(47)                        47-1




 Chlororaethane(48)                                              48-1




 2-Chloronaph'thalene(49)                                         49-1




 2-Chlorophenol(50)               _                             50-1




 Chromium(51)                                                    51-1



 Chrysene(52)  •                                                  52-1




 Cresote(53)                                                     53-1




 Cresols  and  Cresylic Acid(54)                                   54-1




 Crotonaldehyde(55)                                             55-1




 Cyanides(56)                                                    56-1




 Cyanogen Chloride(57)                                           57-1




 DDD(58)                                                         58-1




 DDE(59)                                                         59-1




 DDT(60)                                                         60-1




 Dibromochlororaethane(61)                                        61-1




•Di-n-butyl Phthalate(62)                                        62-1




 Dibenzo(a ,h)anthracene( 63)                                      63-1




 1,2-Dichlorobenzene(64)                                         64-1




 l,3-Dichlorobenzene(65)                         .                65-1




 1,4-Dichlorobenzene( 66)                                         66-1




 Dichlorobenzenes(67)                                            67-1




 3,3'-Dichlorobenzidine(68)                                      68-1




 l,l-Dichloroethane(69)                                          69-1
                                   -iv-

-------
Chemical Sub3tance(Pocument Number)                        '   Page




l,2-Dichloroethane(70)                                        70-1




l,l-Dichloroethylene(71)                                      71-1




trans-l,2-Dichloroethylene(72)                                72-1




Dichloroethylenes(73)                                         73-1



Dichloromethane(74)                                           74-1




2,4-Dichlorophenol(75)                                        75-1




2,6-Dlchlorophenol(76)                                        76-1



2,4-Dichlorophenoxyacetic Acid (2,4-D)(77)                    77-1




l,2-Dichloropropane(78)                                       78-1




Dlchloropropanes/Dichloropropenes(79)                         79-1



Dichloropropanol(80)                                          80-1




l,3-Dichloropropene(81)                                       81-1




Dieldrin(82)                                                  82-1



o,o-Diethyl Dithiophosphoric Acid(83)                         83-1




o,o-T)iethyl-S-methyl Phosphorodithioate( 84)                   81-1




Diethyl Phthalate(85)                                         85-1



Diraethylnitrosamine(86)                                       86-1



2,4-Dimethylphenol(87)                                        87-1




Dimethyl Phthalate(88)                                        88-1



Dinitrobenzenes(89)                                           89-1



4,6-Dinltro-o-creaol(90)                                      90-1




2,4-Diuitrophenol(91)                                         91-1




Dlnitrotoluene(92)                                            91-1



2,4-Dinitrotoluene(93)                                        93-1
                                   -v-

-------
 Chemical Substance(Document Number)                            Page
    •
 2,6-Dlnitrotoluene(94)                                        94-1

 Di-n-octyl Phthalate(95)                                       95-1

 Diphenylamlne (Reserved)

 l,2-Diphenylhydrazlne(96)                  .                    96-1

 T)is>ulfoton(97)                                                 97-1

 Endosulfan(98)                                                 98-1

 Endrin(99)                                                    99-1

 Epichlorohydrin (l-Chloro-2,3-epoxypropane)(100)              100-1

 Ethyl  Methacrylate(lOl)                                       101-1

 Ferric Cyanide(lOZ)                                           102-1

 Fluoranthene(103)                                •             103-1

 Formaldehyde(104)                     '                        104-1

 Forric Acid(105)                                              105-1

 Fumaronitrile(106)                                            106-1

 Haloraethanes(107)                                             107-1

 Heptachlor(lOS)                                               108-1

 Heptachlor Epoxide(109)                                       109-1

 Hexachlorobenzene(llO)       •                                 110-1

 Hexachlorobutadiene(lll)                                      111-1

 Hexachlorocyclohexane(112)                                    112-1

 garana-rHexachlorocyclohexane(113)                              113-1

Hexachlorocyclopentadiene(114)                                114-1

Hexachloroethane(llS)                                         115-1

Hexachlorophene(116)      .                                    116 1

Hydrofluoric Acid(ll7)                                        117-1


                                   -vi-

-------
Chemical Substance(Document Number)                           Page




Hydrogen Sulfide(118)                                        118-1




Indeno (1,2,3-cd) Pyrene(119)                                119-1




Isobutyl Alcohol(120)                                        120-1




Lead(121)                                                    121-1




Maleic Anhydride(122)                                        122-1




Maloaonitrile(123)                                           123-1




Mercury(124)                                                 124-1




Methorayl(125)                                                125-1




Methyl Alcoho1(126)                                          126-1



S.S'-tnethylene-OjO.o1,o'-Tetraethyl Phosphorodithioate(127)  127-1




Methyl Ethyl Ketone(128)                                     128-1




Methyl Methacrylate(130)                                     130-1



Naphthalene(131)                                             131-1



l,4-Naphthoqulnone(132)                                      132-1




Nickel(133)                                                  133-1



Nitrobenzene(134)                                            134-1




4-NItrophenol(135)                                           135-1




Nitrophenols(136)                                            136-1




Nitrosaoines(137)                                            137-1




N-Nitrosodiphenylamine(138)                                  138-1




N-Nitrosodi-n-propylamlne(139)                        -      139-1



Paraldehyde(140)                                             140-1



Pentachlorobenzene(141)                                      141-1
                                  -vli-

-------
 Chemical  Substance(Document Number)                            Page




 Pent.achloronitrobenzene(142)                                  142-1




 Pentachlorophenol(143)                                        143-1




 Phenol(l44)                                                   144-1




 Phenylenediamlne  (Reserved)                                    	




 Phorate(145)                            .                      145-1




 Phthalate Esters(146)                                         146-1




 Phthalic  Anhydride(147)                                       147-1




 2-Picoline(148)                                               148-1




 Polynuclear Aromatic Hydrocarbons(PAHs)(149)                  149-1




 Pyridine(lSO)                                                 150-1




 Quinones(151)                                                 151-1




 Resorcinol(152)                                               152-1




 Selenium(153)                                                 153-1




 Silver(154)                                                   154-1




 TCDD(155)                                                     155-1




 1,1,1,2-Tetrachloroethane(156)                                156-1




 l,l,2,2-Tetrachloroethane(157)                                157-1




 Tetrachloroethylene(Perchloroethylene)(158)                   158-1




 Thallium(159)                                                 159-1




 Toluene(160)                                                  160-1




 2,4-Toluenediamine(161)                                       161-1




Toluene Diisocyanate(162)                                     162-1




Toxaphene(l63)                                                163-1




 l,l,l-Trichloroethane(164)                                    164-1
                                  -viii-

-------
Chemical. Substanee(Pocunent Number)                           Page


l,l,2-Trichloro.ethane(165)                                   165-1
    %

Trichloroethylene(166)                                       166-1


Trichlorofluoromethane and Dichlorodifluororaethane(167)      167-1


2,4,6-Trichlorophenol(168)       .                            168-1


l,2,3-T-richloropropane(169)                                  169-1


0,0,0-Triethyl Phosphorothioate(170)                         170-1


Trlnltrobenzene(171)                                         171-1
                                  -ix-

-------
                                      No. 1
           Acetaldehyde


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

           APRIL 30, 1980
           H

-------
                          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.

-------
                            ACETALDEHYDE


                              Summary



     An increased incidence of malignant neoplasms was reported in

workers in an aldehyde factory.   Acetaldehyde was found in

concentration of 1 to 7 mg/rn^ but there was no indication that

acetaldehyde was the causative factor for the cancers.

     Equivacol results were obtained from a number of mutugenicity

assays.

I.   INTRODUCTION

     Acetaldehyde (CI^COH) is a clear, flammable liquid with a

pungent, fuity odor.  It has the following physical/chemical

properties (Hawley, 1977; U.S. EPA, 1976a):


                                          ^.0
          Chemical Structure:      CH3 - C^^
                                           ^H

          CAS No.:                 75-07-0

          Molecular Formula:       C2H40

          Boiling Point:           20.2°C

          Melting Point:           -123.5°C

          Vapor Pressure:          740 mm (20°C)

          Density:                 0.7834 at 18eC/4°C

          Octanol/Water
            Partition Coefficient: 0.43

          Vapor Density:           1.52
                                                             •
          Solubility:              soluble in water and most
                                   organic solvents

-------
     A review of the production range (Includes importation)

statistics for acetaldehyde (CAS No. 75-07-0) which was listed in

the initial TSCA Inventory (1977) has shown that between 1 billion

and 2 billion pounds of this chemical were produced/imported in

1977. *y

     Acetaldehyde is used mainly as a chemical intermediate in the

production of paraldehydes, acetic acid, acetic anhydride, and a

variety of other chemicals (Hawley, 1977).

II.  EXPOSURE

     The NIOSH National Occupational Hazard Survey estimates that

2,430 workers are exposed to acetaldehyde annually (1976).

     A.   Environmental Fate

          The available data do not indicate a potential for persis-

tance. and accumulation in the environment.  While there is little

information on the environmental fate of acetaldehyde, the BOD/COD

of 0.72 confirms that acetaldehyde will readily biodegrade

(Verschueren, 1978).

     As to its fate in air, aldehydes are expected to photodisso-

ciate rapidly and competively with their oxidation for a half-life

of 2 to 3 hours.  Aldehydes do not persist in the atmosphere but

the fact that acetaldehyde is a component of vehicle exhaust may be

significant in its contribution to smog (U.S. EPA, 1977b).
   This production range information does not include any production/
   importation data claimed as confidential by the person(s) report-
   ing 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 Regulation (40 CFR 710).
                              H

-------
     B.    Bioconcentration

          Acetaldehyde has an octanol/water partition coefficient

of 0.43  indicating that it is highly hydrophilic and should not

accumulate (U.S.  EPA, 1976).

     C.    Environmental Occurrence

          Acetaldehyde is a normal intermediate product in the

respiration of higher plants; it occurs in traces in ripe fruits

and may  form in alcoholic beverages after exposure to air.  It has

been reported that acetaldehyde is found in leaf tobacco, ciga-

rette smoke, and automobile and diesel exhaust (U.S. EPA, 1977a).

Acetaldehyde has been reported in both finished drinking water

supplies and effluents from sewage treatment plants in several

locations throughout the U.S. (EPA, I976b).

III. PHARMACOKINETICS

     Acetaldehyde which is the first occurring metabolite of ethanol

in mammals is produced in the liver and is often found in various

tissues  after the consumption of alcohol (Obe and Ristow, 1977).

It is an intermediate product in the metabolism of sugars in the

body and hence occurs in traces in blood (EPA, I977b).

IV.  HEALTH EFFECTS

     A.    Carcinogenic!ty

          Watanabe and Sugimoto (1956) administered 0.5-5% acetalde-

hyde subcutaneously to rats for a period of 489 to 554 days.  Four

of the 14 animals developed spindle cell carcinomas at the site of

injection.
                                                             •
     An  increased incidence of malignant neoplasms has been observed

in workers at an aldehyde factory who were exposed to acetaldehyde,

-------
butyraldehyde,  crotonaldehyde,  aldol, several alcohols, and longer



chain aldehydes.   Acetaldehyde  was found in concentrations of



1-7 mg/m3.  Of  the 220 people employed in this factory, 150 has



been exposed for  more than 20 years.   During the period 1967 to



1972, tumors were observed in nine males (all of whom were smokers).



The tumor incidences observed in the  workers exceeded incidences of



carcinomas of the oral cavity and bronchogenic lung cancer expected



in the general  population and,  for the age group 55-59 years, the



incidence of all  cancers in chemical  plant workers.  There is no



indication that acetaldehyde was the  causative factor in the excess



incidence of cancer (Bittersohl, 1974; Bittersohl, 1975).



     Acetaldehyde has been found positive in a variety of mutagenicity



tests:  siter chromatid exchange in cultured human lymphocytes and



a Chinese hamster (ovary) cell  line (Ristow and Obe, 1978; Obe and



Ristow, 1977);  S. typhimirium (Ames Test); (Pol A~) E. colt



(Rosenkranz, 1977); and WP2 uvrA trp~) E. coli (Veghelyi et al.,



1978).  It has, however, also been reported negative by other



investigators:   S. typhimurium, with  and without activation (Cotruvo



et al., 1977; Commoner, 1976; Laumbach e_t_ a_l_. , 1977); Saccharomyces



cerevisiae test for recombination (Cotruvo et al., JL977); and



Bacillus subtilis repair essay (Laumbach et al.,_1^77)._ Thus, of



ten reports of  in vitro tests for the mutagenicity of acetaldehyde,



5 were positive and 5 were negative*   Acetaldehyde was also found



to cross-link isolated calf thymus DNA (Ristow and Obe, 1978)..



     C.   Other Toxicity
                                                             *


     1.   Acute

-------
          A table summarizing the acute toxicity of acetaldehyde

in cats and mice is found below:
Species

rat
rat
rat
rat
rat
mouse
mouse
      Dose

I6,000ppm x 4 hrs.
 4,000ppm x 4 hrs.
   640 rag/kg
20,000ppm x 30 min.
 1,930 mg/kg
   560 mg/kg
 1,232 mg/kg
Route
Result
Reference
ihl
ihl
s . c.
ihl
oral
s . c .
oral
lethal
lethal
LD50
LC50
LD50
LD50
LD50
Smyth, 1956
NIOSH, 1977
Skog, 1950
Skog, 1950
NIOSH, 1977
Skog, 1950
NIOSH, 1977
     D.   Other Relevant Data

          Acetaldehyde is a mucous membrane irritant in humans

(Verschueren, 1978).

V.   AQUATIC EFFECTS

     A.   Acute

          The 24-hour median threshold limit (TLm) for acetaldehyde

pinperch is 70 mg/1.  The 96-hour TLm in sunfish is 53 mg/1

(Verschueren, 1978).

VI.  EXISTING GUIDELINES

     A.   Humans

          The American Conference of Governmental and Industrial

Hygienists (ACGIH) has adopted a Threshold Limit Value (TLV)  of

100 ppm for acetaldehyde.  The OSHA standard in air is a Time

Weighted Average (TWA) of 200 ppm.
                            1-7

-------
                            REFERENCES
ACGIH (1977).  American Conference of Governmental and Industrial
Hygienists, Threshold Limit Values for Chemical Substances and
Physical Agents in the Workroom Environment, Cincinnati, Ohio.

Bittersohl, G. (1974).  Epdemiological investigations on cancer
in workers exposed to aldol and other aliphatic aldehydes.  Arch.
Geschwalstforsch.  43:172-176.

Bittersohl, G. (1975).  Env. Qual. Safety.  4:285-238 (as cited
in NCI, 1978).

Commoner, B. (1976).  Reliability of bacterial mutagenesis
techniques to distinguish carcinogenic and non-carcinogenic
chemicals,  EPA-600/1-76-002.

Cotruvo, J.A. -ej^ JL^. , (1977).  Investigation of mutagenic effects
of products of ozonation reactions in water.  Ann. N.Y. Acad.
Sci.  298:124-140.

Hawley, G.G. (1977).  Condensed Chemical Dictionary. 9th edition.
Van Nostrand Reinhold Co.

Laumbach, A.D., e_t_ a^. (1977).  Studies on the mutagenlcity of
vinyl chloride metabolites and related chemicals.  Prev. Select.
Cancer. (Proc. Int. Symp.) 1:155-170.

NIOSH (1976).  National Occupational Hazard Survey.

NIOSH (1977).  Registry of Toxic Effects of Chemical Substances.

Obe, G., and H. Rlstow. (1977).  Acetaldehyde, But Not Ethanol,
Induces Sister Chromatid Exchanges in Chinese Hamster Cells in
Vitro.  Mutation Research.  56:211-213.

National Cancer Institute, Chemical Selection Working Group,
September 28, 1978.

OSHA (1976).  Occupational Safety and Health Standards (29 CFR
1910), OSHA 2206.

Ristow, H., and G. Obe. (1978).  Acetaldehyde Induces Cross-Links
in DNA and Causes Slster-Chromated Exchanges in Human Cells.
Mutation Research 58:115-119.

-------
Rosenkranz, H.S. (1977).  Mutagenicity of halogenated alkanes and
their derivatives.   Env. Hlth. Perspect. 21:79-84.

Skog, E. (1950).  A toxicological investigation of lower aliphatic
aldehydes I.  Toxicity of formaldehyde, acetaldehyde, propionaldehyde,
and butyraldehyde;  as well as of acrolein and crotonaldehyde.
Acta Pharmacol.  6:29-318.

Smyth, H.F. (1956).  An. Ind. Hyg. Assn. Quarterly, 17:144.

U.S. EPA (I976a).  Preliminary Scoring of Selected Organic Air
Pollutants.  EPA-450/3-77-008.  PB 264-443.

U.S. EPA (I977a).  Potential Industrial Carcinogens and Mutagens.
EPA-560/5-77-005.

U.S. EPA (I977b).  Review of the Environmental Fate of Selected
Chemicals.   EPA-560/5-77-003.

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

Veghelyi, P.V. et al. (1978).  The fetal alcohol syndrome: symptoms
and pathogenesis.  Acta Pediatr. Acad. Sci. Hung. 19:171-189.

Verschueren, K. (1978).  Handbook of Environmental Data on Organic
Chemicals.   Van Nostrand Reinhold Co., New York.

Watanabe, F. and S. Sugimoto (19.56).  Study on the carcinogenic! ty
of aldehyde.  3rd Report.  Four cases of sarcomas of rats appearing
in areas of repeated subcutaneous injections of acetaldehyde.
Gann.  47:599-601.
                               1-1

-------
                                      No. 2
            Ace ton!trlie


  Health and Environmental Effects
U.S. ENVIRONJENTAL 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.

-------
                        ACETONITRILE




                           SUMMARY



     Depending on the amount absorbed/ acetonitri le may  cause



disorders in the central nervous system/ Liver/ kidneys, car-



diovascular system and gastrointestinal system/ regardless of




the route of administration.  These effects are attributed to



the metabolic release of cyanide from the acetonitrile mole-



cule/ although the parent molecule itself may cause these ef-



fects.



     This Hazard Assessment Profile was based largely on in-



formation obtained from NIOSH and its Criteria for a Recom-



mended Standard: Occupational Exposure to Nitrites/ (NIOSH/



1978).



     The NIOSH 1972-1974 National Occupational Hazards Survey



estimates that about 26/000 workers are occupationa lly ex-



posed to ni tri les.



     Major occupational exposures to nitrile occur by inhala-



tion of vapor or aerosols and by skin absorption.  Adverse



effects of nitriles are also found from eye contact.



     There is no available evidence to indicate that acetoni-



trile has mutagenic or carcinogenic activity.  Two studies



have reported teratogenic effects in rats.



     Unlike the immediate onset of cyanide  toxicity/ nitrile



poisoning displays a delayed onset of symptoms.

-------
  I.    INTRODUCTION

       Acetoni t r i Le CCHjCN) is a morion i t ri I e and falls into

  the  saturated aliphatic class of nitriles.  It is a colorless

  liquid and has a vapor pressure of 73 mm Hg at 20* C.  It has

  a  molecular weight of 41.05 and a specific gravity of 0.786

  CNIOSH,  1978).

       When heated to decomposition, nitriles emit toxic fumes

  containing cyanides (Sax,. 1968).

       Acetonitrile was introduced to the commerical market in

  1952, and its industrial  uses lie in the manufacture of plas-

  tics, synthetic  fibres, elastomers, and solvents.  Acetoni-

  trile is  used as a solvent in the extractive distillation

 .that separates olefins from diolefins, butadiene from buty-

  lene, and isoprene from isopentane.

       In  1964, 3.5 million pounds of acetonitrile were con-

  sumed industrially.

'  II.   EXPOSURE

       A.    Water  and Food

            Pertinent data  were not found in the available lit-

  erature.

       B.    Inhalation

            Acetonitrile can be readily absorbed from oral mu-

  cosa (McKee,  et  al.  1962;  Dalhamn, et al.  1968).

            In  the workplace, acute poisoning and death have
I          £*-
i  been reported following the inhalation of  acetonitrile 
-------
      C.    Dermal

           Dermal exposures to acetonitrile have caused ad-

 verse  reactions  including  death  in some cases (NIOSH, 1978).

           Acetonitrile has been  reported to have been absorb-

 ed  through  the  intact  skin of rabbits, yielding a dermal

 LD5Q  of  980 mg/kg (Pozzani, et al. 1959).

 III.  PHARMACOKINETICS

      A.    Absorption
x—•
           Acetonitrile is  a.component of cigarette smoke and

 is  absorbed by  the  oral  tissues  (McKee,. et al. 1962;  Dalhamn,

 et  a I. 1968).
•—•

           Humans have  been shown to absorb acetonitrile di-

 rectly through  the  skin  and respiratory tract (Zeller,. et al.

 1969;  Amdur,  1959;  Dequidt, et al. 1974)..

      B.    Distribution

           Studies by McKee, et at. (1962) and Dalhamn, et al.

 (1968) show th-at acetonitrile from cigarette smoking  is re-

 tained by  the  lungs.

           Tissue distribution studies indicated that  mononi-

 triles (and acetonitrile,  in particular) are distributed uni-

 formly in  the  internal organs of humans and that cyanide me-

 tabolites  are  found predominantly in  the spleen, stomach and

 skin,  and  to  a  lesser  extent, in the  liver, lungs, kidneys,

 hearts,  brain,  muscle, intestines, and testes (Dequidt, et

 al. 1974).

           Haguenoer, et  al. (1975) exposed three rats to *

 2,800  or 25,000  ppm acetonitri le by inhalation.  At  25,000

 ppnr,  all three  rats died after 30 minutes.  Chemical  analysis
                                    A.-5

-------
of the organs showed that the mean  concentration  of



acetonitrile in muscle was 136 pg/100 g of  tissue  and  2/438



ug/100 g of kidney tissue.  High acetonitrile  excretion  or



possible renal blockage were postulated as  the  causes  for  the



high renal concentration.



          Nitriles and their metabolic products  have been  de-



tected in urine/ blood and tissues  (McKee/  et  al.  1962).



     C.   Metabolism



          Since human and animal studies  report  symptoms



characteristics of cyanide poisoning/ it  is  reasonable to



assume that a portion of the effects of exposure  to acetoni-



tn'le is due to the release of the  cyanide  ion  from the  par-



ent compound (Zeller/ et al. 196~9;  Amdur/ 1959;  Pozzani/



1959).



          After absorption/ nitriles may  be  metabolized  to  an



alpha cyanohydrin or to inorganic cyanide/  which  is oxidized



to thiocyanate and is excreted in the urine.   The  C=N  group



may be converted into a carboxylic  acid derivative and ammon-



ia/ or may be incorporated into cyanocobalamine.   Ionic  cya-



nide also reacts with carboxyl groups and with  disulfides



(McKee/ et al. 1962).



          Haguenoer/ et al (1975) injected  white  male  Wistar



rats with varying levels of acetonitrile  ranging  from  600



mg/kg to 2/340 mg/kg.  A-t autopsy/  the internal  organs showed



that the combined hydrogen cyanide  consisted essentially of



thiocyanates/ cyanohydrins and cyanocoba I amines .          '



     0.   Excretion



          Acetonitrile is found in  the morning  urine of  cigar-



ette smokers.  Concentrations of acetonitrile  range from 2.2

-------
of the organs showed that the mean concentration of




acetonitrile in muscle was 136 ^jg/100 g of tissue and 2,438



ug/10Q g of kidney tissue.  High acetonitriLe excretion or




possible renal blockage were postulated as the causes for the



high renal concentration.



          Nitriles and their metabolic products have been de-




tected in urine, blood and tissues (McKee, et al. 1962).



     C.   Metabolism



          Since human and animal studies report symptoms



characteristics of cyanide poisoning, it is reasonable to



assume that a portion of the effects of exposure to acetoni-



trile is due to the release of the cyanide ion from the par-



ent compound CZeller, et al.. 1969; Amdur, 1959; Pozzani,



1959).



          After absorption, nitriles may be metabolized to an



alpha cyanohydrin or to inorganic cyanide, which is oxidized



to thiocyanate and is excreted in the urine.  The C=N group



may be converted into a carboxylic acid derivative and ammon-



ia, or may be incorporated into cyanocobalamine.  Ionic cya-



nide also reacts with carboxyl groups and with disulfides



CMcKee, et al. 1962).



          Haguenoer, et al (1975) injected white male Uistar



rats with varying levels of acetonitrile ranging from 600



mg/kg to 2,340 mg/kg.  At autopsy, the internal organs showed



that the combined hydrogen cyanide consisted essentially of



thiocyanates, cyanohydrins and cyanocobaLamines.          .



     D.   Excretion



          Acetonitrile is found in the morning urine of cigar-



ette smokers.  Concentrations of acetonitrile range from 2.2
                       JL-7

-------
ug/100 ml urine for those smoking three cigarettes  per  day  up




to 20 jug/100 mL urine for heavy smokers (up to 2.5  packs  per



day).  The results showed that acetonitri le, once absorbed



into the body, can be excreted unchanged  in the urine  (NcKee,



et at. 1962).



          Acetonitrile is also excreted unchanged in exhaled



air (Haguenoer, et al. 1975).



IV.  EFFECTS



     A.   Carcinogenicity



          Dorigan, et al. (1976) failed to show significant



carcinogenic effects in a two-year exposure study conducted



with rats.



     8.   Mutagenicity



          Pertinent data were not found in the available  lit-



erature.



     C.   Teratogenicity



          Intraperitoneal (i.p.) administration of  acetoni-



tri le to pregnant rats produced fetal malformations  (Dorigan,



et al. 1976).  Schmidt, et al. (1976) have determined  skele-



tal abnormalities in rats following i.p.  exposure to acetoni-



tri le.



     D.   Other Reproductive Effects



          Pertinent data were not found in the available  lit-



erature.



     E.   Chronic Toxicity



          In an experiment to stimulate chronic occupational



exposure (seven hours per day, five days  per week), 30  rats



were exposed to a concentration of 655 ppm acetonitrile for

-------
90 days.  The rats exhibited bronchial inflammation, desqua-




matization and hypersecration of mucus, and hepatic and  renal



lesions.  Monkeys exposed by the same regimen, but to 350 ppm



acetonitrile for 91  days, experienced bronchitis and moderate




hemorrhage of the superior and inferior sagittal sinuses of



the brain (Pozzani,  et al. 19S9).



          Dogs exposed to acetonitrile at a concentration of



300 ppm for 91 days  showed a reduction in body weight as well



as a reduction in hemoglobin and hematocrit values (Pozzani,,



et al. 1959).



          Monkeys exposed to 660 ppm acetonitrile per day



showed poor coordination during the second week of exposure



and a monkey exposed to 330 ppm showed hyperexcitabi lity



toward the- end of the 13th week (Pozzani, et al. 1959).



          The same investigators reported chronic LDgg



values of 0.85 and 0.95 ml/kg for female rats which i.p.  ad-



ministration of acetonitrile.




     G.   Other Relevant Information



          Dogs exposed with lethal quantities of acetonitrile



(16,000 ppm for four hours) showed blood cyanide levels  rang-



ing from 305-433 ug/100 ml of blood after three hours (Poz-



zani, et al. 1959)..



V.   AQUATIC TOXICITY



     A.   Acute



          Observed 96-hour LC$Q values for the fathead



minnow (Pimephales promelas) are 1020 mg/l in hardwater  a ad



1000 ml/I in softwater (Bringmann, 1976).  For bluegills,



(Lepomi s mac roc hi rus) and guppies (Lebi stes reticulatus), the

-------
respective 96-hour values in softw.ater are 1850 mg/L and 1650


mg/l (Jones, 1971; Henderson, et at. 1960).


     B.   Chronic, Plant Effects, and Residue


          Pertinent data were not found in the available lit-


erature.


     C.   Other Relevant Information


          Acetonitrile has been observed to damage the bron-


chial epithelium of fish (Belousov, 1969).  This compound,


when added to the aqueous environment of roaches and fil-


berts, disrupted blood circulation and protein metabolism and


induced hyperemia, hemorrhages, and the appearance of small


granules in the heart, brain, liver, and gills of fish.  The


hepatic glycogen level decreased sharply.  CHjCN induced-


death apparently resulted from circulatory disturbances and


necrobiotic changes in the cerebral neurons (Belousov, 1972).


          Acetonitrile at a concentration of 100 mg/l inhib-


ited nitrificat ion in saprophytic organisms (Chekhovskaya,


1966).


VI.  EXISTING GUIDELINES


     A.   Human


          A federal occupational standard exists for acetoni-


trile and is based on the TLV for workplace exposure pre-


viously adopted by American Conference of Governmental and


Industrial Hygienists.  This TLV is 40 ppm (70 mg/nH) and


is an eight-hour TWA.

                                                          •
     3.   Aquatic


          Pertinent data were not found in the available lit-


erature.

-------
                         REFERENCES

Amdur, M.L.  1959.  Accidental group exposure to acetoni-
triLes - A clinical study.  J. Occup. Med.  1: 627.

American Conference of Governmental Industrial Hygienists.
Threshold  limit values for chemical substances and physical
agents in  the workroom environment, with intended changes for
1979.- Cincinnati, Ohio. 94 pp.

Belousov,  Y..A.  1969.  Effects of some chemical agents on the
histophysiological state of the bronchial epithelium. (Uch.
Zap. Yoroslav. Gos. Pedagog. Inst. USSR 62:126-129). Chem.
Abst. 97853c.

Belousov,  Y.A.  1972.  Morphological changes in some fish
organs during poisoning.  Vlujanie Pestits. Dikikh Zhivotn.
41-45.  Chem. Abst. 141567d, Vol. 80.

Bringmann, G_  1976.  Vergleichende Vefunde der Schadwirkung
wassergefahrdender.  Stoffee gezen Bakterien (Speudomomas
putida)  und Blaualgen (Microcystis aeruginosa) nwfa llwasser.
117-119.

Checkhovskaya, E.V., et. al.  196~6.  Data for experimental
studies  of toxicity of waste waters from aery lonitri le pro-
duction.   (Vodosnabzh. Kanaliz. Gidrotekh. Sooruzh. nezhved.
Resp. Nauch. USSR SB 1: 83-88).  Chem. Abst. 88437k.

Dalhamn, T., et al.  1968.  Mouth absorption of various com-
pounds in  cigarette smoke.  Arch. Environ. Health  16: 831.

Dequidt, J., et al.  1974.  Intoxication with acetonitrile
with a report on a fatal case.  Eur. J. Toxicol.  7: 91.

Dirigan, et al.  1976.  Preliminary scoring of selected
organic  air pollutants.  Environ. Prot. Agency, Contract No.
68-02-1495.

Grabois, B.  1955.  Fatal exposure to methyl cyanide.  NY
State Oep. Labor Oiv. Ind. Hyg. Won. Rev.  34: 1,7,3.

Haguenoer, J.M., et al..,  1975.  Experimental acetonitrile
intoxications - I. Acute intoxicatios by the intraperitonea I
route..  Eur. J.. Toxicol.  8: 94.

Henderson, C., et a I.  i960.  The effect of some organic
cyanides (nitriles) on fish.  Purdue Univ. Eng. Bull. Exp.
Ser.  106: 120.

Jones, H.  1971.  Environmental control in the organic and*
petrochemical industries.  Noyse Data Corp.
                       SL-ll

-------
McKee, H.C., et al.  1962.  Acetonitrile in body fluids re-
lated to smoking.   Public Health Rep. 77: 553.

NIOSH.  1978.  NIOSH Criteria for a Recommended Standard:
Occupational Exposure to Nitriles.  U.S. DHEW, Cincinnati.

Pozzani, V.C., et  al.  1959.  An investigation of the mammal-
ian toxicity of acetonitrile.  J. Occup. Med.  1: 634.

Sax. N.I.  1968.  Dangerous Properties of Industrial Materi-
als, 3rd ed.  NY Van Nostrand Reinhold Co.

Schmidt/ W., et al.  1976.  Formation of skeletal abnormali-
ties after treatment with aminoacetonitri le and cycy lophosph-.
amide during rat fetogenesis.  (Verh. Anat. 71:635-638 Ger.)
Chem. Abst. 1515w.

Sunderman, F.W., and J.F. Kincaid.  1953.  Toxicity studies
of acetone cyanohydrin and ethylene cyanohydrin.  Arch. Ind.
Hyg. Occup. Med.  8: 371.

Zeller, H.V., et al.  1969.  Toxicity of nitriles.  Zentralbl
Arbirtsmed Arbeitsschutz.  19: 255.

-------
                                     No.  3
            Acetophenone


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

           APRIL 30, 1980
                    3-1

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

-------
                                 ACETOPHENONE
                                    Summary

     Acetophenone  is  present in various  fossil  fuel processes and products,
particularly coal  and petroleum products.   It  is used as  a flavoring agent
in  products  for  human  consumption  and  as  an  intermediate  in  organic
synthetic processes, particularly plastics manufacturing.
     No  data  on the  potential  for carcinogenic, mutagenic,  or teratogenic
effects  or on   the  chronic  toxicity  of  acetophenone were   found  in  the
available literature.
     There  are  no existing  OSHA,  NIOSH,  or ACGIH standards  or guidelines.
Acetophenone is a skin irritant and has been shown  to cause severe eye irri-
tation in rabbits  at microgram  quantities.  Acetophenone is  highly toxic to
aquatic life

-------
 I.    INTRODUCTION
           Acetophenone  (1-phenylethanone,  phenyl  methyl   ketone,   acetyl-
 benzene,   benzoyl  methide,   hypnone,   C^coo^;   molecular  weight   120.15)
 is  a  liquid with  a  melting point  of  20.5°C  and  is slightly  soluble  in
 water.   Acetophenone  is  used  to  impart  a  pleasant  jasmine  or   orange-
 blossom-like odor to perfumes, as a  catalyst for the polymerization  of  ole-
 fins,  and  in organic syntheses, especially  as a photosynthesizer  (Windholz,
 1976).   Additionally,  it  is used as a  tobacco  flavoring,   as  a  solvent  or
 intermediate in  the synthesis of Pharmaceuticals,  and as a by-product of the
 coal  processing  industry.   Acetophenone  is  present in gasoline  exhaust  at
 less than  0.1 to  0.4 ppm (Verschueren,  1977).
 II.  EXPOSURE
           No data  on  levels of acetophenone in food  or  water or on other
 potential  (inhalation  or  dermal) exposures were found  in  the readily avail-
 able literature.
 III. PHARMACOKINETICS
           Information  on  the absorption, distribution,  metabolism,  or  ex-
 cretion of acetophenone  was  not  found in the  readily  available literature,
 despite  the  fact  that  it  is  used  in  pharmaceutical  preparations  and in
 tobacco, perfume, and other products for  human comsumption.
 IV.  EFFECTS
     A.   Carcinogenic!ty,  Mutagenicity, Teratogenicity, and Chronic Toxicity
          Readily available  data  are  extremely limited.  One paper suggests
the possible mutagenicity  of  acetophenone due to  its  ability  to  cause  DNA
breakage in  bacterial systems following DNA photosensitization   (Rahn,  et
al.  1974).   Because  of  the  particular sensitivity of the bacterial  system
to DNA  breakage, this  information by  itself is  insufficient   to  establish
acetophenone as  a mutagenic agent.

-------
          There is no additional data readily available on  the  potential for
carcinogenic, mutagenic,  or  teratogenic activity  by  acetophenone.  No  data
are available on chronic toxicity.
     B.   Acute Toxicity
          Skin irritaion  was  observed in the rabbit  at 10 mg/24  hrs.  using
the draize procedure  and  at  515 mg when applied  to  the skin in the  absence
of the absorbent gauze  patch.  Severe  eye irritation was obtained in  the
rabbit  following  application  of 771  ug of  acetophenene.   The oral LD5Q in
rats  was  900  mg acetophenone/kg, "while the  lethal  dose  following  intra-
peritoneal injection in mice was 200 mg/kg  (NIOSH, 1978).   Acetophenone is a
hypnotic in  high  concentrations and was used  as an  anesthetic in the  last
century before less toxic substances were found  (Kirk and  Othmer,  1963).
     C.   Other Relevant Information
          Based upon  the  retention time in a gas  chromatographic/mass  spec-
trographic column,  Veith  and  Austin  (1976) suggest a  potential for  bio-
accumulation of acetophenone.   There is no  additional information available
to verify this situation,  however.
          Microbial metabolism  of  acetophenone  as the sole source of  carbon
and energy has been demonstrated in pure culture (Cripps,  1975).
V.   AQUATIC TOXICITY
          Based  upon reported  values  in  the  literature,  acetophenone  has
been  shown  to  be highly toxic, to  aquatic life,  (U.S.  EPA,  1979).   LC5Q
values  for  fathead  minnow are  reported for the  following  time periods:   1
hour,  greater  than  200  mg/1;  24  hours, 200 mg/1;   48 hours,  163 mg/1;  72
hours, 158 mg/1; and 96 hours, 155 mg/1 (U.S. EPA,  1976).
          Acetophenone has been reported to be  a major constituent  (36  per-
cent)  of a weathered bunker  fuel.   This suggests  that it may be  present in
large  quantity  following  spills of some bunker fuels (Guard,  et  al.  1975).

-------
Bunker fuels are  highly  variable form refinery to  refinery;  thus,  a blanket
statement as to percentage  composition  of acetophenone or other constituents
cannot be made.
VI.  EXISTING GUIDELINES AND STANDARDS
          There are  no existing guidelines  and standards from  OSHA,  NIOSH,
or ACGIH.   Similarily,  no ambient water  quality  standards  for  acetophenone
exist.

-------
                                  REFERENCES
Cripps, R.E.   1975.   The microbial  metabolism of  acetophenone:   metabolism
of  acetophenone and  some  chloroacetophenones by  an Arthrobacter  species.
Biochem. Jour.  152: 233.

Guard,  H.E.,  et al.   1975.   Identification and potential  biological effects
of  the major components  in the seawater  extract of  a  bunker fuel.   Bull.
Environ. Contam. Toxicol.  14: 395.

Kirk,  R.E.  and D.F.  Othmer.   1963.   Kirk-Othmer.  Encyclopedia  of  Chemical
Technology.  2nd ed.  J. Wiley and Sons, Inc., New York.

National  Institute  for Occupational Safety  and Health.   1978.   Registry  of
Toxic  Effects of Chemical Substances.   E. Fairchild  (ed.).   U.S.  Department
of Health, Education, and Welfare.  Cincinnati, Ohio.  -

Rahn,  R.O., et  al.  1974.   Formation and chain breaks and  thymine dimers  in
ONA upon  photosensitization at 313 nm with acetophenone, acetone, or benzo-
phenone.  Photochem. Photobio.  19: 75.

U.S.  EPA.   1976.   Acute  Toxicity  of  Selected Organic Compounds to Fathead
Minnows.   EPA-600-3-76-097.   U.S.  EPA  Environmental  Research Lab.,  Duluth,
Minnesota.

U.S.   EPA.    1979.    Biological  Screening  of   Complex  Samples  From  In-
dustrial/Energy Processes.   EPA-600-8-79-021.  U.S.  EPA,   Research  Triangle
Park,  North Carolina.

Veith,  G.O.  and N.M. Austin.   1976.   Detection and  isolation of bioaccumu-
latable chemicals  in complex  effluents.   In:  L.H.  Keith  (ed.),  Identifi-
cation and  Analysis  of  Organic  Pollutants   in  Water.   Ann Arbor  Science
Publishers, Inc.,  Ann Arbor, MI.  p. 297.

Verschueren,  K.  1977.   Handbook  of  Environmental  Data  on Organic  Chem-
icals.  Van Nostrand Reinhold Company, New York.

Windholz,  M.  (ed.)   1976.   Merck  Index.   9th ed.   Merck  and Co.,  Rahway,
N.J.
                                   3-7

-------
                                     No. 4
          Acetyl Chloride



  Health and Environmental Effects
U.S. ENVIRONMENTAL  PROTECTION AGENC7

       WASHINGTON,  D.C.  20460


           APRIL 30,  1980
          y-/
                                                          U|
                                                          \, '

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

-------
                               ACETYL CHLORIDE
                                   Summary

     Acetyl  chloride  is  an irritant  and a  corrosive.   Cutaneous  exposure
results in skin burns, while vapor exposure causes extreme  irritation of  the
eyes and  mucous  membranes.   Inhalation of two  ppm acetyl chloride  has been
found  irritating  to  humans.   Death  or permanent  injury may  result after
short exposures to small quantities of  acetyl chloride.   An  aquatic  toxicity
rating has been estimated to range from 10 to  100 ppm.
     However, acetyl  chloride  reacts  violently  with water.  Thus, its half-
life in ambient water should be short and exposure from water should be nil.
The degradation products should likewise pose no  exposure problems if the pH
of the water remains stable.
                                   y-3

-------
                               ACETYL CHLORIDE
I.   INTRODUCTION
     Acetyl  chloride  (ethanoyl chloride;  CH^CQCl;  molecular  weight,  78.50)
is  a colorless,  fuming liquid  with a pungent  odor,  a boiling  point  of
51-52°C,  and a  melting point of  -112°C  (Windholz,  1976).    It  is used  as
an  acetylating  agent  in  testing  for  cholesterol  and  in  the  qualitative
determination  of water  in organic  liquids.   It is  miscible with  benzene,
chloroform, ether or glacial  acetic  acid  (Windholr, 1976).   In  the presence
of water  or alcohol,  however, acetyl chloride  hydrolyzes violently to  form
hydrogen chloride and  acetic  acid.  Phosgene fumes, which are highly  toxic,
are emitted when acetyl chloride is heated to decomposition (Sax, 1975).
     The  1975  U.S.  annual  production  of  acetyl  chloride was approximately
4.54 x  10  grams (SRI,  1976).   During  transportation, this  chemical  should
be stored in a cool, well-ventilated place, out of  direct sunlight,  and  away
from areas  of high fire hazard;  it  should periodically be  inspected  (Sax,
1975).   Acetyl chloride must be protected from water (Windholz, 1976).
II.  EXPOSURE
     Acetyl  chloride  reacts  violently  with  water (see  above).  Thus,  its
half-life in ambient water should  be short and exposure  from  water  should be
nil. - The degradation  products  should likewise pose no exposure  problems if
the  pH  of the water remains  stable.   Internal  exposure  to  acetyl  chloride
will most  likely occur  through  inhalation of the  vapor, or, on rare  occa-
sions,  through ingestion.   Skin  absorption is very unlikely  although  severe
burns would be expected.
III. PHARMACOKINETICS
                                                                       »
     Pertinent data could not be located in the available literature.
                                  t-f

-------
IV.  EFFECTS
     Acetyl  chloride  is  an irritant  and  a  corrosive.   Cutaneous  exposure
results in skin burns.  Vapor exposure causes  extreme  irritation of the eyes
and mucous membranes  (Windholz,  1976).   Inhalation of  2  ppm acetyl chloride
was  found  irritating to  humans  (Handbook of  Organic Industrial  Solvents,
1961).  Death  or  permanent injury may  result after very  short exposures to
small quantities of acetyl chloride (Sax, 1975).
     Because the  toxicity of acetyl  chloride  might  be expected  to pattern
that  of its breakdown  product  hydrogen  chloride  (HCL),  LCLQ value  (the
lowest concentration of a  substance in  air which has been reported  to cause
death  in  humans  or  animals)  for  HC1  might be indicative  of  its  toxicity.
This value in humans is 1000 ppm for one minute (Mason, 1974).
     Pertinent  information could not  be located  in  the available literature
regarding  the  carcinogenicity,  mutagenicity,  teratogenicity  and  chronic
toxicity of acetyl chloride.
V.   AQUATIC TOXICITY
     Acetyl  chloride  has  been  shown to be  toxic  to  aquatic organisms in the
ranges of  10 to 100 ppm (Hann and Jensen,  1974).  No  other information has
been found in the literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     No  standards  for  acetyl   chloride  have been  reported.   However,  a
ceiling limit  of 5 ppm  has been  reported for hydrogen  chloride  (the  most
irratating hydrolysis  product  of  acetyl chloride)  in  industrial exposures.
(Mason, 1974).

-------
                               ACETYL  CHLORIDE

                                  REFERENCES
Handbook of  Organic  Industrial Solvents,  2nd ed.  1961.   Cited  in:  Registry
of toxic effects of chemical substances.  NIOSH (DHEW) Pub. No. 79-100, p. 4.

Hann, W. and P.A.  Jensen.   1974.   Water quality characteristics  of hazardous
materials.  Vol. 2.  Texas A4M University.

Mason,  R.V.   1974.  Smoke  and toxicity  hazards  in aircraft  cabin  furnish-
ings.  Ann. Occup. Hyg.  17: 159.

Sax, N.I.  1975.   Dangerous properties  of industrial  materials,  4th  ed.  Van
Nostrand Reinhold Co.,  New York, p. 355.

Stanford Research Institute.  1976.  Chemical economics handbook.

Windholz, M. -(ed.)  1976.  The  Merck  Index,  9th ed.   Merck and  Co.,  Inc.,
Rahway, N.J., p. 11.

-------
                                      No.  5
              Acroleln
  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.

-------
                                   ACROLEIN .
                                    SUMMARY
     Acrolein has  not been shown  to be a carcinogen  or cocarcinogen in in-
halation experiments.   Acrolein  is mutagenic in some  assay systems.  Infor-
mation on teratogenicity is not  available.   The only reported chronic effect
of acrolein in  humans is  irritation of the  mucous  membranes.   Chronic expo-
sure  of  Syrian golden  hamsters  to  acrolein  in the air  caused  reduced body
weight,  gains  and  inflammation  and  epithelial '• metaplasia  in  the  nasal
cavity.   In addition,  females  had decreased  liver weight,  increased lung
weight, and slight hematologic changes.
     Acrolein has been  demonstrated to be  acutely  toxic in freshwater organ-
isms  at concentrations  of  57 to 160 ug/1.   A single marine fish  tested was
somewhat  more  resistant   with  a  48-hour LC5_. of  240  jug/1.  Toxicity  to
marine invertebrates was comparable to that of freshwater organisms.

-------
                                   ACROLEIN
I.  INTRODUCTION
     This profile  is based  on the Ambient  Water Quality  Criteria Document
for Acrolein (U.S. EPA, 1979).
     Acrolein  (2-propenal;  CH2=CHCHO;  molecular weight  56.07)  is  a flamm-
able liquid with a pungent odor.   It  has  the following physical and chemical
properties (Weast, 1975; Standen, 1967):
               Melting Point             -86.95QC
               Boiling Point Range       52.5 - 53.5°C
               Vapor Pressure            215mm Hgvat 20°C
               Solubility                Water:  210.8 percent by weight
                                         at 20°C
               Density                   0.8410 at 20°C
               Production (Worldwide)    59 kilotons (Hess, et al. 1978)
               Capacity (Worldwide)      102 kilotcns/year
               Capacity (United States)  47.6 kilotons/year

     Acrolein  is used  as a biocide,  crosslinking  agent,  and  tissue  fix-
ative.  It is used as an intermediate throughout the chemical industry.
     The  fate  of acrolein  in water  was  observed in  natural  channel waters
(Bowmer and Higgins,  1976).   No equilibrium was  reached  between dissipating
acrolein  and  degradation  products, with  the  dissipating  reaction apparently
being continued  to completion.   Degradation  and  evaporation appear to be the
major pathways  for  loss,  while  a smaller amount  is  lost through absorption
and  uptake  in  aquatic organisms and  sediments  (Bowmer  and Sainty,  1977;
Hopkins and Hattrup, 1974).
II.  EXPOSURE
     There is  no available  evidence  that acrolein is  a  contaminant of pot-
able water or water supplies (U.S. EPA, 1979).
     Acrolein  is a  common  component  of food.   It  is- commonly  generated
during cooking or other processing, and is sometimes  produced  as an unwanted

-------
by-product in  the fermentation of alcoholic beverages  (Izard and Libermann,
1978;  Kishi,  et  al.   1975;  Hrdlicka  and  Kuca,  1965;  Boyd,  et al.  1965;
Rosenthaler  and  Vegezzi,  1955).   However,  the  data  are  insufficient  to
develop a  conclusive  measure  of acrolein  exposure  from food  processing  or
cooking.
     The U.S. EPA (1979) has  estimated the weighted average bioconcentration
factor for acrolein to be  790 for the edible portions  of  fish and shellfish
consumed by Americans.  This  estimate  is based  on measured steady-state bio-
                                                  \
concentration studies in bluegills.
     Atmospheric  acrolein  is  generated as a combustion  product of fuels and
of cellulosic  materials  (e.g., wood  and cigarettes),  as an  intermediate  in
atmospheric oxidation of propylene, and  as a  component of the volatiles pro-
duced  by  heating organic  substrates  (U.S.  EPA, 1979).  Acrolein is present
in urban  smog;  average  concentrations of  0.012  - 0.018 mg  acrolein/m  and
peak concentrations  of 0.030  - 0.032 mg  acrolein/m   were noted  in  the air
of Los Angeles (Renzetti  and  Bryan,  1961; Altshuller  and  McPherson,  1963).
Diesel  exhaust  emissions  contained  12.4  mg acrolein/m ;  trace  amounts  of
acrolein were present in samples taken from an  area of traffic; and  no acro-
lein was detected  in ambient  air  from an open field (sensitivity of measure-
ment was  below one part per  million) (Bellar  and Sigsby, 1970).   Acrolein
content of smoke  from  tobacco  and marijuana cigarettes ranged from 85 to 145
ug/cigarette (Hoffman, et  al.  1975;  Horton and Guerin,  1974).   Acrolein was
detected at  levels of 2.5 - 30  mg/m   at 15 cm  above the surface  of pota-
toes or onions cooking in edible oil (Kishi,  et al.  1975).

-------
III. .'HARMACOKINETICS
     A.  Absorption
         Total respiratory  tract  retention of acrolein  in anesthetized dogs
was 77 to 86 percent (Egle, 1972).
     8.  Distribution
         Pertinent data were not found in the available literature.
     C.  Metabolism
         Relatively little  direct  information  is  available on the metabolism
of acrolein.  In vitro, acrolein  can  serve as a  substrate for alcohol dehy-
drogenases  from  human and  horse  liver  (Pietruszko,  et al.  1973).   In vivo
studies in  rats indicate that  a portion  of subcutaneously administered acro-
lein is converted  to  3-hydroxylpropylmercapturic  acid (Kaye and Young, 1972;
Kaye,  1973).   Acrolein undergoes  both  spontaneous  and  enzymatically cata-
lyzed conjugation  with glutathione (Boyland and  Chasseaud, 1967; Esterbauer,
et al. 1975).  The low pH's encountered  in  the upper portions of the gastro-
intestinal  tract probably  would rapidly convert  acrolein  to saturated alco-
hol compounds (primarily beta  propionaldehyde) (U.S.  EPA,  1979).  As several
of the  toxic effects of acrolein  are  related  to the high reactivity  of the
carbon-carbon double bond,  saturation  of that bond  should result in detoxi-
fication (U.S. EPA, 1979).
     0.  Excretion
         In rats given single  subcutaneous  injections of acrolein, 10.5 per-
cent  of the  administered   dose  was recovered  in  the  urine as  3-hydroxy-
propylmercapturic acid after 24 hours (Kaye and Young, 1972; Kaye, 1973).
                                  S-6

-------
IV.  EFFECTS
     A.  Carcinogenicity
         One-year  and  lifespan  inhalation  studies with  hamsters  indicate
that acrolein is not  a  carcinogen or cocarcinogen  (Feron and  Kruysse,  1977;
National Cancer Institute, 1979).
     B.  Mutagenicity
         Both  positive  and  negative  results have been obtained in  muta-
genicity  assays.   Acrolein  induced  sex-linked   mutations   in  Drosophila
melanoqaster (Rapoport, 1948) and  was  mutagenic  for DNA polymerase-deficient
Escherichia coli  (Bilimoria,  1975) and  Salmonella typhimurium  (Bignami,  et
al. 1977).  Mutagenic activity was not detected  in the dominant lethal assay
in ICR/Ha Swiss  mice  (Epstein,  et al. 1972)  or  in a strain of  E.  coli used
for  detecting  forward  and  reverse mutations  (with  or without  microsomal
activation)  (Ellenberger  and  Mohn, 1976;  1977).   Acrolein  was  weakly  muta-
genic for Saccharomyces cerevisiae (Izard, 1973).
     C.  Teratogenicity
         Pertinent data were not found in the available literature.
     C.  Other Reproductive Effects
         Exposure  of  male and  female  rats to  1.3 mg/m  acrolein  vapor for
26 days did not  have  a  significant effect on the  number of  pregnant  animals
or the number and mean weight of fetuses (Bouley, et al. 1976).
     E.  Chronic Effects
         Little  information  is  available on the chronic effects of acrolein
on humans.  An abstract of a  Russian study indicates  that occupational expo-
sure  to  acrolein  (0.8  to  8.2   mg/m  ),  methylmereaptan   (0.003  to  5.6
                                                                      •
mg/m ),  methylmercaptopropionaldehyde   (0.1  to  6.0   mg/m3),  formaldehyde
(0.05  to 8.1  mg/m ),  and  acetaldehyde (0.48  to 22  mg/m3)  is  associated
                                  S-7

-------
with  irritation  of the  mucous  membranes.   This  effect is  most  frequent in
women working  for  less than one  and  greater than  seven years (Kantemirova,
1975).  Acrolein is known to produce irritation  of the eyes and nose (Albin
1962; Pattle and Cullumbine,  1956; Sim and  Rattle, 1957) and  is  thought to
be   responsible,   at   least  in   part,   for  the   irritant  properties  of
photochemical  smog  (Altshuller,  1978;   Schuck   and  Renzetti,   1960)  and
cigarette smoke (Weber-Tschopp,  et al. 1976a; 1976b; 1977).
         In the only published chronic  toxicity  study on acrolein in animals
(Feron and  Kruysse,  1977), male  and  female Syrian  golden hamsters were ex-
                                                          •
posed to  acrolein  at  9.2 mg/m   in air,  seven  hours per  day,  five days per
week, for 52 weeks.  During the  first week  only,  animals  evidenced signs of
eye  irritation,  salivated,  had  nasal  discharge,   and  were  very  restless.
During the  exposure period, both males  and females had  reduced  body weight
gains- compared to  control  groups. .  Survival  rate was  unaffected.   Slight
hematological changes, increased  hemoglobin content and  packed cell volume,
decreases in liver weight (-16 percent),  and increases in lung weights  (-1-32
percent)  occurred  only  in females.   In both  sexes,  the  only pathological
changes in  the respiratory tract  were inflammation and epithelial metaplasia
in the nasal cavity.
         In a  study of  subacute  oral  exposure,  acrolein was added  to the
drinking water of male and female rats at  5  to  200 mg acrolein/1 for 90 days
(Newell,  1958).   NO  hematologic,  organ-weight,  or  pathologic changes could
be attributed to acrolein ingestion.
     F.   Other Relevant Information
         Acrolein is highly reactive  with thiol  groups.   Cysteine  and other
                                                                       »
compounds containing thiol groups antagonize the toxic effects of acrolein

-------
 (Tillian,  et al. 1976;  Low,  et al.  1977;  Sprince, et  al.  1978;  Munsch, et
 al.  1973;1974;  Whitehouse and  Beck,  1975).   Ascorbic  acid  also antagonizes
 the  toxic effects of acrolein (Sprince, et al.  1978).
          The  effects of  acrolein, on  the  adrenocortical  response  of  rats
 unlike  those of DOT  and parathion,  are  not inhibited  by  pretreatment  with
 phenobarbital  and  are  only partially  inhibited  by  dexamethason  (Szot and
 Murphy,  1970).   Pretreatment  of  rats  with acrolein  significantly  prolongs
 hexobarbital and pentobarbital  sleeping time (Jaeger and Murphy, 1973).
 V.   AQUATIC TOXICITY
      A.  Acute Toxicity
          A  relatively  narrow  range  of  acute  toxicity to  six  species of
 freshwater  fish has been  reported  for   acrolein (U.S.  EPA,  1979).    LC5Q
...values, ranged   from  61  to  160  pg/1  with   fathead  minnows,  (Pimephales
 promelas),   being   most   sensitive   and   largemouth   bass,   (Micropterus
 salmoides),  the  most resistant  of  the species  tested.   Results from  7  static
 bioassays varying from  24. to 96 hours in duration  were  reported.  The  fresh-
 water  invertebrate  Daphnia  magna was as sensitive to  acrolein as freshwater
 fish with 48-hour  static LC_Q values  of  59 and 80 /jg/1  being reported in
 two  individual studies.   The longnose killifish, (Fandulus similis), was the
 only marine  species tested  for acute toxicity  of acrolein;  a 48-hour  flow-
__thrpugh  LC^n of 150 pg/1  was  obtained.   The  eastern  oyster,  (Crassostrea
 virqinica),  and  adult  brown shrimp,  (Penacus aztecus),  were  the most  sensi-
 tive species  tested an  EC5Q  value  of 55 jjg/1  based on  50% decrease in
 shell  growth of oysters and an EC5Q  value  of  100 based  on loss  of  equi-
 librium of brown shrimp (Butler,  1965).   Adult barnacles were more resistant
                                                                       »
 in  static assays  with 48-hour LC5Q values of  1,600  and  2,100 jug/1   being
 reported.
                                                                                57

-------
     B.  Chronic Toxicity
         In a  chronic  life cycle  test  with the  freshwater  fathead minnow,
Pimephales  promelas,  survival of  newly  hatched  second  generation fry  was
reduced significantly  at 42 but not  11 ug/1,  leading to a  chronic value of
21.8 ug/1 (Macek, et al.  1976).  A comparable  value of 24 ug/1  was obtained
from reduced  survival  of three generations of Daphnia maqna.   Chronic data
for marine organisms was not available.
     C.  Plant Effects
         Pertinent  data  relating   the   phytotoxitity  of  freshwater  marine
plants could not be located in the available literature.
     0.  Residues
         A  bioconcentration factor  of   344 was  obtained  for radio  labeled
acrolein  administered  to bluegills,  (Lepomis macrochivas).   A  biological
half-life greater than seven days was indicated (U.S. EPA. 1979).
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the  human health nor  the  aquatic criteria derived  by the U.S.
EPA  (1979),  which are summarized  below,  have gone through the process of
public review; therefore, there is  a  possibility  that  these  criteria will be
changed.
     A.  Human
         Based  on  the  use  of  subacute  toxicological   data  for  rats  (no
observable effect level of 1.56 mg/kg body weight)  and an uncertainty  factor
of 1000,  the  U.S.  EPA  (1979) has derived  a draft criterion  of 6.50 pg/1 for
acrolein  in  ambient water.  This  draft criterion  level  corresponds  to  the
calculated (U.S. EPA,  1979) acceptable daily intake of 109 ug.
         The ACGIH  (1977)  time-weighted average TLV for acrolein is 0.1 ppm
(0.25  mg/m  ).   The same  value  is  recommended  by OSHA (39 FR 23540).   This
                                  f-it

-------
standard was designed  to "minimize,  but not. entirely  prevent,  irritation to
all exposed individuals" (ACGIH, 1974).
         The FDA permits  acrolein  as a slime-control  substance  in the manu-
facture of  paper and paperboard for usage in  food packaging (27  FR  46)  and
in the  treatment  of food  starch  (28 FR 2676)  at not more  than 0.6 percent
acrolein.
     B.  Aquatic
         The draft criterion  for protecting  freshwater organisms is 1.2 ug/1
as a  24-hour  average  not  to exceed  2.7  ug/1.   For  marine life,  the draft
criterion has been proposed as 0.88 ug/1,  not to exceed 2.0 ug/1.

-------
                           ACROLEIN

                          REFERENCES

Albin, T. B.  1962.  Page 234.  In;  C.W. Smith, ed. Handling
and toxicology, in acrolein.  John Wiley and Sons, Inc.,
New York.

Altshuller, A. P.  1978.  Assessment of the contribution
of chemical species to the eye irritation potential of photo-
chemical smog.  Jour. Air Pollut.. Control Assoc. 28: 594.

Altshuller, A. R. , and S. P. McPherson.  1963.  Spectrophoto-
metric. analysis of aldehydes in the Los Angeles atmosphere.
Jour.  Air Pollut.  Control Assoc. 13: 109.
                                          v
American Conference of Governmental Industrial Hygienists.
1974.  Documentation, of the threshold limit value. 3rd ed.

American Conference of Governmental Industrial Hygienists.
1977.  Threshold limit values for chemical substances in
workroom air.

Bellar, T. A., and J. E. Sigsby.  1970.  Direct gas chromato-
graphic analysis of low molecular weight substituted organic
compounds in emissions.  Environ. Sci. Technol. 4:  150.

Bignami, M. , et al.  1977.  Relationship between chemical
structure and mutagenic activity in some pesticides:  The
use of Salmonella typhimurium and Aspergillus nidulans.
Mutat. Res. 4t»:
Bilimoria, M. H.  1975.  Detection of mutagenic activity
of chemicals and tobacco smoke in bacterial system.  Mutat.
Res. 31: 328.

Bouley, G., et al.  1976.  Phenomena of adaptation in rats
continuously exposed to low concentrations of acrolein.
Ann. Occup. Hyg. 19: 27.

Bowraer, K. H. , and M. L. Higgins.  1976.  Some aspects of
the persistence and fate of acrolein herbicide in water.
Arch.  Environ. Con tarn. Toxicol. 5: 87.

Bowmer, K. H., and G. R. Sainty.  1977.  Management of aqua-
tic plants with acrolein. Jour. Aquatic Plant Manage. 15:
40.

Boyd, E. N., et al.  1965.  Measurement of monocarbonyl classes
in cocoa beans and chocolate liquor with special reference
to flavor.  Jour. Food Sci. 30: 854.
                              **
                             S--/3L

-------
Boyland, E., and L. F. Chasseaud.  1967.  Enzyme-catalyzed
conjugations of glutathione with unsaturated compounds.
Biochem. Jour. 104: 95.

Butler, P. A.  1965.  Commercial fisheries investigations.
Effects of pesticides on fish and wildlife, 1964 research
findings Fish Wildl. Serv.  U.S. Fish Wildl. Serv. Circ.

Egle, J. L., Jr.  1972.'  Retention of inhaled formaldehyde,
propionaldehyde, and acrolein in the dog.  Arch. Environ.
Health 25: 119.

Ellenberger, J., and G. R. Mohn.  1976.  Comparative mutageni-
city testing of cyclophosphamide and some of its metabolites.
Mutat. Res. 38: 120.

Ellenberger, J., and G. R. Mohn.  1977.  Mbtagenic activity
of major mammalian metabolites of cyclophosphamide toward
several genes of Escherichia coli.  Jour. Toxicol. Enviorn.
Health 3: 637.

Epstein, S. S., et al.  1972.  Detection of chemical mutagens
by the dominant lethal assay in the mouse.  Toxicol. Appl.
Pharmacol. 23: 288.

Esterbauer, H., et al.  1975.  Reaction of glutathione with
conjugated carbonyls.  Z. Naturforsch.  C: Biosci.  30c:
466.

Feron, V. J., and A. Kruysse.  1977.  Effects of exposure
to acrolein vapor in hamsters simultaneously treated with
benzo  (a)pyrene or diethylnitrosamine.  Jour. Toxicol. Environ.
Health 3: 379.

Hess, L. B., et al.  1978.  Acrolein and derivatives.  Iri
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd edT
Interscience Publishers, New York.

Hoffman, D., et al.  1975.  On the carcinogenicity of mari-
juana 'smoke.  Recent Adv. Phytochem. 9: 63.

Hopkins, D. M., and A. R. Hattrup.  1974.  Field evaluation
of a method to detect acrolein in irrigation canals.  U.S.
PB Rep. No. 234926/4GA. Natl. Tech. Inf. Serv.

Horton, A. D., and M. R. Guerin.  1974.  Determination of
acetaldehydes and acrolein in the gas phase of cigarette
smoke using cryothermal gas chromatography.  Tob. Sci. 18:
19-

Hrdlicka, J., and J. Kuca.  1965.  The changes of carbonyl
compounds in the heat-processing of meat.  Poultry Sci.
44:27.

-------
Izard, C.  1973.  Recherches sur les effets mutagenes de
1' acroleine et des ses deux epoxydes: le glycidol et le
glycidal, sur Saecharomyces cerevisiae, C.R. Acad. Sci.
Ser. D. 276: 3(3771

Izard, C., and C. Libermann.  1978.  Acrolein. Mutat. Res.
47: 115.

Jaeger, R. J., and S. D. Murphy.  1973.  Alterations of
barbiturate action following 1,1-dichloroethylene, corti-
costerone, or. acrolein. Arch. Int. Pharmacodyn. Ther. 205:
281.

Kantemirova, A. E.  1975.  Illness with temporary work dis-
ability in workers engaged in acrolein and raethylmercaptopro-
pionaldehyde  (MMP) production. Tr. Volgogr. Cos. Med. Inst.
26: 79.. Chem.  Abst. 88:.109868g.

Kaye, C. M.  1973..  Biosynthesis of raercapturic acids from
allyl alcohol, allyl esters, and acrolein.  Biochem. Jour.
134: 1093.

Kaye, C. M., and L. Young.  1972.  Synthesis of raercapturic
acids from allyl compounds in the rat.  Biochem. Jour. 127:
87.

Kishi, M., et al.  1975.  Effects of inhalation of the vapor
from heated edible oil on the circulatory and respiratory
systems in rabbits.  Shokuhin Eiseigaku Zasshi. 16: 313.

Low, E.. S., et al.  1977.  Correlated effects of cigarette
smoke components on alveolar macrophage adenosine triphos-
phatase activity and phagocytosis.  Am. Rev. Respir. Dis..
115: 963.

Macek, K. J., et al.  1976.  Toxicity of four pesticides
to water fleas and fathead minnows: Acute and chronic toxi-
city of acrolein, heptachlor, endosulfan, and tribluralin
to the water flea  (Daphnia magna) and the fathead minnow
(Primephales promelas).EPAbTni/3-76-099.  U.S. Environ.
Prot. Agency.

Munsch, N., et al.  1973.  Effects of acrolein on DNA syn-
thesis i£ vitro.  Fed. Eur. Biochem. Soc. Lett. 30: 286.

Munsch, N., et al.  1974.  In vitro binding of tritium labeled
acrolein to regenerating rat liver DNA polymuase.  Experi-
mentia 30: 1234.

National Cancer Institute.  1979.  Personal communication
from Sharon Feeney.

Newell, G. W.  1958.  Acute and  subacute toxicity of acro-
lein.  Stanford Res. Ins. SRI Project No. 5-868-2.  Summar-
ized in Natl. Acad. Sci. 1977.
                             /://

-------
Pattle, R. E., and H. Cullumbine.  1956.  Toxicity of some
atmospheric pollutants.  Brit. Med. Jour. 2: 913.

Pietruszko, R.,  et al.  1973.  Comparison of substrate specifi-
city of alcohol dehydrogenases from human liver, horse liver,
and yeast towards saturated and 2-enoic alcohols and alde-
hydes.  Arch. Biochem. Biophys. 159: 50.

Rapoport., I. A.  1948.  Mutations under the influence of
unsaturated aldehydes. Dokl. Akad. Nauk. (U.S.S.R.), 61:
713.  Summarized in Izard and Libermann, 1978.

Renzetti, N. A., and R. J. Bryan.  1961.  Atmospheric samp-
ling for aldehydes and eye irritation in Los Angeles smog
- 1960.  Jour. Air Pollut. Control Assoc. 11: 421.

Rosenthaler, L., and G. Vegezzi.  1955.  Acrolein in alco-
holic liquors.  Z. Lebensm.-Untersuch. u. - Forsch. 102:
117.

Schuck, E. A., and N. A. Renzetti.  1960.  Eye irritants
formed during photooxidation of hydro-carbons in the pre-
sence of oxides of nitrogen.  Jour. Air Pollut. Control
Assoc. 10:  389.

Sim, V. M., and R. E. Pattle.  1957.  Effect of possible
smog irritants on human subjects.  Jour. Am. Med. Assoc.
165:  1908.

Sprince, H., et al.  1978.  Ascorbic-acid and cysteine pro-
tection against aldehyde toxicants of cigarette smoke.
Fed. Proc.  37:  247.

Standen, A., ed.  1967.  Kirk-Othmer Encyclopedia of Chemi-
cal Technology.   Interscience Publishers, New York.

Szot, R. J., and S. D. Murphy.  1970.  Phenobarbital and
dexamethasone inhibition of the adrenocortical response
of rats to toxic chemicals and other stresses.  Toxicol.
Appl. Pharmacol.  17: 761.

Tillian, H. M.,  et al.  1976.  Therapeutic effects of cys-
teine adducts of alpha, beta-unsaturated aldehydes on ehr-
lich ascites tumor of mice.  Eur. Jour. Cancer 12: 989.

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

Weast, R. C., ed.  1975.  Handbook of chemistry and physics.
56th ed. CRC Press, Cleveland, Ohio.

Weber-Tschopp, A., et al.  1976a.  Air pollution and irri-
tation due to cigarette smoke. Soz.-Praeventivmed 21: 101.
                           s-ur

-------
Weber-Tschopp, A., et al.  1976b.  Objective and subjective
physiological effects of passive smoking.  Int. Arch. Occup,
Environ. Health 37: 277.

Weber-Tschopp, A., et al.  1977.  Experimental irritating
effects of acrolein on man.  Int. Arch. Occup. Environ.
Health 40: 117.

Whitehouse, M. W., and F.W.J. Beck.  1975.  Irritancy of
cyclophosphamide-derived aldehydes (acrolein, chloracetalde-
hyde) and their effect on lymphocyte distribution ui vivo;
Protective effect of thiols and bisulfite ions.  Agents
Actions 5: 541.
                            5V*

-------
                                     No.  7
           Acrylonitrile


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

           APRIL  30, 1980
              7-1

-------
                          DISCLAIMER
     This report represents a  survey of the potential health
and environmental hazards fron exposure to the subject chemi-
cal.  The information contained in  the report is drawn chiefly
from secondary  sources  and available  reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all available  information  including all the
adverse health  and   environmental  impacts  presented by  the
subject chemical.   This  document  has undergone scrutiny  to
ensure its technical accuracy.
                          7-4

-------
                       SPECIAL NOTATION


U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
acrylonitrile and  has found sufficient evidence to indicate
that this compound is carcinogenic.
                           7-3

-------
                                ACRYLONITRILE
                                   Summary

     Acrylonitrile  is  the most  extensively produced  aliphatic nitrile  and
ranks 45th on the list of high-volume chemicals produced  in  the U.S.   Chron-
ic exposure to  acrylonitrile  produces  mild liver damage  and  functional dis-
orders of  the central nervous  system,  cardiovascular  and hemopoietic sys-
tems.  Acrylonitrile has  shown  mutagenic activity in Drosophila and  bacter-
ia.  This compound  is teratogenic  in rats whether exposure is  by  inhalation
or ingestion  in  drinking  water.   There  are both  animal and  epidemiologic
data to suggest "that acrylonitrile may  be a human carcinogen.
     The  fathead minnow  has  an  observed  96-hour  LC-Q  value   ranging  from
10,100 to  18,100 ug/1 depending  on  test condition  and a 30-day  LC5Q value
of 2,600  ug/1.   For the freshwater  invertebrate,  Daphnia maqna,  a  reported
48-hour LC5Q  value  is  7,550  ug/1  with  no  adverse effects to concentrations
as high as 3,600 ug/1 in a life cycle test.  A saltwater  fish has  an  observ-
ed 96-hour  LCcQ  of 24,500  jug/1.   A bluegill in  a  28-day study  bioconcen-
trated acrylonitrile 48-fold with  a half-life of 4-7 days.
                                    7-V

-------
                                 ACRYLONITRILE
I.    INTRODUCTION
     This profile  is based  on the Ambient  Water Quality  Criteria Document
for Acrylonitrile (U.S. EPA, 1979).
     Acrylonitrile  (CH2=CHCN)   is  an  explosive,  flammable  liquid having  a
normal  boiling  point  of  77°C and  a  vapor  pressure  of 80  mm  Hg  (20°C).
Currently, 1.6  billion  pounds  per year of acrylonitrile  are manufactured in
the United States.   The major  use of  acrylonitrile  is in the manufacture of
copolymers for  the  production  of  acrylic and modacrylic  fibers.   Acryloni-
trile has been  used as a  fumigant; however,  all U.S.  registrations for this
use were voluntarily withdrawn as of August 8, 1978 (U.S. EPA, 1979).
II.  EXPOSURE
     A.  Water
         While  no data on monitoring  of  water supplies  for the presence of
acrylonitrile were  found  in the literature,  potential problems  may  exist.
Possible sources of  acrylonitrile  in  the  aqueous environment are:   (a) dump-
ing of  chemical wastes,  (b)  leaching  of wastes from  industrial  landfills,
(c) leaching of monomers  from  polymeric acrylonitrile,  and (d) precipitation
from rain.   Acrylonitrile is  short-lived in  the  aqueous environment;  a 10
ppm solution was completely degraded  after 6  days in Mississippi River water
(Midwest Research Institute, 1977).
     B.  Food
         There  is no data on the levels  of acrylonitrile  in food.  However,
acrylonitrile may contaminate  food by  leaching of the  monomer from polyacry-
lonitrile containers (National Resources Defense Council,  1976).   The  U.S.
EPA (1979)  has estimated  the  weighted average  bioconcentration  factor* for

-------
acrylonitrile to be  110 for the edible  portions of fish  and shellfish con-
sumed by Americans.  This  estimate is based on steady-state  bioconcentration
studies in bluegills.
     C.  Inhalation
         NIOSH  (1978)  estimated that 125,000 workers  are  exposed to acrylo-
nitrile  each year.  Acrylonitrile may  be liberated  to the atmosphere via
industrial processes or by the burning of polyacrylonitrile  fiber (Monsanto,
1973).   Data could not  be found in  the available  literature regarding the
concentrations of acrylonitrile in ambient air.
III. PHARMACOKINETICS
     A.  Absorption
         When orally administered  to rats, essentially  all of the acryloni-
trile is absorbed (Young,  et al. 1977).
     .8.  Distribution
         In  rabbits, after administration of a  30 mg/kg dose, acrylonitrile
rapidly  disappeared  from  the  blood;  only 1  mg/kg remained after  4  hours
(Hashimoto and  Kanai,  1965).   In rats the metabolites of  acrylonitrile dis-
tributed to  the stomach wall,  erythrccytes,  skin, and  liver (Young,  et al.
1977).   .
     C.  Metabolism
         Earlier reports (Giacosa,  1883; Maurice,  1900) indicated that most
aliphatic nitriles  are  metabolized  to cyanide  which  is then detoxified to
thiocyanate.   A more recent report  concluded that  acrylonitrile  exerts its
toxicity by the metabolic  release of  cyanide  ion,  and  that the relative abi-
lity  of various  species  to  convert  CN~  to SCN" determined  their  suscep-
tibility to the toxic action of  acrylonitrile  (Brieger,  et al. 1952).  Other
facts,  however,  suggest that  acrylonitrile  toxicity  is due  in part to the

-------
acrylonitrile  molecule  itself  or  other unknown  metabolite(s)  rather  than
just to the  cyanide functional group  (U.S.  EPA, 1979).   In a comprehensive
tracer  study with  rats  Young,  et  al.   (1977)  found  three uncharacterized
metabolites"  as  well as  CCL after acrylonitrile administration.   Also,  cya-
noethylated mercapturic  acid conjugates  have  been  detected after administra-
tion of acrylonitrile  (U.S. EPA, 1979).
     D.  Excretion
         Urinary excretion  of  thiocyanate after acrylonitrile administration
ranges from  4-33 percent of the  administered dose --depending  on  the species
(U.S. EPA, 1979).   Urinary  excretion also depends  on route of administration
(Gut, et al. 1975).
IV.  EFFECTS
     A.  Carcinogenicity
         In two  studies  rats received acrylonitrile in the drinking water at
concentrations of 0, 35,  100 and  300 mg/1,  which is equivalent to daily dos-
ages of approximately  4, 10,  30 mg/kg body  weight respectively,  excess mam-
mary tumors  and  tumors of the  ear canal and  nervous  system were  noted (Nor-
ris, 1977; Quast, et al.  1977).   Both the intermediate and the highest doses
produced increased  tumor incidences.  In rats  administered acrylonitrile in
olive  oil  by stomach  tube at  5  mg/kg body  weight 3 times per  week  for 52
weeks, a slight  enhancement of the  incidence of mammary tumors,  forestomach
papillomas and  acanthomas, skin  carcinomas,  and encephalic  tumors  has  been
repprted (Maltoni,  et  al. 1977).   Also,  exposure of  rats by inhalation (40,
20, 10, and  5 ppm  for 4  hours  daily,  5 times/week)  for  52 weeks caused in-
creases in tumor incidence  (Maltoni, et  al.  1977).   It should be  pointed out
                                                                        »
that possible impurities  found  in  the  acrylonitrile used by various investi-
gators might  determine the carcinogenic effect.  The  specific  role  of these
impurities has not yet been determined -(U.S. EPA, 1979).

-------
         Retrospective studies  on  workers in a  textile  fiber plant (O'Berg,
1977) and on workers  in  the polymerization recovery  and laboratory areas of
a B.F.  Goodrich plant (Monson,  1977)  have shown  higher than expected inci-
dences  of  cancers of  all sites in  workers  exposed  to  acrylonitrile.   The
greatest increase was  noted with lung  cancer.  It should be noted that these
workers were exposed to other chemicals in their working environment.
     B.  Mutagenicity
         Acrylonitrile is a weak  mutagen in Drosophila melanoqaster (Benes
and  Sram,  1969); although  toxicity  limited  this testing.  Milvy  and Wolff
(1977)  reported  mutagenic activity for acrylonitrile in Salmonella typhimur-
ium with a mammalian  liver-activating  system.  In Escherichia coli mutagenic
activity was observed without an activating system (Venitt, et al. 1977).
     C.  Teratogenicity
         Studies  in  pregnant  rats demonstrated  that acrylonitrile adminis-
tered by gavage  at  65 mg/kg/day caused fetal malformations  (Murray,  et al.
1976).  These  malformations included acaudea, short-tail, short trunk, miss-
ing vertebrae,  and right-sided aortic arch.  In  a subsequent study, Murray,
et al.  (1978)  concludad  that  in pregnant  rats exposed to 0, 40, or 80 ppm of
acrylonitrile  by  inhalation,  teratogenic  effects in  the  offspring  were seen
at 80  ppm  but not 40 ppm.   Significant maternal toxicity  was  found at both
80 and 40 ppm, as well as in the previous study at 65 mg/kg/day.
     0.  Other Reproductive Effects
         Pregnant rats  receiving  500  ppm acrylonitrile  in their  drinking
                                                                       «.
water  showed  reduced pup  survival,  possibly  due  to  a maternal  toxicity
(Beliles and Mueller,  1977).

-------
     E.  Chronic Toxicity
         Knoblock, et al.  (1972) observed  a  perceptible change in peripheral
blood  pattern,  functional disorders  in the respiratory and  cardiovascular
systems, and  the  excretory system, as  well  as signs of  neuronal lesions in
the central nervous  system of  rats  and rabbits breathing  acrylonitrile  (50
mg/m   air)  for 6  months.   Babanov,  et  al.  (1972) reported that inhalation
of  acrylonitrile  vapor  (0.495 mg/m  ,  5  hours/day,  6  days/week)  for  6
months  resulted  in central nervous  system disorders,  increased  erythrocyte
count, and decreased leukocyte  count in  rats.   Workers  exposed for long per-
iods of time  to acrylonitrile have subjective  complaints including headache,
fatigue, nausea and  weakness,  as well as  clinical  symptoms of anemia,  jaun-
dice, conjunctivitis and abnormal  values of  specific  gravity of whole blood,
blood serum and cholinesterase  values,  urobilinogen,  bilirubin, urinary pro-
tein  and  sugar (Sakarai- and Kusimoto,  1972).   In  another  study, functional
disorders of  the central nervous system, cardiovascular and hemopoietic sys-
tems  were  noted (Shustov  and  Mavrina, 1975).   Sakarai and Kasumoto (1972)
concluded  that acrylonitrile exposures  at  levels  of  5-20 ppm  caused  mild
liver injury and probably a cumulative general toxic effect.
     F.  Other Relevant Information
         HCN  and CO  were  found  to enhance acrylonitrile  toxicity in experi-
mental animals  (Yamamoto,  1976) as well as  in workers engaged in acryloni-
trile production (Ostrovskaya,  et al.  1976).
V.   Aquatic Toxicity
     A.  Acute Toxicity
         The  96-hour  LC5Q values  of  fathead  minnows  (Pimephales  promelas)
were 10,100 and 18,100 ug/1 for flow-through and static tests, respectively,
and  14,300  and 18,100 ug/1 for hard  (330 mg/1)  and  soft  (29  mg/1)  waters,
                                   7-r

-------
respectively  (Henderson,  et al.  1961).   A  reported  48-hour LC5Q  for Daoh-
nia maqna  is  7,550 ug/1  (U.S.  EPA,  1978).   The saltwater  pinfish (Lagodon
rhbmboides) has  an observed  96-hour LC5Q value  of 24,500 jug/1  in a static
concentration unmeasured test (Oaugherty and Garrett, 1951).
     B.  Chronic Toxicity
         Daphnia maqna  has been exposed  for its life  cycle and the  results
indicate no adverse effects at  concentrations as  high as  3,600 jug/1 (U.S.
EPA,  1978).    Henderson,   et  al.  (1961)  observed  a  30-day  LC-g  value of
2,600 pg/1 with Pimephales promelas  (fathead minnows).   No chronic test  data
are available for saltwater species.
     C.  Plant Effects
         Pertinent  data could  not be located  in  the  available literature on
the sensitivity of plants  to acrylonitrile.
     D.  Residues
         In the  only  reported study, the  bluegill  (Lepomis macrochirus) was
exposed  for  28 days  and   the determined  whole body  bioconcentration factor
was 48, with a half-life between 4-7 days  (U.S. EPA, 1978).
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
threshold limit value (TLV) (ACGIH,  1974)  for acrylonitrile is  20 ppm.   In
                                                                         »
January, 1978,  the Occupational Safety and  Health  Administration (OSHA) an-
nounced an emergency  temporary  standard for acrylonitrile of 2 ppm averaged

-------
over an  eight-hour  period.  Based  on  rat data (Norris,  1977;  Quast,  et al.
1977; Maltoni,  et al.  1977),  and  using  the "one-hit"  model,  the  U.S.  EPA
(1979) has estimated levels of  acrylonitrile in ambient water which will re-
sult in specified risk levels of human cancer:      ••  ~
Exposure Assumptions Risk
(per day)
0
2 liters of drinking water
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish and
shellfish only..
Levels and Corresponding Draft Criteria
10-7
0.008 x
10-* ng/1
0.016 x
10-* ng/1
10-6
0.08 x
10-* ng/1
0.16 x
10-* ng/1
10-5
0.8 x
10-* ng/1
1.6 x
10-* ng/1
     B.  Aquatic
         For acrylonitrile, the  draft  criterion to protect freshwater aquat-
ic life is  130 ug/1 as a  24-hour  average,  and the concentration  should not
exceed 300  ug/1 at any  time.   To protect saltwater  species,  the  draft cri-
terion is 130 ug/1 as a 24-hour  average, with  the  concentration not to exceed
290 ug/1 at any time (U.S. EPA, 1979).

-------
                        ACRYLONITRILE

                          REFERENCES

Babanov, G.P., et al.  1972.  Adaptation of an organism
to acylonitrile at a low concentration factor in an indus-
trial environment.  Toksikol. Gig. Prod. Neftekhim. 45:
58.

Beliles, R.P., and S. Mueller.  1977.  Three-generation
reproduction study of rats receiving acrylonitrile in drink-
ing water.  Acrylonitrile progress report second generation.
Submitted by Litton Bionetics, Inc. to the Manufacturing
Chemists Association.  LBI Project No. 2660.  November, 1977.

Benes, V., and R. Sram.  1969.  Mutagenic activity of some
pesticides in Drosophila melanogaster.  Ind. Med. Surg.
38: 442.

Brieger, et al.  1952.  Acrylonitrile:  Spectrophotometric
determination, acute toxicity and mechanism of action.
Arch. Indust. Hyg. Occup. Med. 6: 128.

Daugherty, P.M., Jr., and J.T. Garrett.  1951.  Toxicity
levels of hydrocyanic acid and some industrial by-products.
Tex. Jour. Sci. 3: 391.

Giacosa, P.  1883.  Toxicity of aliphatic nitriles.  Hoppe-
Seyle 2: 95.

Hashimoto, K., and R. Kanai.  1965.  Toxicology of acrylo-
nitrile:  metabolism, mode of action, and therapy.  Ind. Health
3:  30.

Henderson, C., et al.  1961.  The effect of some organic
cyanides . (nitriles) on fish.  Eng. Bull. Ext. Ser. Purdue
Univ. No. 106: 130.

Knobloch, K., et al. 1972.  Chronic toxicity of acryloni-
trile.  Med. Pracy 23: 243.

Maltoni, C., et al.  1977.  Carcinogenicity bioassays on
rats of acrylonitrile administered by inhalation and by
ingestion.  La Medicina del Lavoro 68: 401.

Meurice, J.  1900.  Intoxication and detoxification of dif-
ferent nitriles.  Arch. Internat. de Pharmacodynamie et
de Therapie 7: 2.

Midwest Research Institute.  1977.  Sampling and analysis
of selected toxic substances.  Section V.  Sampling and
analysis protocol for acrylonitrile.  Progress Report No.
13, Oct. 1-31, 1977.  EPA Contract No. 68-01-4115, MRI Pro-
ject No. 4280-C(3).

-------
Milvy, P., and M. Wolff.  1977.  Mutagenic studies with
acrylonitrile.  Mutation Res. 48: 271.

Monsanto Company.  July 19, 1973.  Environmental Impact
of Nitrile Barrier Containers, LOPAC: A case study.  Monsanto
Co.  St. Louis, Missouri.

Monson, R.R.  November 21, 1977.  Mortality and Cancer Mo-
bidity among B.F. Goodrich White Male Union Members who
ever worked in Departments 5570 through 5579.  Report to
B.F. Goodrich Company and to the United Rubber Workers.
Federal Register No. 43FR45762  (see OSHA Dockit H-108, ex-
hibits 67 and 163).

Murray, F.J., et al.  1976.  Tertologic evaluation of acrylo-
nitrile monomer given to rats by gavage.  Report from Toxi-
cology Research Lab., Dow Chem.

Murray, F.J., et al.  1978.  Teratologic evaluation of in-
haled acrylonitrile monomer in rats.  Report of the Toxi-
cology Research Laboratory, Dow Chemical U.S.A. Midland,
Michigan.  May 31, 1978.

National Resources Defense Council.  1976.  Pop bottles:
The plastic generation—a study of the environmental and
health problems of plastic beverage bottles,  p. 33.

NIOSH.  1978.  A Recommended Standard for Occupational Expo-
sure to Acrylonitrile. DREW  (NIOSH) Publication No. 78-116,
U.S. Government Printing Office.

Norris, J.M.  1977.  Status report on two-year study incor-
porating acrylonitrile in the drinking water of rats.  Health
Environ.  Res.  The Dow Chemical Company.

O'Berg, M.  1977.  Epidemiologic studies of workers exposed
to acrylonitrile:  Preliminary results.  E.I. Du Pont de
Nemours & Company.

Ostrovskaya, R.S., et al.  1976.  Health status of workers
currently engaged in production of acrylonitrile.  Gig.
T. Prof. Zabol. 6: 8.

Quast, J.F., et al.  1977.  Toxicity of drinking water con-
taining acrylonitrile in rats:  Results after 12 months.
Toxicology Res. Lab., Health and Environmental Res. Dow
Chemical U.S.A.

Sakarai, H., and M. Kusimoto.  1972.  Epidemiologic Study
of Health Impairment Among AN Workers.  Rodo Kagaku.48:    .
273.

Shustov, V.Y., and E.A. Mavrina.  1975.  Clinical picture
of chronic poisoning in the production of nitron.  Gig. Tr.
Prof. Zabol 3: 27.
                              7-13

-------
Threshold Limit Values.  1974.  TLV's:  Threshold Limit
Values for Chemical Substances and Physical Agents in the
Work Room Environment with Intended Changes for 1974.  Am.
Conf. Govern. Ind. Hyg.

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.  Acrylonitrile:  Ambient Water Quality
Criteria  (Draft).

Venitt, S., et al.  1977.  Mutagenicity of acrylonitrile
(cyanoethylane)  in Escherichia coli.  Mutation Res. 45:
283.

Yamamoto, K.  1976.  Acute combined effects of HCN and CO,
with the use of combustion products from PAN (polyacrylo-
nitrile)—gauze mixtures.  Z. Rechtsmed. 78: 303.

Young, J.D.,4et al.  1977.  The pharmacokinetic and metabolic
profile of   C-acrylonitrile given to rats by three routes.
Report of the Toxicological Research Laboratory.  Dow Chemi-
cal.  Midland, Michigan.
                          7-11

-------
                                      No. 8
               Aldrin
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION


U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
aldrin and has found sufficient evidence to indicate that
this compound is carcinogenic.

-------
                                    ALDRIN  •
                                    Summary

     Aldrin is a  man-made compound belonging to  the  group of cyclodiene in-
secticides.  The  chronic toxicity of  low doses of aldrin include shortened
lifespan,  liver  changes, and teratogenic effects.  The  induction of hepato-
cellular carcinoma in  both male and  female mice from the administration of
aldrin leads  to  the conclusion that  it is likely to be a human carcinogen.
Aldrin has not been  found mutagenic in several test  systems although it did
induce unscheduled DNA  synthesis  in  human  fibroblasts.   The  World Health
Organization acceptable daily intake level for aldrin is 0.1 pg/kg/day.
     Aldrin is rapidly converted  to dieldrin by  a  number of fresh and salt-
water species.  The  overall toxicity  of aldrin is  similar to dieldrin.  The
96-hour  LC-Q  values for  freshwater  fish vary from 2.2  to  37 pg/1 with in^
vertebrates being one  order of magnitude less sensitive.   Both marine fish
and plants were   susceptible  to levels  of  aldrin corresponding  to those of
freshwater fish.

-------
                                    ALDRIN
I.   INTRODUCTION
     This profile  is based  on the Ambient  Water Quality  Criteria Document
for Aldrin and Dieldrin (U.S. EPA, 1979a).
     Aldrin  is  a  white  crystalline  substance with  a  melting  point  of
104°C.   It  is  soluble  in  organic  solvents.   The  chemical name  for aldrin
is   1,2,3,4,10,10-hexachloro-l,4,4a,5,8,8a-hexahydro-l,4,:5,8-exo-dimethano-
naphthalene.  Aldrin is  biologically  altered in the  environment to dieldrin,
a more  stable and equally  toxic  form.  For  information  concerning dieldrin
refer to the  dieldrin hazard profile  or the  draft Ambient Water Quality Cri-
teria Document for Aldrin and Dieldrin (U.S.  EPA, 1979a,b).
     Aldrin was  primarily used as  a  broad  spectrum insecticide  until 1974
when the U.S.  EPA restricted its use  to  termite control by direct soil in-
jection, and  non-food seed  and  plant  treatment (U.S. EPA, 1979a).  From 1966
to  1970 the  use  of aldrin  in  the  United States dropped from 9.5  x 10  to
5.25  x  103 tons  (U.S.  EPA,  1979a).   This  decrease  in use has  been attri-
buted primarily  to  increased insect resistance  to aldrin  and  to development
of  substitute materials.  Although the production  of  aldrin   in  the United
States  is  restricted,  formulated products  containing  aldrin are imported
from Europe (U.S. EPA, 1979a).
II.  EXPOSURE
     A.    Water
          Aldrin  has  been applied  to vast  areas  of agricultural  land,  and
aquatic areas  in the United  States and in  most parts of  the world.   As  a
result,  this  pesticide  is found  in most fresh  and  marine  waters  (U.S. EPA,
1979a).   Levels of aldrin, ranging from 15 to 18 ng/1 or  as  high  as 407 ng/1

-------
have been  found in  waters of the  United States (U.S.  EPA,  1976; leichten-
berg, et al. 1970).  The half-life  of aldrin  in water one meter in depth has
been estimated to be 10.1 days (MacKay and Wolkoff, 1973).
     B.   Food
          The estimated  daily  dietary intake of aldrin  in 16 to 19 year old
males was estimated  to be 0.001 mg in  1965 and only  a  trace amount in 1970
(Natl. Acad. Sci., 1975).
          No  direct  measured bioconcentration  factor for  aldrin  can be ob-
tained  because  it  is  rapidly  converted  to dieldrin by  aquatic organisms
(U.S. EPA,  1979a).   The U.S. EPA (1979a)  has estimated the weighted average
bioconcentration  factor of  aldrin  at  32.  This  estimate is  based  on the
octanbl/water partition coefficient for aldrin.
     C.   Inhalation
          Aldrin enters  the  air  through various mechanisms such as spraying,
wind action, water evaporation,  and adhesion to particles  (U.S. EPA, 1979a).
Ambient  air levels  of 8  ng/m  of  aldrin have  been reported  .(Stanley,  et
al. 1971).
     0.   Dermal
          Dermal  exposure to  aldrin is  limited to  workers  employed during
its manufacture and  use  as a pesticide.  Wolfe, et  al.  (1572)  reported that
exposure in  workers  is mainly through dermal absorption rather than inhala-
tion.  The ban on the manufacture of  aldrin in  the United States has greatly
reduced the risk of exposure.
III. PHARMACOKINETICS
     A.   Absorption
          Pertinent  data could  not be  located in the  available  literature
concerning the absorption of aldrin (U.S. EPA, 1979a).

-------
     B.   Distribution
          The distribution  of aldrin in  humans  or animals has  not  been ex-
tensively studied  because aldrin  is readily converted  to dieldrin  in  vivo
via epoxidation  (U.S.  EPA,  1979a).  For example,  the  blood  plasma levels of
aldrin were lower  than the  corresponding blood plasma levels  of dieldrin in
six workers  just after chronic  exposure to aldrin for  five weeks (Mick, et
al. 1971).
     C.   Metabolism
          The epoxidation of aldrin  to dieldrin.. has  been reported  in  many
organisms including man (U.S. EPA, 1979a).  The  reaction  is NADPH-dependent
and the  enzymes are  heat-labile (Wong  and Terriere,  1965).   The metabolic
products of aldrin include dieldrin,  as  well as  aldrin diol,  and polar meta-
bolites excreted in the urine and feces (U.S. EPA, 1979a).
     D.   Excretion
          Aldrin is  excreted mainly  in  the feces and to  some extent in the
urine  in  the  form  of  several polar metabolites   (U.S. EPA,  1979a).   Ludwig,
et al.  (1964) reported nine  times  as much radioactivity  in the feces as in
the urine  of rats chronically  administered 14C-aldrin.   A  saturation level
was reached in these animals  and concentrations  of radioactivity in the body
decreased rapidly when feeding was terminated.
          Specific values for  the  half-life of  aldrin  in  humans  were  not
found  in  the available literature.  However,  in humans  exposed to  aldrin
and/or dieldrin  the half-life of dieldrin  in the blood  was estimated to be
266 days (Jager, 1970).   In  another study  with 12 volunteers ingesting vari-
ous doses of  dieldrin,  Hunter,  et al. (1969) estimated  the  average  dieldrin
half-life to be 369 days.
                                    8-7

-------
IV.  EFFECTS
     A.   Carcinogenicity
          Aldrin has  induced liver  tumors in  males  and  females  in various
strains of mice according to  reports  of four separate feeding studies (Davis
and Fitzhugh,  1962; Davis,  1965; 43  FR  2450;  Song and Harville, 1964).  Ac-
cording to reports of  five  studies  in two different  strains of rats, aldrin
failed  to  induce  a  statistically  significant carcinogenic  response at all
but one  site (Deichmann, et  al. 1967,  1970;  Fitzhugh,  et  al.  1964; Cleve-
land, 1966; 43 FR 2450).
          The  only  information  concerning  the  carcinogenic  potential  of
aldrin  in  man 'is an  occupational study by  Versteeg  and  Jager  (1973).   The
workers  had  been employed  in a  plant producing aldrin and dieldrin with a
mean exposure  time of 6.6 years.  An average  time of 7.4 years had elapsed
since  the  end of  exposure.   No  permanent adverse effects including cancer
were observed.
     B.   Mutagenicity
          Aldrin was  found  not  to  be mutagenic in two  bacterial assays (S^
typhimurium  and  §._ coli) with  metabolic activation  (Shirasu,  et al. 1977).
Aldrin  did,  however,  produce unscheduled  DNA  synthesis  in human fibroblasts
with and without metabolic activation  (Ahmed, et al.  1977).
     C.   Teratogenicity
          Aldrin  administered  in  single  oral doses  to  pregnant   hamsters
caused significant increases  in  hamster fetal  death and increased fetal ano-
malies  (i.e.,  open eye,  webbed  foot,  cleft palate, and others).  When a sim-
ilar study  was done in  mice at  lower doses,  teratogenic  effects  were also
                                                                        •
observed,  although these effects were  less pronounced  (Ottolenghi,  et al.
1974).

-------
     D.   Other Reproductive Effects
          Deichmann (1972) reported  that  aldrin and dieldrin (25 mg/kg diet)
fed to  mice for  six  generations  affected fertility,  gestation,  viability,
lactation and survival of the young.
     E.   Chronic Toxicity
          The other effects  produced by chronic  administration  of aldrin to
mice,   rats,  and  dogs include  shortened  lifespan,  increased liver  to body
weight  ratios,  various  changes  in  liver  histology,  and  the  induction  of
hepatic enzymes (U.S.  EPA, 1979a).
     F.   Other Relevant Information
          Since aldrin and dieldrin  are metabolized by way of mixed function
oxidase (MFO), any inducer or inhibitor of the  MFO enzymes should affect the
metabolism of aldrin and dieldrin (U.S. EPA, 1979a).
          When aldrin is administered  with DDT, or  after  a  plateau has been
reached in dogs  with  chronic DDT 
-------
fathead  minnows (Pimephales  promelas)  32 and  37 jjg/1 (Henderson,  et  al.
1959).   Acute  toxicity varies greatly  in  freshwater invertebrates.  In  bio-
assays  in  which the  aldrin concentrations  were not  measured,  the  observed
48-hour  LC5Q -value for Daohnia  pulex was 28 ^g/1  (Sanders and Cope,  1966),
and  the observed  96-hour  LC5Q values  ranged  from 4,300 to  38,500 ;jg/l  for
scud, Gammarus spp. (Sanders, 1969, 1972; Gaufin, et al. 1965).
          In  flow-through  exposures  to  aldrin,  the  48  and  96-hour  LC5Q
values  for six saltwater fish  species ranged from 2.0 to 7.2 pg/1.   Inverte-
brate LC5Q values ranged from 0.37 to 33.0 jjg/1  (U:-S. EPA,  1979a).
     B.   Chronic Toxicity
          No entire cycle  or embryo-larval tests have  been reported for  any
fresh or saltwater species  (U.S. EPA, 1979a).
     C.   Plant Effects
          An  aldrin  concentration  of  10,000  ^ig/1  reduced  the   population
growth  in  12  days  for water  meal,  Wolffia papulifera  (Worthley and Schott,
1971).  The productivity of a phytoplankton community was  reduced  85 percent
after four hour exposure to l,000pg/l aldrin (Butler, 1963).
     0.   Residues
          No freshwater  or saltwater residue studies  have  been reported  for
aldrin  (U.S. EPA, 1979a).
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the human health nor  the aquatic  criteria  derived by U.S.  EPA
(1979a), which are summarized  below,  have  gone  through the process of  public
review;  therefore, there   is  a  possibility  that  these  criteria  will be
changed.

-------
     A.   Human
          The  current  exposure  level  for  aldrin  set  by  the Occupational
Safety  and  Health  Administration  is  a time-weighted  average of  250 jjg/m
for skin absorption  (37 FR  22139).   In 1969, the  U.S.  Public Health Service
Advisory Committee  recommended that  the  drinking water  standard  for aldrin
be 17 ^ig/1  (Mrak,  1969).  The U.N. Food  and Agricultural Organization/World
Health  Organization  acceptable  daily  intake  for  aldrin  is  0.1  pg/kg/day
(Mrak, 1969).
          The  carcinogenicity  data of  the National  Cancer  Institute (1976)
(43 FR  2450)  were used to  calculate the  draft water quality criterion  for
aldrin  which  keeps  the  lifetime  cancer  risk  for  humans below  10" .    The
concentration  for aldrin is 4.6 x 10"2 ng/1 (U.S. EPA, 1979a).
     B.   Aquatic
          Draft  criterion  has  not been proposed  directly for aldrin because
of its rapid conversion to dieldrin (U.S. EPA,  1979a).

-------
                                    ALDRIN
                                  REFERENCES
Ahmed, F.E.,  et al.  1977.   Pesticide-induced ONA damage  and its repair in
cultured human cells.  Mutat. Res.  42: 161.
Butler, P.A.   1963.   Commercial fisheries investigations.  In: Pesticide and
wildlife  studies:   A  review  of Fish  and  Wildlife  Service investigations
during 1961 and 1962.  U.S. Fish Wildl. Serv. Circ.  167: 11.
Clark,  C.R  and   R.I.   Krieger.    1976.    Beta-diethylaminoethyldiphenyl-
propylacetate  (SKF 525-A)  enhancement of  tissue  accumulation of aldrin in
mice.  Toxicol. Appl. Pharmacol.  38: 315.
Cleveland, F.P.  1966.  A  summary  of work on aldrin and dieldrin  toxicity at
the Kettering Laboratory.  Arch. Environ. Health.  ^.3: 195.
Davis, K.J.,   1965.  Pathology  report  on mice for  aldrin,  dieldrin, hepta-
chlor, or heptachlor epoxide  for two years.  Internal Memorandum to Or. A.J.
Lehman.  U.S. Food Drug Admin.
Davis, K.J.  and O.G. Fitzhugh.   1962.   Tumorigenic potential of aldrin and
dieldrin for mice.  Toxicol. Appl. Pharmacol.  4: 187.
Oeichmann,  W.B.   1972.   Toxicology  of DDT  and  related  chlorinated hydro-
carbon pesticides.  Jour. Occup. Med.  14:  285.
Oeichmann,  W.B.j   et  al.    1967.   Synergism  among oral  carcinogens  in the
simultaneous  feeding  of  four tumorigens to rats.  Toxicol.  Appl. Pharmacol.
11: 88.
Deichmann, W.B., et al.  1969.   Retention of dieldrin and DDT in  the tissues
of dogs  fed aldrin and DDT individually and  as  a micture.   Toxicol.  Appl.
Pharmacol.  14: 205.
Oeichmann,  W.B.,  et al.    1970. .  Tumorigenicity  of aldrin,  dieldrin and en-
drin in the albino rat.  Ind, Med. Surg.  39: 426.
Fitzhugh,  O.G., et al.   1964.  Chronic oral  toxicity  of aldrin and dieldrin
in rats and dogs.  Food Cosmet. Toxicol.  2: 551.
Gaufin, A.R,  et al.   1965.   The toxicity  of ten organic insecticides to var-
ious aquatic invertebrates.  Water Sewage Works  12: 276.
Henderson,  C.,  et al.   1959.  Relative  toxicity  of  ten  chlorinated hydro-
carbon insecticides to four species of fish.  Trans. Am. Fish. Soc.  88: 23.
Hunter, C.G., et  al.  1969.   Pharmacodynamics of  Oieldrin  (HEOD).    Arch.
Environ. Health  18: 12.
Jager,  K.W.   1970.   Aldrin,  dieldrin,  endrin and  telodrin:  An epidemio-
logical   and   toxicological   study   of  long-term   occupational  exposure.
Elsevier Publishing Co.  Amsterdam.

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

Leichtenberg,  J.J.,   et  al.   1970.   Pesticides in  surface  waters  in  the
United  States -  A  five-year  summary,  1964-1968.    Pestic.   Monitor.  Jour.
4: 71.

Ludwig,  G.,   et  al.   1964.   Excretion  and distribution  of  aldrin-l^C  and
its metabolites after oral administration  for  a long period  of time.   Life
Sci.  3: 123.

Macek, K.J.,  et al.   1969.   The  effects of temperature on the susceptibility
of  bluegills  and  rainbow  trout  to  selected   pesticides.    Bull.  Environ.
Contam. Toxicol.  4: 174.

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

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

Mrak,  E.M.   1969.    Report  of the  Secretary's  commission  on  pesticides and
their  relationship to environment health.  U.S. Dept. Health, Edu. Welfare, '
Washington, D.C.

National Academy of  Sciences,  National  Research Council.   1975.   Vol. 1 Pest
control:  An  assessment  of  present and  alternative  technologies.    Contem-
porary pest  control  practices  and  prospects.   Natl.  Acad.  Sci.   Washington,
O.C.

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

Sanders,  H.O.  1969.   Toxicity   of pesticides  to  the crustacean, Gammarus
Lacustris.  Bur. Sport Fish. Wildl. Tech.  Pap. No.  25.

Sanders, H.O.  1972.  Toxicity of some  insecticides to four species of mala-
costracan crustaceans.  Bur. Sport Fish. Wildl. Tech.  Pap. No. 66.

Sanders, H.O.  and O.B. Cope.   1966.  Toxicities of  several pesticides to two
species of cladocerans.   Trans. Am. Fish. Soc.  95:  165.

Shirasu, Y.,  et al.   1977.   Mutagenicity screening  on pesticides and modifi-
cation products:   A  basis of  carcinogenicity  evaluation.  Page  267  in H.H.
Hiatt, et al.  (eds.).  Origins of Human Cancer.  Cold Spring Harbor Lab. New
York.

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

-------
Stanley, C.W.,  et al.   1971.   Measurement  of  atmospheric levels  of pesti-
cides.  Environ. Sci. Technol.  5: 430.
U.S. EPA.  1976.  National  interim  primary drinking water regulations.  U.S.
Environ. Prot. Agency. Publ. No. 570/9-76-003.
U.S. EPA.   1979a.   Aldrin/Oieldrin Ambient  Water  Quality Criteria Document.
Washington, D.C.  (Draft).
U.S. EPA.   1979b.   Environmental Criteria and  Assessment Office.  Dieldrin:
Hazard Profile.  (Draft).
Versteeg,  J.P.J.  and K.w. Jager.  1973.   Long-term occupational exposure to
the  insecticides  aldrin, dieldrin,  endrin,  and telodrin,   Br.  Jour.  Ind.
Med. 30: 201.
Wolfe,  H.R.,  et  al.   1972.   Exposure of  spraymen  to  pesticides.   Arch.
Environ. Health.  25: 29.
Wong, D.T.  and -L.C.  Terriere.   1965.  Epoxidation of  aldrin,  isodrin,  and
heptachlor by rat liver microsomes.  Biochem. Pharmacol.  14: 375.
Worthley,  E.G.  and C.O.  Schott.   1971.   The  comparative effects  of CS and
various  pollutants   on   freshwater   phytoplankton   colonies   of  Wolffia
papulifera   Thompson.    Dep.  Army.  Edgewood   Arsenal  Biomed.  Lab.  Task
IW662710-AD6302.

-------
                                      No. 9
           Allyl Alcohol


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

           APRIL 30, 1980

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

-------
                                ALLYL ALCOHOL
                                   Summary

     Allyl alcohol is a severe irritant to the mucous membranes at high con-
centrations.    Hepatotoxicity  has  been  seen  after  oral  and  inhalation
exposures,  however,   results  indicate   that   this  effect  may   not  be
cumulative.  Allyl alcohol is also absorbed percutaneously.
     Information on the carcinogenic, mutagenic, teratogenic or other repro-
ductive effects of allyl alcohol was not found in the^available literature.
     Data concerning the  effects  of allyl alcohol  to aquatic organisms were
not found in the available literature.
                                   7-3

-------
I.   INTRODUCTION
          This profile is  based  on computerized searches of Toxline, Biosis
and  Chemical  Abstracts,  and  a  review  of  other  available  appropriate
information sources as available.
          Allyl  alcohol  (molecular  weight-58.08)  is  a limpid  liquid with
pungent odor.   It is  soluble in  water,  alcohol and  ether, has  a melting
point of -50°c and a boiling point of 96-97°C  (Sax, 1979).
          The major uses of allyl alcohol are  in the  manufacture of allyl
compounds, war  gas,  resins,  and plasticizers  (Windholz,  1976).   Sixty kt.
are used  in  this country per year, of which 50  kt.  are used to manufacture
glycerol (Kirk and Othmer,  1963).
          After  several years of storage, allyl  alcohol polymerizes into a
substance that is soluble  in chloroform  but  not water.   When  treated with
ether this substance becomes brittle (Windholz,  1976).
II.  EXPOSURE
          Pertinent data were  not found in the  available  literature on air
or water exposure.
          Esters of allyl  alcohol  are  used as food flavorings.   Natural de-
rivatives of allyl  alcohol are  widely  distributed  in  vegetable material
(Lake, et al. 1978).
III. PHARMACOKINETICS
     A.   Absorption and  Distribution
          Pertinent data  were not found in the available literature.
     8.   Metabolism
          It has been suggested that allyl alcohol is completely metabolized
and that acrolein might be an intermediate metabolite (Browning, 1965).  *The
rate of metabolism in rats was  found  to  be  about 23  mg/kg/hr.  during con-
stant intravenous infusion  (Carpanini,  et  al. 1978).
                                    9-y

-------
     C.   Excretion
          Allyl alcohol was not  found  in the urine of animals that had been
dosed  subcutaneously  or intravenously  with the  compound  (Browning,  1965).
Other pertinent data were not  found in  the available  literature.
IV.  EFFECTS
     A.   Carcinogenicity,  Mutagenicity, Teratogenicity,  and Reproductive
          Effects
          Information on the  carcinogenic effects of  allyl  alcohol was not
found in the available literature.
     B.   Chronic Toxicity
          Lake, et al.  (1978)  administered allyl  alcohol to  rats by gastric
intubation.  The rats were dosed daily for 1, 10, or  28 days.   Liver homo-
genates  from  treated animals  were analyzed  for  enzyme  activity.  Adminis-
tration  for  one day produced  marked periportal  necrosis, but  repeated ad-
ministration for 10 or 28 days did  not  seem to increase the damage.
          Allyl alcohol administration  in the drinking water at a dose of 72
mg/kg/day caused  weight loss, transient  pulmonary rales,  crustiness  of the
eyelids, and local areas of liver necrosis (Browning, 1965).
          Rats exposed to 40,  60,  or 100 ppm of  allyl alcohol by inhalation
showed signs of acute mucous membrane  irritation, such as gasping and nasal
discharge.   At  the  100  ppm  dose, the  animals died  after 10 exposures
(Browning, 1965).  No gross toxicity was  seen at  5 or  10 ppm,  5  days  a week
for  13  months in  rats,  rabbits,  guinea  pigs,  and  dogs.   However,  mild
reversible degenerative  changes  in the  liver and kidney  were seen  at the
seven  ppm  dose.   A  dose  of 50   ppm  was  lethal  to   rats  after 30  days
(Torkelson, et al. 1959).

-------
          Carpanini, et al. (1978) gave rats doses of allyl alcohol 50, 100,
200, or 800 ppm im the drinking water for 15 weeks.  Weight loss was seen in
males  given  100,  200,   or  800  ppm  and   females  given  800  ppm.   Food
consumption values were lower than the controls in males  at  200 ppm and 800
ppm and  females at 800  ppm.   A  dose-related  decrease  in water consumption
was seen  in all  treated animals.   Minor changes were  seen in  the liver,
kidneys,  and  lungs of both  treated and  control groups  upon  histological
examination.
     C.   Acute Toxicity         .                   v
          Oral LD50's  of  allyl alcohol have  been found to be
64-100 mg/kg for  rats, 96-139 mg/kg  for mice, and 52-71  mg/kg  for rabbits;
43  mg/kg  was  lethal  to dogs.   Intraperitoneal  LDgg's were 42  mg/kg for
rats and  60 mg/kg  for mice.   In  rabbits  an LD-g of 53-89  mg/kg  was  found
by percutan- eous absorption  (Carpanini,  et al.   1978).   Inhalation of 1000
ppm was lethal  to rabbits and monkeys after 3 to 4  hours.   Erythema of the
conjunctiva and swelling  of the cornea are seen in the eye. after exposure to
allyl alcohol,  however,  no permanent damage was  noted.   Application to the
skin caused only  mild erythema.   Intravenous  injection  produced  a  drop in
blood  pressure.   Injection of  40 minims  in  a  20 percent  saline solution
caused fluctuations in the blood pressure, of rabbits  resulting  in violent
convulsions.  Vomiting,  diarrhea, convulsions, apathy,  ataxia, lacrimation
and coma  are  seen after oral administration.   Few cases of  serious injury
due to  inhalation have been  reported,  however,  because  concentrations that
would cause severe damage in  a short period of time are  painful to the eyes
and  nose.   Five  ppm are detectable  by  irritation and   2  ppm by  odor
                                                                         »
(Browning, 1965).
          Moderate  air contamination has been  found to  cause  lacrimation,
pain  around the  eyes and  blurred vision  in man  lasting  up  to  48   hours
(Carpanini, et al.  1978).
                                     • ^
                                   9-C

-------
     D.   Other Relevant Information
          Allyl alcohol has an unusual  effect  on the central nervous system
of  mice  and rats.   The effect  is seen  as  apathy,  unwillingness  to  move,
anxiety,  and no interest in  escaping.   It is apparently different from nar-
cosis seen with other agents  (Dunlap, et al.  1958).
V.   AQUATIC. TOXICITY
          Pertinent data were not found  in the  available literature.
VI.  EXISTING GUIDELINES
          The recommended maximum atmospheric  concentration (8  hours)  is 2
ppm (Indust. Hyg.  Assoc., 1963).
                                  7-7

-------
                                  REFERENCES
Browning,  E.C.    1965.   Toxicity  and  Metabolism  of  Industrial  Solvents.
Elsevier Publishing Co., Amsterdam,  p.  739.

Carpanini, F.M.B.,  et al.   1978.   Short-term toxicity  of allyl  alcohol  in
rats.  Toxicol.   9: 29.

Dunlap, M.K., et al.  1958.  The toxicity  of allyl alcohol.   A.M.A. Archives
of Indust. Health.  18: 303.

Industrial  Hygiene   Association.    1963.    Hygienic   Guide   Series:   Allyl
Alcohol.  Indust. Hyg. Assoc. Jour.  24: 636.

Lake,  B.C.,  et  al.   1978.   The effect  of repeated administration  on  allyl
alcohol-induced hepatotoxicity in the rat.   Biochem. Soc. Trans.  6: 145. .

Sax,  N.I.   1979.   Dangerous Properties  of  Industrial  Materials.  5th  ed.
Von Nostrand Reinhold Co.,  New York.

Torkelson, T.R.,  et  al.   1959.   Vapor toxicity  of allyl alcohol  as  deter-
mined on laboratory animals.  Indust. Hyg.  Assoc. Jour.  20:  224.

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

Windholz,  M.  (ed.)   1976.   Merck  Index.   9th  ed.   Merck  and Co.,  Inc.,
Rahway, New Jersey.
                                    f-r

-------
                                      No. 10
              Antimony


  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.

-------
                                 ANTIMONY





                                  Summary







    The adverse  health  effects most commonly associated with  exposure  to


antimony  are  pulmonary, cardiovascular,  dermal,  and  certain  effects  on


reproduction,   development,  arid  longevity.   Cardiovascular  changes  have


been well-established  with exposure  to antimony  and probably  represent
                                                   v

the most  serious threat to  human health.   Antimony  has not  been  assoc-


iated  with  carcinogenic effects.  The  lowest observed  effect level  for


antimony  in the  drinking water of rats  was 5 ppm.  A draft criterion  of


145 jug/1  has  been recommended  for  antimony in water  based  on an  accep-


table daily intake of antimony  from water,  fish,  and  shellfish for  man  of


294 pg.


    Antimony  is   highly  toxic  to  aquatic  organisms  at a  concentration


ranging from 19 mg/1 to  530  mg/1.   Chronic values for antimony in  fresh-


water organisms range from 0.8 mg/1 to 5.4 mg/1.
                                 lo-J

-------
                                  ANTIMONY

I.  INTRODUCTION

    This profile is based primarily  on the Ambient Water Quality Criteria
Document for  Antimony (U.S. EPA,  1979).   The health  hazards of antimony
and its  compounds  have also been recently reviewed  by  the National Ins-
titute for Occupational Safety and Health  (NIOSH, 1?78).
    Antimony  (Sb;  molecular weight  121.8)  is a silvery,  brittle, solid
belonging to group VB of  the periodic table and  lies between arsenic and
bismuth.  It is classified  as  both a metal and a metalloid, and its prin-
cipal oxidation  states are +3  and +5.  Antimony has a boiling  point of
1366°C  and  a  melting point of 636°C.   Most  inorganic compounds  of an-
timony  are  either only  slightly  water soluble  or decompose  in  aqueous
media.
    Antimony  reacts  with both sulfur  and chlorine  to form  the  tri-and
pentavalent  sulfides  and  chlorides.   Oxidation  to  antimony  trioxide
(stibine),   the major   commercial oxide   of  antimony, is  achieved under
controlled conditions.
    Consumption  of antimony  in  the  United  States  is on  the  order  of
40,000 metric  tons per year (Callaway, 1969),  of which half is obtained
from  recycled  scrap  and the balance mainly imported. Use  of antimony in
the United  States  is directed  chiefly to the manufacture  of ammunition,
storage  batteries,  matches  and  fireworks,  and  in the fire-proofing  of
textiles.

-------
II. EXPOSURE
    A.   Water
         Schroeder  (1966)  compiled data  from surveys of  municipal water
supplies  in 94 cities  and reported  that levels  averaged less  than  0.2
pg/1 in  finished water.   In  a related study,  Schroeder and Kraemer (1974)
noted  that tap water  levels of  antimony can be  elevated in  soft water
supplies due to leaching from plumbing.
    B.   Food
         Because of the wide  range  of antimony  levels in various types of
foods, it  is  not possible to  accurately  estimate an  average  dietary  in-
take.   Tanner  and  Friedman  (1977)   concluded   that dietary  intake  of
antimony is negligible,  based upon trace metal  food  monitoring data from
the U.S. Food  and  Drug  Administration.  However,  in earlier studies, cal-
culated  average  dietary  intakes were reported at  100 pg per day  far  man
(Schroeder, 1970)  and  in the range of 0.25 to 1.28 mg per day for insti-
tutionalized children  (Murthy, et  al.  1971).   In one study  on  antimony
levels in  Italian  diets a mean daily  value of  several micrograms was  re-
ported (Clemente, 1976).
    C.   Inhalation
         Antimony  is  not  generally  found  in ambient air at  measurable
concentrations.  National  Air Sampling Network  data  for 1966  showed pos-
sibly  significant  levels  at  only  four  urban  stations  (0.042 to  0.085
pg/m3)   (Schroeder, 1970; Woolrich, 1973).
    D.   Other Routes
         The total body  burden of antimony  arising from all environmental
                                                                        »
media  is  apparently  very small  relative  to other  trace metals  (i.e.,
lead,  mercury, cadmium)  in  the  environment.   Clemente (1976)  published
                                 lo-f

-------
limited data on  fecal and urinary levels  of antimon \ in selected Italian
populations and  concluded that daily  intakes were  less  than 2.0 ug/day.
In addition, data on the  bioconcentration potential of  antimony in  fish
(U.S.  EPA,  1978)  indicate that  no  bioaccumulation  is likely  to occur.
The U.S.  EPA  (1979) has calculated  the  weighted average bioconcentration
factor (8CF) for antimony to be  1.4 for the edible  portions  of fish and
shellfish consumed  by Americans.   This estimate was based  on 25-day  bio-
concentration studies in bluegill.
Ill.PHARMACOKINETICS
    Absorption of antimony in man and animals is  mainly via the respir-
atory and gastrq-intestinal tracts.  The  extent of absorption is  dependent
on  factors  such  as  solubility,   particle  size,  and  chemical  forms
(Felicetti, et al.  1974a;  1974b). Absorption via  the  GI tract is of the
order  of  several percent  with antimony trioxide,  a relatively  insoluble
compound , and presumably would be'much greater with  soluble antimonials.
    Blood  is  the main  carrier  for  antimony,  the  extent  of  partition
between blood .compartments depending on the  valence state  of the element
and the animal species  studied (Felicetti, et al. 1974a).  The  rodent ex-
clusively tends  to  concentrate trivalent antimony for long periods in the
erythrocyte (Djuric,  et al. 1962).   Whatever the  species,  it can gener-
ally be said that pentavalent antimony  is borne by  plasma and  trivalent
antimony in the  erythrocyte.   Clearance  of antimony from blood  to tissues
is relatively  rapid,  and  this  is especially true  in the  case  of paren-
teral  administration  and  the  use of pentavalent antimony  (Casals,  1972;
Abdalla and Saif, 1962; El-8assouri,  et al. 1963).
    The  tissue   distribution  and subsequent excretion  of  antimony  is  a
function of the valence state.

-------
    In animals, trivalent antimony aerosols  lead  to  highest levels in the
lung, skeleton, liver,  pelt,  and thyroid while pentavalent  aerosols show
a similar distribution,  with  the exception of slower  uptake by the liver
(Felicetti,  et al. 1974a; 1974b; Thomas, et al. 1973).
    Parenteral administration to  animals shows trivalent antimony accumu-
lating in the liver and kidney as well as  in pelt and  thyroid  (Molkhia
and Smith,  1969; Waitz, et al. 1965).
    In man,  non-occupational  or  non-therapeutic  exposure  shows  very low
antimony levels in various tissues  with little- evidence  of accumulation
(Abdalla and  Saif,  1962).   Chemotherapeutic use  leads  to highest accumu-
lation in liver, thyroid, and heart for trivalent antimony.
    The biological half-life of antimony in  man  and  animals is a function
of  route of  exposure,  chemical  form,  and  oxidation  state.   The  rat
appears to  be unique  in demonstrating  a long biological half-time owing
to antimony accumulation in the erythrocyte.   In  other species, including
man,  moderate half-times  of  the  order of  days  have  been demonstrated.
While most  soft tissues do not appear  to  accumulate  antimony,  the skin
does show accumulation,  perhaps because of  its high  content of sulfhydryl
groups.  With  respect  to excretion,  injection  of  trivalent antimony leads
mainly  to  urinary  excretion  in  guinea pigs  and dogs,  and  mainly fecal
clearance in hamsters, mice and rats.
    Pentavalent  antimony  is    mainly   excreted  via  the  kidney   in  most
species owing to its higher levels in plasma.
    Unexposed  humans  excrete  less than 1.0  jug antimony  daily  via urine,
while occupational  or  clinical  exposure may result  in  markedly increased
amounts.
                                 10-7

-------
IV. EFFECTS
    A.   Carcinogenicity
         Antimony has  not been tested for  carcinogenic  activity using an
appropriately  designed  chronic  bioassay  protocol.   However,  Shroeder
(1970) indicated that  the chronic administration of  antimony at 5 ppm in
the drinking water of  rats,  had  no  apparent tumorigenic effect.  However,
the shortened  life  span of treated animals  (average  106 to 107 days less
than controls) limits  the  usefulness  of  these data.  Similar results were
also observed  in a study  with mice chronically exposed  to antimony at 5
ppm in the drinking water (Kanisawa and Schroeder, 1569).
         A single- epidemiologic  investigation has been conducted into the
role of antimony in the development of  occupational  lung cancer (Oavies,
1973).  This retrospective study, which  was limited in scope, provided no
definitive information to support the possible role of  antimony  in lung
cancer development.
    B.  Mutagenicity
                           %
         Antimony has   not been  tested  for  activity  in  standard muta-
genicity bioassays.
    C.   Teratogenicity
         Little  information  is available concerning  possible teratogenic
effects of  antimony.    In  one study, Casals (1972)  observed no effects,
i.e., no  fetal abnormalities,  following administration of  a solution of
antimony  dextran glycoside  containing  125  or 250 mg  Sb/kg  to pregnant
rats on days 8 to 15 of gestation.
    0.   Other Reproductive Effects
                                                                          »
         Aiello  (1955) observed  a  higher   rate  of  premature  deliveries*
among female  workers  engaged in antimony   smelting  and  processing.   In

-------
addition,  dysmenorrhea  was  frequently  reported  among  women  workers.
Similarly, Belyaeva  (1967)  reported that a  greater incidence of  gyneco-
logical disorders was  found among antimony smelter  workers  than  in a con-
trol  group  (77.5 percent vs.  56 percent;  significance unknown).   Spon-
taneous late abortions occurred in  12 percent  of the  exposed  females com-
pared  to  4.1 percent  among  controls.   Average  urine levels of  antimony
for  exposed  workers,  however, were extremely high,  ranging  from 2.1  to
2.9  mg/100 ml.   Antimony was also  found  in breast milk (3.3+ 2  mg/10),
placental  tissue (3.2  to 12.6  mg/100 mg),  amhiotic  fluid  (6.2 to  2.8
mg/100 mg), and umbilical cord blood (6.3 + 3 mg/100 ml).
         In studies with  rats  exposed  either to antimony dust  (50 mg/kg,
i.p.)  or  to  antimony trioxide dust (250 mg/m , 4  hours per day  for  1.5
to  2 months),   Belyaeva  (1967) reported  increased  reproductive  failure,
fewer  offspring,  and  damage  to   the  reproductive  tissues  (ovary  and
uterus).
    E.   Chronic Toxicity
         The toxic  effects  of exposure  to antimony have been  repeatedly
observed  in  both  humans and  experimental  rodents.   Pulmonary,  cardio-
vascular,  dermal,  and certain effects  on reproduction, development,  and
longevity are among  the  health effects most commonly associated with  an-
timony exposure.
         Cardiovascular changes have been well  established following  ex-
posure  to  antimony  and probably represent the most serious human health
effects  demonstrated  thus far  (U.S.  EPA, 1979).   Air  concentrations  of
                                  10-7

-------
antimony  trisulfide  exceeding 3 mg/cu  m were associated  with the  induc-
tion  of altered  ECG patterns  and some  deaths  attributed  to myocardial
damage  among  certain .antimony workers  (Brieger,  et  al.  1954).   Also,  in
parallel  studies  on animals,  Brieger and  coworkers  (1954)  observed ECG
alterations in  rats and  rabbits  exposed to antimony  in  air at levels  of
3.1 to 5.6 mg/m , 7 hours/day, 5 days/week  for at least 6 weeks.
    Gross and coworkers  (1955) presented evidence  for growth retardation
occurring  when  rats  were  chronically  fed  diets containing  two percent
antimony trioxide.  Other investigators  (Schroeder,  et al. 1970; Kanisawa
and Schroeder,  1969)  reported that oral  exposure  to 5 ppm of antimony  in
drinking  water  had no  effect on  the rate  of growth  of either  rats  or
mice..   However,  the  5  ppm  exposure level  was  effective  in  producing
slight  but significant  lifespan  shortening  in  both  rats and  mice, and
altered blood chemistries in exposed rats.   Therefore,  the 5ppm exposure
level has  been  considered  the  "lowest  observed effect  level" in animals
that  likely  approximates  the  "no effect"  level  for antimony-induced ef-
fects on growth and longevity.
V.  AQUATIC TOXICITY
    A.   Acute Toxicity
         The'data base for antimony  and  freshwater organisms is small and
indicates  that  plants may be  more  sensitive  than  fish  or  invertebrate
species.
         A  96-hour  LCe«  of 22,000 /jg/1 was  reported for  antimony tri-
chloride  with  the  fathead minnow,  whereas the  value for  bluegills and
antimony  trioxide is above 530,000  ug/1  (U.S.  EPA,  1979).   For Daohnia
maqna a 48-hour LC^  value of 19,000 jug/1 and  a 64-hour  EC5Q  value  of
19,800 /jg/1 have  been  reported for antimony trichloride.   Another 48-hour

-------
ECcn value  for antimony trioxide  and  Daphnia magna  has  been reported to
be above 530,000  jug/1 (U.S. EPA, 1979).
    B.   Chronic Toxicity
         No adverse effects on  the  fathead minnow were observed during an
embryo-larval  test with antimony  trioxide  at the  highest  test  concen-
tration  of  7.5 jjg/1  (U.S.  EPA, 1978).   However, a  comparable test with
antimony  trichloride  produced  limits  of  1,100  and  2,300  jug/1  for  a
chronic  value  of  800 pg/1.   A  life  cycle test with Daphnia magna and an-
timony trichloride produced limits  of  4,200 and..  7,000 jug/1 for a chronic
value of 5,400/jg/l  (U.S. EPA,  1979).   Pertinent  information could not be
located  in  the  available literature  regarding chronic effects of antimony
on saltwater organisms.
    C.   Plants Effects
         The  96-hour  EC5Q  values  for chlorophyll  a inhibition  and re-
duction  in  cell number of the  freshwater alga,  Selenastrum capricornutum
are 610  and 630 pg/1,  respectively.  This  indicates  that aquatic plants
may  be  more  sensitive  than   fish  or  invertebrate  species  (U.S.  EPA,
1978).   No  inhibition of  chlorophyll  a  reduction  or in  cell  numbers of
the marine  alga,  Skeletonema costatum,  were observed at concentrations as
high as  4,200;ug/l (U.S. EPA, 1978).
    D.   Residues
         There  was no bioconcentration of  antimony  by  the bluegill above
control  concentrations during  a 28 day exposure  to antimony.   NO data
have been reported on  bioconcentration of antimony in marine species.
VI  EXISTING GUIDELINES AND STANDARDS
                                                                     9
    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
          Existing  occupational  standards  for  exposure  to  antimony  are
 reviewed in  the  recently  released  NIQSH criteria document,  Occupational
 Exposure to.Antimony (U.S. Department  of Health, Education  and Welfare,
T978). "As stated  in the  NIOSH  (1978)  document, the American Conference
 of Governmental  Industrial Hygienists  (ACGIH),  in  1977, listed  the TLV
 for antimony  as  0.5 mg/m3 along with  a notice*- of  intended  change  to a
 proposed TLV  of  2.0 mg/m   for soluble  antimony  salts.   The  proposed TLV
 was based mainly on  the  reports of Taylor  (1966) and  Cordasco  (1974)  on
 accidental poisoning  by antimony  trichloride and pentachloride,  respec-
 tively.   Proposed  limits of 0.5 mg/m   for  handling and use  of antimony
 trioxide and  0.05 mg/m   for  antimony  trioxide production were included
 in the ACGIH (1977) notice of intended changes.
     The Occupational Safety and  Health  Administration earlier adopted the
 1968  ACGIH  TLV  for  antimony  of 0.5 mg/m3  as  the  Federal  standard  (29
 CFR 1910.1000).   This  limit  is consistent  with limits  adopted  by  many
 other countries as described in  Occupational Exposure Limits  for Airborne
 Toxic Substances  - A tabular  Compilation of  Values from Selected  Coun-
 tries,  a publication  released  by  the  International  Labour Office  in
 1977.   The NIOSH  (1978)  document also presented  table  of exposure limits
 from several countries,  reproduced here as Table 1;  the  typical
 standard adopted  was 0.5 mg/m .

-------
                                  TABLE 1

                HYGIENIC STANDARDS OF SEVERAL COUNTRIES FOR
             ANTIMONY AND COMPOUNDS IN THE WORKING ENVIRONMENT

    CountryStandardQualifications
                                      (mg/m3)

    FinlandONot stated
    Federal Republic of Germany       0.5           8-hour TWA
    Democratic Republic of Germany    0.5           Not stated
    Rumania                           0.5           Not stated
    USSR                              0.5           For antimony dust
                                      0.3           For    fluorides    and
                                                    chlorides     (tri-and
                                                    pentavalent);     obli-
                                                    gatory control  of  HF
                                                    and HC1
                                      1.0           For  trivalent  oxides
                                                    and sulfides
                                      1.0           For        pentavalent
                                                    oxides and sulfides
    Sweden                            0.5           Not stated
    USA                                             0.5
    8-hour TWA
    Yugoslavia                        0.5           Not stated

    Modified from Occupational Exposure Limits in Airborne ToxicSub-
stances, International Labour Office.


The 0.5 mg/m   level  was  also  recommended  as  the United States  occupa-

tional  exposure standard  by  the  NIOSH  (1978)  criteria document,  based

mainly  on  estimated  no-effect  levels for  cardiotoxic and  pulmonary  ef-

fects.

    Based upon  the  data presented  in  the  Ambient Water  Quality  Criteria

Document for Antimony  (U.S.  EPA,  1979),  a  recommended draft  criterion of

145 pg/1  has been  established.   This value  is based upon  an  acceptable

daily intake for man  of 294 ug,  derived from experimental animal  studies

in which 5  ppm  of antimony produced a slight  shortening of  lifespan with

no other deserved effects.  An uncertainty  factor of 100 was used  in  ex-
                                                                     »
trapolating from animal data to human health effects.
                                 10-13

-------
    B.   Aquatic
         The draft  criterion for  Antimony to  protect  freshwater aquatic
life as derived using the Guidelines is 120 jug/1  as  a 24 hour average and
the concentration should not exceed 1,000 /jg/1 at any time.
         A saltwater criterion was not derived (U.S.  EPA, 1979)

-------
                           ANTIMONY

                          REFERENCES

Abdalla, A.,  and  M.  Saif.  1962.  Tracer  studies with anti-
mony-124 i-n  Irian.   In;  G.E.W.  Walstenhalne  and  M. 0'Conner,
eds., Bilharziasis.  Little Brown and Co., Boston, p. 287.

Aiello, G.   1955.  Pathology of antimony.  Folia Med., Naples
38: 100.

American Conference  of  Governmental  Industrial Hygienists.
1977.   Threshold  limit  values  for  chemical substances in
workroom air.

Belyaeva, A.P.   1967.   The effect  of  antimony  on reproduc-
tion.  Gig.  Truda Prof. Zabol  11: 32.

Brieger, H.,  et al.    1954.   Industrial  antimony poisoning.
Ind. Med. Surg. 23: 521.

Callaway, H.M.  1969.   Antimony.   In:  The Encyclopedia Britan-
nica.  Ency. Brit., Inc., 2: 20.  "cliicago.

Casals, J.B.  1972. Pharmacokinetic  and toxicological studies
of antimony dextran glycoside  (RL-712).  Brit. Jour. Pharmac.
46: 281.

Clemente, G.F.   1976.   Trace  element pathways from environ-
ment to man.  Jour. Radioanal. Chem.  32: 25.

Cordasco, E.M.   1974.    Newer  concepts  in  the  management
of environmental pulmonary  edema.  Angiology  25: 590.

Davies,  T.A.L.   1973.   The  health of  workers  engaged in
antimony oxide  manufacture—a  statement.   London, Department
of Employment, Employment Medical Adivsory Service, p. 2.

Djuric, D. ,  et al.   1962.   The distribution  and excretion
of  trivalent  antimony in  the  rat   following   inhalation.
Arch. Gewerbepath. Gewerbehyg. 19: 529.

El-Bassouri, M. ,  et  al.   1963.   Treatment  of active urinary
schistosomiasis  in  children with  sodium  antimony dimercapto
succinate by  the slow  method.   Trans. Roy.  Soc.  Trop.   Med.
Hyg. 57: 136.

Felicetti,   S.W.,  et  al.   1974a.   Metabolism of two valence
states  of  inhaled antimony in  hamsters.    Amer.  Ind.   Hyg.
Assoc. Jour. 355: 292.                                    " '

Felicetti,   S.W.,  et  al.   1974b.   Retention of inhaled anti-
mony-124  in  the  beagle  dog   as  a  function of  temperature
of aerosol formation.   Health Phys.  26: 525.

-------
Gross, et  al.    1955.   lexicological  study  of calcium halo-
phasphate phosphors  and antimony  tribxide.    In:   Acute and
chronic  toxicity and  some  pharmacological  aspects.   Arch.
Indust. Health 11: 473.

International  Labour  Office.   1977.   Occupational exposure
limits for  airborne  toxic substance -  a tabular compilation
of  values  -from  selected  countries.    Occupa'tional  Health
Series No.  37.   United Intarnational  Labour Office, Geneva.
p. 44.

Kanisawa, M.,  and H.A. Schroeder.   1969.   Life term studies
on  the effect  of trace  elements of  spontaneous  tumors  in
mice and rats.  Cancer Res.  29: 892._

Molokhia, M.M.,  and H.  Smith.   1969.    Tissue distribution
of  trivalent  antimony  in  mice   infected,  with  Schistosoma
Mansoni.  Bull. WHO 40: 123.             ~   '

Murthy,  G.K.,  et al.   1971.   Levels  of  antimony, cadmium,
chromium, cobalt, manganese and zinc  in institutional total
diets.  Environ. Sci. and Tech. 5: 436.

NIOSH.   1978.   Criteria for a recommended standard:  Occupa-
tional exposure  to  antimony.  DHEW  (NIOSH)  G.P.O.   No.  017-
033-00335-1.

Schroeder,  H.A.   1966.   Municipal drinking water and cardio-
vascular death rates.  Jour. Amer. Med. Assoc. 195:  81.

Schroeder,  H.A.   1970.    A sensible  look  at  air   pollution
by metals.  Arch. Environ. Health  21: 798.

Schroeder,  H.A.,  and  L.A.   Kraemer.   1974.   Cardiovascular
mortality,  municipal  water  and corrosion.    Arch. Enviorn.
Health 28:  303.

Schroeder,  H.A.,  et  al.   1970.  Zirconium,  niabium, antimony
and lead in rats:  Life term studies.  Jour. Nutr.  100: 59.

Tanner,  J.T.,  and M.H. Friedman.    1977.   Neutron  activation
analysis  for  trace  elements  in  foods.    Jour.   Radioanal.
Chem. 37: 529.

Taylor,  P.J.   1966.   Acute intoxication  from antimony  tri-
chloride.   Br. Jour. Ind. Med. 23: 318.

Thomas,  R.G.,  et al.   1973.   Retention patterns of antimony
in mice  following inhalation of particles formed at  different
temperatures.  Proc. Soc. Exp. Biol. Med. 144(2): 544.

-------
v^V
   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.   Antimony:  Ambient  Water Quality  Criteria.
   U.S.  Environ.  Prot.  Agency,  Washington, D.C.

   Waitz,  J.A'. ,  et  al.    1965.    Physiological disposition  of
   antimony  after administration of    Sb-labeled tartar  emetic
   to rats,  mice and monkeys  and  the effects of tris  (p-  amino
   phenyl)   carbonium  pamoate  on this  distribution.   Bull.  WHO
   33:  537.

   Woolrich, P.P.   1973.   Occurrence of  trace  metals in  the
   environment:   an  overview.   Amer.  Ind. Hyg.  Assoc. Jour.  34:
   217.
                              16-17

-------
                                       No.  11
              Arsenic
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION







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

arsenic and has found sufficient evidence to indicate that


this compound is carcinogenic.
                            11-3

-------
                           ARSENIC



                           SUMMARY



     Epidemiological studies have shown increased death rates



from lung,cancer in workers exposed to arsenic, probably



through inhalation.  Other human studies have shown  increased



skin cancers in non-occupationally exposed populations.  In-



creased incidence of lymphomas and hemangioendotheliomas are



also occasionally reported.



     Arsenicals have produced mutagenic effects in plants,



bacteria, in vitro- leukocyte cultures, and in the lymphocytes



of exposed humans.  The teratogenic effects of arsenicals



have been demonstrated in many animal species.  An increased



frequency of abortions in pregnant women exposed to  arsenic



has been reported in a single study (U.S. EPA, 1979).



     The chronic toxic effects of arsenic involve skin hyper-



keratosis, liver damage, neurological disturbances (including



hearing loss), and a gangrenous condition of the extremities



(Blackfoot disease).  An increased mortality from cardiovas-



cular disease resulting from chronic arsenic exposure has



been suggested in two studies.



     The data base for the toxicity of arsenic to aquatic or-



ganisms is more complete for freshwater organisms, where con-



centrations as low as 128 ug/1 have been acutely toxic to



freshwater fish.  A single marine species produced an acute



value in excess of 8,000 ug/1.  Based on one chronic life



cycle test using Daphnia magna, a chronic value for  arsenic



was estimated at 853 ug/1.
                            thy

-------
                           ARSENIC



I.   INTRODUCTION



     This profile is based on the Ambient Water Quality  Cri-



teria Document for Arsenic (U.S. EPA, 1979).



     Arsenic is a gray, crystalline metalloid with  a  molecu-



lar weight of 74.92, a density of 5,727, a melting  point (at



28 atmospheres) of 817°C, and a boiling point (sublimates)  of



613°C (Weast, 1975).  Arsenic exists in a variety of  valence



states;  the most common forms include pentavalent (arsenate),



trivalent (arsenite), and -3 valency (arsine).  Properties  of



some inorganic arsenic compounds are shown in Table 1.



     Conditions of low pH, low oxidation-reduction  potential,



and low dissolved oxygen in water favor formation of  the



lower valency states (arsenite and arsine); more basic,  oxy-



genated waters favor the presence of arsenate.  Inorganic



arsenic can be converted to organic alkyl-arsenic acids  and



to methylated arsines under both aerobic and anaerobic condi-



tions (U.S. EPA, 1979).



     Arsenic and its compounds are used in the manufacture  of



glass, cloth, and electrical semiconductors, as fungicides



and wood preservatives, as growth stimulants for plants  and



animals, and in veterinary applications (U.S. EPA,  1976).



     Production is currently 1.8 x 104 metric tons  per year



(U.S. EPA, 1979).



     Arsenic will persist in some form in the environment.



Inorganic arsenate is thermodynamically favored under normal



conditions over arsenite in water and is a more soluble  form



(Ferguson and Gavis, 1972).  Both arsenate and arsenite  may



be precipitated from water by adsorption onto iron  and alum-

-------
                                 Table 1.  Properties of Some Inorganic Arsenic Compounds
                                            (Standen, 1967; U.S. EPA, 1976)
         Compound
                         Formula
    Water Solubility
        Specific  Properties
f
         Arsenic trioxide         As2°3
         Arsenic pentoxide
         Arsenic hydride
Arsenic(III) sulfide     As4S6



Arsenic sulfido          AS4S^

Arsenic(V) sulfide       AsS
                                     12 x  106 ug/1 @  0°C
                                     21 x  106 ug/1 @ 25°C
                                     2300 x 106 ug/1 @ 20°C
                                     20 ml/100 g cold water
520 ug/1 @ 18°C
Dissolves  in  water to form
arsenious  acid  (H3As03:
K  =  8 x  10-1° @  25°C)

Dissolves  in  water to form
arsenic  acid  (H3As04:Ki  = 2.5 10~4
K2 = 5.6 x  10~8;
K3 = 3 x 10~13)

This compound and  its methyl
derivatives are  considered to
be the most toxic.

Burns  in air  forming arsenic
trioxide and  sulfur dioxide;
.occurs naturally as orpiment.

Occurs naturally as realgar.
                                              1400 ug/1 @ 0°C

-------
inum wompounds (U.S. EPA, 1979).  Methylated  arsines  appear

to be volatile and sparingly soluble.  Waters, containing  high

organic matter may bind arsenic compounds  to  colloidal  humic

matter (U.S. EPA, 1979).

II.  EXPOSURE

     Arsenic appears to be ubiquitous  in 'the  environment.

The earth's crust contains an average  arsenic concentration

of 5 mgAg  (U.S. EPA, 1976).  The major sources of  arsenic  in

the environment are industrial, such as those in the  smelting

of non-ferrous ores and in coal-fired  power plants  that uti-

lize fuel containing arsenic.  Substantial arsenic  contamina-

tion of water can occur from the improper  use of arsenical

pesticides  (U.S. EPA, 1979).

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

has estimated the uptake of arsenic by adult  humans from  air,

water, and  food:

Source                             mg/day


                 Maximum Conditions     Minimum Conditions
Atmosphere              .125                   .001
Water                 4.9                     0.002
Food Supply             .9                     .007
    Total             5.925                   .010

     Contaminated well water, seafood, and air near smelting

plants all present sources of high potential  arsenic  intake.

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

bioconcentration factor (BCF) for arsenic  to  be 2.3 in  the

edible portions of fish and shellfish  consumed by Americans.
                                                           *
This estimate was based on bioconcentration studies in  fresh-

water fish.
                            11-7

-------
III. PHARMACOKINETICS

     A.   Absorption

          The main routes by which  arsenic  can  enter the body

are inhalation and ingestion.  Particle  size  and  solubility

greatly influence the biological  fate  of inhaled  arsenic.

Falk and Kotin (1961) have reported  that the  optimal range  of

particle size for deposition in the  lower tracheobronchial

tree is 0.1 to 2 u«  Larger particles  are trapped  by the

mucous membranes of the nose and  throat  and swallowed;
                                          \
following this, the particles may be absorbed from the

gastrointestinal tract  (U.S. EPA, 1979).

          Human inhalation studies  in  terminal  lung  cancer

patients (Holland, et al. 1959) have indicated  that  4.8  to

8.8 percent of inhaled  arsenic-74 in cigarette  smoke may be

absorbed.  Radioactive  arsenite inhaled  in  an aerosol  solu-

tion by two patients showed 32 and  62  percent absorption,  re-

spectively.  Pinto, et  al. (1976) studied arsenic  excretion

in 24 workers exposed to the compound  during  copper  smelting;

urinary arsenic levels  were found to correlate  significantly

with average airborne arsenic concentrations.

     Water soluble arsenicals are readily absorbed through

the gastrointestinal tract.  Studies with radioactive  arse-

nate administered orally to rats  have  shown 70  to  90 percent

absorption from the gastrointestinal tract  (Urakubo, et  al.

1975; Dutkiewicz, 1977).  Arsenic trioxide  is only slightly

soluble in water and is not well  absorbed.  Theoretically,*

trivalent arsenicals should be less  readily absorbed than

pentavalent forms due to reactivity with membrane  components

-------
and lower solubility  (U.S. EPA, 1979).   However,  investiga-



tors have reported high absorption of trivalent  arsenic  from



the gastrointestinal  tract in humans  (Bettley  and O'Shea,



1975; Crecelius, 1977).



          The absorption of arsenicals  following dermal  expo-



sure has been described in rats (Dutkiewicz, 1977)  and humans



(Robinson, 1975; Garb and Hine, 1977).



          Arsenic has been detected in  the  tissues  (Kadowaki,



1960) and cord blood of newborns  (Kagey, et al.  1977), and



thus transfers across the placenta in humans.



     B.   Distribution



          Injection of radiolabelled  arsenite  in terminally



ill patients produced widespread distribution  of the  compound



(WHO, 1973).  Hunter, et al. (1942) studied the  distribution



of radioactive arsenicals in humans following  oral  and paren-



teral administration and found arsenic  in the  liver,  kidney,



lungs, spleen, and skin during the first 24 hours after  ad-



ministration.  Levels of arsenic are  maintained  for long per-



iods in bone, hair'and nails (Kadowaki,  1960;  Liebscher  and



Smith, 1968) .



          Tissue distribution of pentavalent arsenic  has been



described in only a few animal studies;  these  studies  indi-



cate only minor differences in distribution between trivalent



and pentavalent arsenicals (WHO, 1973).

-------
     C.   Metabolism



          Studies with brain tumor patients  given  injections



of trivalent arsenic indicate that about  60  percent  of  the



total urinary arsenic was  in the pentavalent state  the  first



day after, dosing (Mealey,  et al. 1959).   Braman  and  Foreback



(1973) have analyzed human urine samples  and detected high



amounts of methylated forms (dimethyl arsenic  acid  and  methyl



arsenic acid) .  Analysis of the urine of  one patient who  in-



gested arsenic-contaminated wine indicated that  8 percent of



the initial dose was excreted as inorganic arsenic,  50  per-



cent was excreted as dimethyl arsenic acid,  and  14  percent



was excreted as methyl arsenic acid  (Crecelius,  1977).



          The half-lives of inorganic and organic  (methy-



lated) arsenicals in one patient have been reported  as  10 and



30 hours, respectively (Crecelius, 1977).



     D.   Excretion



          Arsenic is excreted primarily in the urine, with



small amounts removed in the feces and through normal hair



loss and skin shedding (U.S. EPA, 1979).  Reports of minor



arsenic loss in sweat have also been made (Vellar,  1969).



          Small amounts of radioactive arsenic (.003 to .35



percent) have been detected in expired air following adminis-



tration to rats (Dutkiewicz, 1977) and chickens  (Overby and



Fredrickson, 1963).



IV.  EFFECTS



     A.   Carcinogenicity



          Epidemiological  studies have shown an  increased



mortality rate from respiratory cancer in workers exposed to
                           // - / 6

-------
arsenic during smelting operations  (Lee  and  Fraumani,  1969?
Pinto and Bennett, 1963; Snegireff  and Lombard,  1951;  Kurat-
sune, et al. 1974).  A retrospective study of  Dow  Chemical
employees indicated that workers exposed primarily to  lead
arsenate and calcium arsenate showed increased death  rates
from lung cancer and malignant neoplasms of  the  lymphatic and
hematopoietic systems (except leukemia)  (Ott,  et al.  1974).
          A similar trend was noted in a study of  retired
Allied Chemical workers (Baetjer, et al. 1975).
          High rates of development of skin  cancers have been
reported in' several studies of populations exposed to  high
concentrations of arsenic in drinking water  (Geyer, 1898;
Bergogilio, 1964; Tseng, et al. 1968).
          Hemangioendothelioma of the liver  associated with
exposure to arsenicals through ingestion has been  reported  in
several case studies (Roth, 1957; Regelson,  et al. 1968).
          Extensive experiments in  animal systems  with arsen-
icals administered in the diet or drinking water,  or  applied
topically or by intratracheal instillation failed  to  show
positive tumorigenic effects (U.S.  EPA,  1979).   However, two
recent reports have shown effects in animals.  Schrauzer and
Ishmael (1974) indicated that feeding of sodium  arsenite in
drinking water accelerated the rate of spontaneous mammary
tumor formation.  Osswald and Goerttler  (1971) found  an
increase in leukemias and lymphomas in mice  injected
repeatedly with sodium arsenate.
          Animal studies on the skin tumor-promoting  or co-
carcinogenic effects of arsenicals  have  produced negative
results (Raposo, 1928; Baroni, et al. 1963;  Boutwell,  1963).
                          II -

-------
     B.   Mutagenicity



          An increased incidence of chromosomal aberrations



has 'been found in persons exposed to arsenic occupationally



and medically (Petres, et al. 1970; Nordenson, et al. 1978;



Burgdorf, et al. 1977).



          In vitro chromosomal changes following exposure  to



arsenicals have been reported in root meristem cultures



(Levan, 1945) and in human leukocyte cultures (Petres and



Hundeiker, 1968;  Petres, et al. 1970, 1972; Paton and



Allison, 1972).



          Arsenate has been found to increase the frequency



of chromosome exchanges in Drosophila.  Several organic ar-



senicals have a synergistic effect with ethylmethane sulfon-



ate in producing chromosome abnormalities  in barley  (Moutsh-



cen and Degraeve, 1965).



          Sodium arsenate, sodium arsenite, and arsenic tri-



chloride produced positive mutagenic effects in a recorebinant



strain of Bacillus subtillus (Nishioka, 1975).  Loforth and



Ames (1978) were unable to show mutagenic  effects of trival-



ent and pentavelent arsenicals in the Ames Salmonella assay.



Arsenite exposure decreased the survival of E. coli  after  UV



damage of cellular PNA (Rossman, et al. 1975).

-------
     C.   Teratogenicity
                                                              i
          ttordstrom, et al. (1978) have reported an  increase


in the frequency of spontaneous abortions  in pregnant women


living in the vicinity of a copper smelting plant; the expo-
   V

sure environment was complex, involving several heavy metals


and sulfur dioxide.


          Sodium arsenate has been shown to induce teratogen-


ic effects in the chick embryo (Ridgway and Karnofsky, 1952),


in golden hamsters  (Perm and Carpenter, 1968; Ferm,  et al.
                                         \.

1971), in mice (Hood and Bishop, 1972), and rats '(Beaudoin,


1974).  Malformations noted included exencephaly, anenceph-


aly, renal agenesis, gonadal agenesis, eye defects,  and rib


and genitourinary abnormalities.  Sodium arsenite injected


intraperitoneally into mice produced a lower incidence of


malformations than  an equivalent dose of sodium arsenate


(Hood and Bishop, 1972; Hood, et al. 1977).  Thacker, et al.


(1977) has noted that a higher oral dose of sodium arsenate


is needed to produce teratogenic effects in mice, when com-


pared to intraperitoneal doses.


          Feeding of three generations of  mice with  low doses


of sodium arsenite  in the chow failed to produce teratogenic


effects, but did decrease litter size (Schroeder and Mitch-


ener, 1971).


     D.   Other Reproductive Effects

          Pertinent information could not  be located in the


available literature regarding other reproductive effects.
                                                          •
     E.   Chronic Toxicity


          A variety of chronic effects of  arsenic exposure


has been noted.  This includes a characteristic palmar-

-------
 plantar  hyperkeratosis  and  a gangrenous condition of the

 hands  and  feet  called Blackfoot  disease (U.S.  EPA, 1979).

 Several  clinical  reports  of liver damage in patients treated

 with arsenical  medication have  been  published  (WHO, 1979).

 An  increased  mortality  from cardiovascular disease has been

 noted  in two  epidemiological studies of smelter workers ex-

 posed  to high airborne  arsenic  (Lee  and Fraumeni, 1969; U.S.

 EPA, 1979).   Neurological disturbances, including hearing

 loss,  in workers  exposed  to arsenicals  have been reported

 (WHO,  1979).

           Effects of  arsenicals on the  hematopoietic system

 following  chronic exposure  have also been  noted (WHO, 1979).

 These  include disturbed erythropoiesis  and granulocytopenia,

 which  may  lead  to impaired  resistance to viral  infections.

 V.   AQUATIC  TOXICITY

     A.    Acute Toxicity

           Seven static  and  seven flow-through  bioassays from

.48  to  96-hours  in duration  provide a range of  LC50 values

 for freshwater  fish of  290  to 150,000 ug/1. Hughes and Davis

 (1967) demonstrated the most sensitive  species  as being blue-

 gill fingerlings,  Lepomis macrochirus,  while Sorenson (1976)

 reports  that  the  most resistant species was the green sun-

 fish,  Lepomis cyanellus.  Both  species  were tested in static

 tests.   Sanders and Cope  (1966)  provided the data for fresh-

 water  invertebrates in  static bioassays.  The  cladoceran,

 Simocephalus  serrulatus,  was the most sensitive with an 48-
                                                           *
 hour LC50  value of 812  ug/1,  while the  stonefly,  Ptaron-

 arcys  californica, was  the  most resistant  species with an
                            h-IS

-------
LCgQ value of 22,040 ug/1.  In marine, organisms,  the  chum


salmon, Onchorhynchus keta, had a 48-hour  flow-through  LC5Q


value of 8,331 ug/1 (Alderdice and Brett,  1957).  Two marine


invertebrates were tested  in 96 or 48-hour static-renewal  or


static assays and produced the following LC5Q values: bay


scallop, Arqopecten irradiana, with 3,490  ug/1; and the  em-  .


bryos of the American oyster, Crassostrea  virginica,  with  a


value of 4,330 ug/1.

     B.   Chronic Toxicity


          One chronic life cycle freshwater test  has  provided


a chronic value of 853 ug/1 for arsenic to Daphnia magna.


Pertinent data could not be'located in the available  litera-


ture for the chronic toxicity of arsenic to marine organisms.


C.   Plant Effects


          The lowest effective concentration recorded was  100


percent kill levels of 2,320 ug/1 for four species of fresh-


water algae.


     D.   Residues


          Bioconcentration factors for five freshwater  inver-


tebrate species and two fish species ranged from  less than 1


to 17  (U.S. EPA, 1979) .


VI.  EXISTING GUIDELINES AND STANDARDS


     A.   Hunan

          Criteria for organic and inorganic arsenicals  have


been derived.  However, due to public comment questioning  the
                                                           •
relevancy and accuracy of  the studies used in the development


of these criteria, further review is necessary  before final

recommendation.

-------
          The OSHA tine-weighted average  exposure  criterion



for arsenic is 10 ug/m^.



     B.   Aquatic



          For arsenic, the draft criterion  for  freshwater  or-



ganisms is 57 ug/1, not to exceed 130 u<3/l.   For marine  or-



ganisms, the draft criterion  is 29 ug/1,  not  to exceed  67



ug/1 (U.S. EPA,1^79).

-------
                           ARSENIC

                          REFERENCES

Alderice, D.F., and J.R. Brett.  1957.  Toxicity  of  sodium
arsenite to young chum salmon.  Prog. Rep. Pacific Coast  Stat.
Fish. Res.'Board Can.  108: 27.

Baetjer, A.M., et al.  1975.  Cancer and occupational  exposure
to inorganic arsenic.  Page 393 j.n Abstracts.  18th  Int.  Cong.
Occup. Health Brighton, England, September 14-19.

Baroni, C., et al.  1963.  Carcinogenesis tests of two inor-
ganic arsenicals.  Arch. Environ.. Health  7:  668.

Beaudoin, A.R.  1974.  Teratogenicity of sodium arsenate  in
rats.  Teratology  10: 153.

Bergoglio, R.M.  1964.  Mortalidad por cancer en  zonas de
aguas arsenicales de la Provincia de Cordoba,  Republica Argen-
tina.  Prensa Med. Argent.  51: 994.

Bettley, F., and J. O'Shea.  1975.  The absorption of  arsenic
and  its relation to carcinoma.  Brit. Jour.  Dermatol.   92:
563.

Boutwell, R.  1963.  A carcinogenicity evaluation of potassium
arsenite and arsenilic acid.  Jour. Agric. Food Chem.   11:
381.

Braman, R.S., and C.C. Foreback.  1973.  Methylated  forms of
arsenic in the environment.  Science  182:. 1247.
                                       •

Burgdorf, W., et al.  1977.  Elevated sister chromatic ex-
change rate in lymphocytes of subjects treated with  arsenic.
Hum. Genet. 36: 69.

Crecelius, E.A.  1977.  Changes in the chemical speciation of
arsenic following ingestion by man.  Environ.  Health Perspect.
19:  147.

Dutkiewicz, T.  1977.  Experimental studies  on arsenic absorp-
tion routes in rats.  Environ. Health Perspect.   19: 173.

Falk, H.L., and P. Kotin.  1961.  An assessment of factors
concerned with the carcinogenic properties of air pollutants.
Natl. Cancer Inst. Mon.  9: 81.

Ferguson, J.F., and J. Gavis.  1972.  A review of the  arsenic
cycle in natural waters.  Water Res.  6: 1259.            .

-------
Perm, V.H., and S.J. Carpenter.  1968.  Malformation  induced
by sodium arsenate.  Jour. Reprod. Fertil.  17: 199.

Ferm, V.H., et al.  1971.  The teratogenic profile of  sodium
arsenate in the golden hamster.  Arch. Environ. Health   22:
557.

Garb, L.G., and C..H. Hine.  1977.  Arsenical neuropathy:  Res-
idual effects following acute industrial exposure.  Jour.
Occup. Med.  19: 567.

Geyer, L.  1898.  Uber die chronischen Hautveranderungen beim
Arsenicismus und Betrachtungen uber die Massenerkrankungen  in
Reichenstein in Schlesien.  Arch. Derm. Syphilol.  43:  221.

Holland, R.H., et al.  1959.  A study of inhaled arsenic-74 in
man.  Cancer Res.  19: 1154.
                                         \
Hood, R.D., and S.L. Bishop.  1972.  Teratogenic effects of
sodium arsenate in mice.  Arch. Environ. Health  24:  62.

Hood, R.D.,-et al.  1977.  Effects in the mouse and rats of
prenatal exposure to arsenic.  Environ. Health Perspect.  19:
219.

Hunter, F.T., et al.  1942.  Radioactive tracer studies  on
arsenic injected as potassium arsenite.  jour. Pharmacol. Exp.
Ther.  76: 207.

Hughes, J.S., and J.T. Davis.  1967.  Effects of selected
herbicides on bluegill sunfish.  Pages 480-482.  In Proc. 18th
Ann. Conf., S.E. Assoc. Game Fish Comm., October T8,  19, 20
and 21, 1964.  Clearwater, Fla.  Columbia, S.C.: S.E. Assoc.
Game Fish Comm.  '

Kadowaki, K.  1960.  Studies on the arsenic contents  in  organ-
tissues of the normal Japanese.  Osaka City Med. Jour.   9:
2083.

Kagey, B., et al.  1977.  Arsenic levels in maternal-fetal
tissue sets.  Trace Subst. Environ. Health  11: 252.

Kuratsune, M., et al.  1974.  Occupational lung cancer  among
copper smelters.  Int. Jour. Cancer  13: 552.

Lee, A.M., and J.F. Fraumeni, Jr.  1969.  Arsenic and  respira-
tory cancer in man:  An occupational study.  Jour. Natl.  Can-
cer Inst.  42: 1045.

Levan, A.  1945.  Cytological reactions induced by inorganic
salt solutions.  Nature  156: 751.
                          11-17

-------
Liebscher, K., and H. Smith.   1968.   Essential  and  nonessen-
tial trace elements.  -A method of determining whether  an  ele-
ment is essential or nonessential in  human  tissue.   Arch.
Environ. Health  17: 881.

Lofroth, G.,  and B. Ames.  1978.  Mutagenicity  of  inorganic
compounds  in  Salmonella typhimurium;  arsenic, chromium, and
selenium.  Mutat. Res.  53: 65.

Mealey, J., Jr., et al.  1959.  Radioarsenic  in plasma,
urine, normal tissues, and intracranial  neoplasms.   Arch.
Neurol. Psychiatry  81: 310.

Moutshcen, J., and N . Degraeve.  1965.   Influence of thiol—
nhibiting  substances on the effects of ethyl methane sulphon-
ate (EMS)  on  chromosomes.  Experientia   21: 200.

Nishioka,  H.  1975.  Mutagenic activities'" of metal  compounds
in bacteria.  Mutat. Res.  31: 185.

Nordenson, I., et al.  1978.   Occupational  and  environmental
risks in and  around a smelter  in northern Sweden.   II.  Chro-
mosomal aberrations in workers exposed to arsenic.   Hereditas
88: 47.

Nordstrom, S., et al.  1978.   Occupational  and  environmental
risks in and  around a smelter  in northern Sweden.   III.   Fre-
quencies of spontaneous abortion.  Hereditas  88: 51.

Osswald, H.,  and Kl. Goerttler.  1971.   Laukosen bei der  Maus
nach diaplacentarer und postnataler Arsenik-Applikation.
Dtsch. Gesmte-Path.  55: 289.

Ott, M.G., et al.  1974.  Respiratory cancer  and occupational
exposure to arsenicals.  Arch. Environ.  Health  29:  250.

Overby, L.R., and R.L. Fredrickson.   1963.  Metabolic  stabil-
ity of radioactive arsanilic acid in  chickens.  Jour.  Agric.
Food Chem.  11: 378.

Paton, G.R.,  and A.C. Allison. . 1972.  Chromosome damage  in
human cell cultures induced by metal  salts.  Mutat.  Res.  16:
332.

Petres, J., and M. Hundeiker.  1968.  "Chromosomenpulverisa-
tion" nach Arseneinwirkung auf Zelljulturen _in  vitro.  Arch.
Klin. Exp. Dermatol.  231: 366.

Petres, J., et al.  1970.  Chromosomenaberrationen  an  mensch-
lichen Lymphozyten bei chronischen Arsenchaden.  Dtsh.  Mecj.
Wochenschr.   95: 79.

Petres, J., et al.  1972.  Zum Einfluss  anorganischen  Arsens
auf die DNS-Synthese menschlicher Lymphocyten _in vitro.   Arch
Derm. Forsch.  242: 343.

-------
Pinto, S.S., and B.M. Bennett.  1963.  Effect  of  arsenic  tri-
oxide exposure on mortality.  Arch. Environ. Health   7: 583.

Pinto, S.S., et al.  1976.  Mortality experience  of  arsenic
exposed workers.  Unpubl.

Raposo, L.  1929.  Le cancer a 1'arsenie.  C.P. Soc.  Biol;
(Paris)  98: 86.

Regelson, W., et al.  1968.  Hemangioendothelial  sarcoma  of
liver from chronic arsenic  intoxication by Fowler's  solution.
Cancer  21: 514.

Ridgway, L.P., and D.A. Karnovsky.  1952.  The effects of
metals on the chick embryo: Toxicity and production  of abnor-
malities in development.  Annu. N.Y. Acad. Sci.   55:  203.

Robinson, T.  1975.  Arsenical polyneuropathy  due  to  caustic
arsenical paste.  Brit. Med. Jour.  3: 139.

Rossman, T.-, et al.  1975.  Effects of sodium  arsenite on the
survival of UV-irradated Escherichia coli; Inhibition of  a
rec A dependent function.   Mutat. Res.  30: 157.

Roth, F.  1957.  The sequelae of chronic arsenic  poisoning  in
Moselle vintners.  German Med. Monthly  2: 172.

Sanders, H.O., and O.B. Cope.  1966.  Toxicities  of  several
pesticides to two species of cladocerans.  Trans.  Am. Fish.
Soc.  95: 165.

Schrauzer, G., and D. Ishmael.  1974.  Effects of  selenium
and of arsenic on the genesis of spontaneous mammary  tumors
in inbred C3H mice.  Ann. Clin. Lab. Sci.  4:  441.

Schroeder, H.A., and M. Mitchener.  1971.  Toxic  effects  of
trace elements on the reproduction of mice and rats.  Arch.
Environ. Health  23: 102.

Snegireff, L.S., and O.M. Lombard.  1951.  Arsenic and can-
cer.  Observation in the metallurgical industry.   AMA Arch.
Ind. Hyg.  4: 199.

Sorenson, E.M.B.  1976.  Toxicity and accumulation of arsenic
in green sunfish, Lepomis cyanellus, exposed to arsenate  in
water.  Bull. Environ. Contam. Toxicol.  15: 756.

Sram, R., and V. Bencko.  1974.  A contribution to the evalu-
ation of the genetic risk of exposure to arsenic.  Cesk Hyg.
19: 308.
                                                           »
Standen, A. (ed.)  1967.  Kirk-Othmer encyclopedia of chemi-
cal technology.  Interscience Publishers, New  York.

-------
Thacker, G., et al.  1977.  Effects of administration routes
on arsenate teratogenesis in mice.  Teratology  15: 30.

Tseng, W.P., et al.  1968.  Prevalence of skin cancer in an
endemic area of chronic arsenicism in Taiwan.  Jour. Natl.
Cancer Inst.  40: 453.

U.S. EPA.  1976.  Arsenic and its compounds.  EPA 560/6-76-
016.  U.S. Environ. Prot. Agency, Washington, D.C.

U.S. EPA.  1979.  Arsenic: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency,  Washington, D.C.

Urakubo, G., et al.  1975.  Studies in the fate of poisonous
metals in experimental animals (V).  Body retention and ex-
cretion of arsenic.  Jour. Food Hyg. Soc. Jpn.  16: 34.
                                         \
Vellar, 0.  1969.  Nutrient lopes through sweating.  Thesis,
Universitetsforlaget, Oslo,  Norway.

Weast, R.C. (ed.)  1975.  Handbook of chemistry and physics.
56th ed.  CRC Press, Cleveland, Ohio.

WHO.  1973.  Environmental Health Criteria;  Arsenic.  World
Health Organization.  Geneva.
                             •vr

                            I t-ltJL

-------
                                     No. 12
              Asbestos

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

           APRIL 30, 1980
             I*-1

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

-------
                       SPECIAL NOTATION










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



asbestos and has  found  sufficient evidence to indicate that



this compound is  carcinogenic.
                       /a-3

-------
                                   ASBESTOS
                                    Summary

     Numerous  studies  indicate  that  asbestos  fibers  introduced  into  the
pleura, peritoneum,  and trachea  of rodents  have  induced  malignant tumors.
The strongest  evidence  for the carcinogenicity of  ingested asbestos is pro-
vided  by  epidemiology of  human populations  occupationally exposed  to high
concentrations  of  airborne asbestos  dust.   Inhalation  exposure  to asbestos
dust is accompanied by ingestion  because a  high  percentage of  the inhaled
fibers  are removed  from  the  lung  by mucociliary  action  and  subsequently
swallowed.  "Peritoneal  mesothelioma,  often in  great excess, and  modest  ex-
cesses of  stomach esophagus, colonrectal, and kidney cancer have been linked
to occupational exposure to asbestos.
     Pertinent  data  on the acute  or chronic effects  of asbestos to aquatic
organisms were not found in the available literature.

-------
                                   ASBESTOS
I.   INTRODUCTION
     This profile is based primarily  upon  the Ambient Water Quality Criteria
Document for  Asbestos  (U.S.  EPA,  1979).   In addition,  valuable information
is available  from recent  reviews  by  the International Agency for Research on
Cancer  (IARC,  1977)  and  the National Institute for  Occupational  Safety and
Health (NIOSH, 1977).
     Asbestos  is a  broad  term  applied  to  numerous  fibrous mineral silicates
composed of  silicon,  oxygen,  hydrogen, and metal  cations such  as  sodium,
magnesium,  calcium,  or iron.  There  are  two major  groups of asbestos,  ser-
pentine (chrysotile or "white asbestos") and amphibole.   Although chrysotile
is considered  to be a distinct  mineral,  there  are  five fibrous amphiboles:
actinolite, amcsite  ("brown  asbestos"),   anthophyllite,   crocidolite  ("blue
asbestos"), and  tremolite. .  The  chemical  composition of different asbestos
fibers varies  widely,  and typical formulas  are  presented  in Table  1.   Some
typical physical properties  of three  different  mineral forms of asbestos are
presented in Table 2.


                                   TABLE 1
                     TYPICAL FORMULAS FOR ASBESTOS FIBERS
1.  Serpentines      chrysotile
2.  Amphiboles       amosite
                     crocidolite            Na/2(Mg,Fe) 5813022(0^)2
                     anthophyllite          (Mg,Fe) 7813022(^)2
                     tremolite
                     actinolite

-------
                                    TABLE 2.
          TYPICAL PHYSICAL PROPERTIES OF  CHRYSOTILE (WHITE ASBESTOS),
                   CROCIDOLITE (BLUE ASBESTOS), AND AMOSITE
                 Units         Chrysotile        Crocidolite    Amosite
                            (white asbestos)   (blue asbestos)
Approximate
diameter of micron
smallest fibers
Specific
gravity
Average
tensile Ib./inch2
strength
Modulus of Ib./inch2
elasticity
0.01

2.55
3.5 x 105

23.5 x 106

0.08

3.37
5 x 1Q5

27.0 x 106

0.1

3.45
1.75 x 105

23.5 x 106

     Asbestos  minerals,  despite  a relatively  high fusion  temperature,  are
completely  decomposed at  temperatures  of 1,000°C.   Both  the  dehydroxyla-
tion temperature  and decomposition temperature increase with  increased  MgO
content among the various amphibole species (Speil and Leineweber, 1969).
     The  solubility  product  constants  for various Chrysotile  fibers  range
from  1.0 x  10    to  3 x  10~   .  Most materials  have a  negative  surface
charge  in aqueous systems.   However,  since  Chrysotile  has a  positive  ( + )
charge, it will  attract,  or be attracted  to,  most dispersed materials.  The
highly  reactive  surface of  asbestos causes many  surface reactions  which are
intermediate  between simple  absorption and a  true chemical  reaction.   The
absorption of various materials  on the surface  of Chrysotile  supports  the
premise  that  the  polar  surface  of  Chrysotile has a  greater  affinity  for
polar  molecules  (e.g., H^O,  NH  )  than for non-polar  molecules (Speil  and
Leineweber,  1969).

-------
     Of  all  the  asbestos  minerals,  chrysotile is  the most  susceptible  to
acid attack.   It  is almost completely destroyed within one hour in  1  N HCL
at  95°C.   Amphibole  fibers  are  much  more  resistant  to  mineral  acids
(Lindell, 1972).
     The resistance  of the asbestos fibers to  attack  by reagents other than
acid  is excellent  up  to  temperatures  of  approximately  100°C with  rapid
deterioration observed at  higher  temperatures.   Chrysotile  is completely de-
composed  in  concentrated  KOH at  200°C.   In general,  organic  acids  have a
tendency to react slowly with chrysotile (Speil aYid Leineweber,  1969).
     Chrysotile is the major  type of asbestos used in the manufacture of as-
bestos products.  These products  include asbestos  cement pipe, flooring pro-
ducts, paper  products (e.g.,  padding), friction materials  (e.g.,  brake lin-
ings and clutch  facings),  roofing products, and  coating and  patching com-
pounds.  In 1975,  the total consumption of  asbestos  in the U.S. was 550,900
thousand metric tons (U.S. EPA, 1979).
     Of  the 243,527 metric tons  of asbestos discharged  to  the environment,
98.3 percent was  discharged to  land,  1.5  percent to air, and 0.2 percent  to
water  (U.S. EPA,  1979).   Solid waste disposal by consumers  was  the single
largest contribution to total discharges.  Although  no process water is used
in dry mining of  asbestos  ore,  there is  the  potential for runoff from asbes-
tos waste tailings,  wet mining,  and iron ore mining.   Mining operations can
also contribute substantially to  asbestos concentrations in water by air and
solid waste contamination.  In  addition  to mining and  industrial discharcss
of asbestos,  asbestos fibers,  which are believed to  be the  result  of reck
outcroppings,  are found in rivers and streams.
                              I3L-7

-------
II.  EXPOSURE
     A.  Water
         Asbestos is  commonly  found in domestic water  supplies.   Of 775 re-
cent samples analyzed  by  electron microscopy under the auspices  of the U.S.
EPA, 50 percent  showed detectable levels  of asbestos,  usually of the chryso-
tile variety (Millette, 1979).  Nicholson and Pundsack (1973) measured aver-
age  asbestos  levels  of 0.3 - 1.5  pg/1  in  drinking  water from  two Eastern
United  States  river  systems.   Levels of 2.0 to  172.7 x 106  fibers/1 have
been reported in Canadian tap water, the  highest  levels being found  in un-
filtered tap water  near a mining  area (Cunningham  and Pontefract, 1971).  In
other  studies  of Canadian drinking water levels of 0.1 to 4 x 10  fibers/1
have been  reported  (Kay,  1973).   The  U.S.  EPA  (1979)  has  concluded that
about  95 percent of water consumers  in the United States are exposed to as-
bestos  fiber  concentrations  of  less  than  10   fibers/1.   The mass concen-
trations of  chrysotile asbestos  in the  water  of  cities with  less than 10°
fibers/1 are  likely  to be less  than 0.01 pg/1,  corresponding to  an adult
daily  intake of  less  than 0.02 ug.  Pertinent data on the ability of aquatic
organisms  to  bioconcentrate  asbestos  from water  were not  located  in  the
available literature.
     B.  Food
         There are  scant  data on  the contribution of  food products to popu-
lation  asbestos  exposure.  However,  asbestos fibers  and talc,  which some-
times  contains  asbestos  as  an impurity,   may  be used  in  the manufacture of
certain processed  foods such as  sugar, coated rice,  vegetable oil and lard
(IARC,  1977).   Cunningham and Pontefract  (1971) reported  that certain beers
and wines could  contain asbestos  fibers at  levels  similar to those found in
drinking water systems  (10  to 10  fibers/1).

-------
     C.  Inhalation
         Asbestos  is  present in  virtually all  metropolitan areas.  Concen-
trations  of asbestos  in urban  atmosphere are  usually  less than  10 ng/m  ,
but  may  reach 100  ng/m-5 (Nicholson,  et al. 1971;  Nicholson and Pundesack,
1973; Sebastien, et al.  1976;  IARC,  1977).  Construction sites and buildings
fireproofed with loose  asbestos  material showed the most significant contam-
ination  with  individual  measurements as  high  as  800 ng/m   (Nicholson,  et
al. 1975).
III. PHARMACOKINETICS
     There  are  contradictory  data  concerning  whether  ingested  asbestos
fibers are  capable  of passage across  the  gastrointestinal  mucosa (Gross,  et
al.  1974;  Cooper  and  Cooper,   1978;   Cunningham  and  Pontefract,  1973;
Cunningham, et al.  1977).  Most ingested  asbestos  particles are excreted in
the  feces  (Cunningham,  et  al.  1976).   However,  at least  one  recent  study
(Cook and Olson, 1979)  indicates  that ingestion of drinking water containing
amphibole fibers may  result in the appearance  of these  fibers in the urine,
thus providing  evidence  for passage  of asbestos  across the  human  gastro-
intestinal tract.
     Ingestion  of  asbestos  fibers   is  accompanied  by  swallowing  of  many
fibers cleared from the respiratory tract by mucociliary action.  More than
half the asbestos inhaled  will  likely  be swallowed  (U.S.  EPA,  1979).   The
deposition  of asbestos  fibers in  the lung is  a  function of  their diameter
rather than length, as  about 50  percent  of particles with a mass median dia-
meter of less  than 0.1  urn  will  be deposited  on nonciliated  pulmonary  sur-
faces.    Deposition on  nasal and  pharyngeal surfaces becomes  important  as
mass median diameter  approaches  1 jun and  rises rapidly  to  become  the  domi-
nant deposition  site  for airborne particles  10 urn in diameter or  greater

-------
(Brain  and  Volberg,  1974).   Portions  of inhaled  asbestos fibers  which  are
not cleared  by  microciliary action may  remain trapped in  the lung  for  de-
cades (Pooley,  1973; Langer,  1973).   However, the chrysotile  content of the
lung does not build up  as  significantly  as  that of the amphiboles  for simi-
lar exposure circumstances (Wagner, et al. 1974).
IV.  EFFECTS
     A.  Carcinogenicity
         All  commercial  forms  of  asbestos  have  demonstrated  carcinogenic
activity in mice, rats, hamsters,  and  rabbits.   'Intraperitoneal  injection of
various asbestos fibers has produced mesotheliomas in rats and mice (Maltoni
and Annoscia> 1974;  Pott and Friedrichs,  1972; Pott,  et al.  1976).   In rats,
chronic inhalation of  various types  of asbestos have  produced lung carcino-
mas  and mesotheliomas  (Reeves,  et  al.  1971,  1974; Gross,  et  al.  1967;
Wagner, et al.  1974;  Davis,  et al. 1978).   Intrapleural  injection  of asbes-
tos fibers has  produced mesotheliomas  in  rats,  hamsters,  and rabbits (Donna,
1970; Reeves, et al.  1971; Stanton and Wrench,  1972;  Stanton, 1973; Wagner,
et al.  1973, 1977; Smith  and  Hubert,  1974).  The oral administration of as-
bestos  filter material  reportedly  caused  malignancies  in  rats  (Gibel, et al.
1976) although other feeding studies have produced equivocal results.
         Occupational 'exposure  .to chrysotile,  amosite,  anthophyllite,  and
mixed fibers containing crocidolite has  resulted in  high  incidences of human
lung  cancers (Selikoff,  et  al.  1979;  Seidman,  et  al.  1979;  Enterline  and
Henderson,  1973; Henderson and Enterline,  1979; IARC, 1977).   Occupational
exposure to  crocidolite,   amosite, and chrysotile  have also been  associated
with  a  large incidence of pleural and peritoneal mesatheliomas.   An excess
of gastrointestinal cancers  has been  associated in  some studies witn expo-
sure  to amosite,  chrysotile, or  mixed  fibers  containing crocidolite  (Seli
                                I3.-I6

-------
koff,  1976;  Selikoff,  et  al.  1979;  Elmes -and Simpson,  1971;  Henderson and
Enterline, 1979; Nicholson, et  al.  1979; Seidman, et  al.  1979;  Newhouse and
Berry, 1979; McDonald and Liddell, 1979; Kogan, et al. 1972).
         In the general  environment,  mesotheliomas have  occurred  in persons
living near  asbestos factories  and crocidolite  mines and  in  the household
contacts  of  asbestos workers  (Wagner,  et  al.  1960;  Newhouse  and Thomson,
1965).   In addition, several  studies  have  implicated asbestos  in drinking
water with the development of cancer  of the  lung and digestive tract cancers  .
(Mason,  et al.  1974; Levy, et  al.  1976; Cooper,'" et  al.  1978,  1979).  There
is convincing evidence  to  support the  contention  that asbestos  exposure and
cigarette  smoking  act  synergistically  to produce  dramatic  increases in lung
cancer over that from exposure to either agent alone (Selikoff,  et al. 1968;
Berry, et  al. 1972).
         In a  study by  Hammond,  et'al.  (1979)  involving  17,800  insulation
workers,  the death rate  for non-smokers was  5.17 times that of a non-smoking
control  population.  The death  rate was  53.24 times  that of the non-smoking
control  population  or  4.90 times the death rate  for a comparable  group  of
non-exposed smokers.   Cancers  of the  larynx,  pharynx and  buccal  cavity  in
insulators were also found to be  associated  with cigarette smoking, together
with some  non-malignant  asbestos  effects such  as  fibrosis  and deaths due to
asbestosis.
     B.  Mutagenicity
         In cultured Chinese  hamster cells, chrysotile  and crocidolite have
produced   genetic   damage   and   morphologic  transformation   (Sincock  and
Seabright,  1975;  Sincock,  1977).   On  the  other hand,  chrysotile,  amosite,
and anthophyllite  showed no mutagenic  activity toward tester strains  of §_._
coli or S^ typhimurium (Chamberlain and Tarmy, 1977).

-------
     C.  Teratogsnicity
         Pertinent data on  the  possible  teratogenic effects of asbestos were
not located in  the available literature, although  transplacental  passage of
asbestos fibers has been reported (Cunningham and Pontefract, 1971, 1973).
     D.  Other Reproductive Effects
         It is  not known whether  asbestos  exposure may  impair  fertility or
interfere with reproductive success .(U.S. EPA, 1979).
     E.  Chronic Toxicity
         The chronic  ingestion  of chrysotile by-rats  (0.5  mg or 50 mg daily
for 14 months) produced no  effects on the esophagus,  stomach, or  cecum tis-
sue, but  histological changes  were seen in the ileum,  particularly  of the
villi (Jacobs, et al. 1978).
         The  long-term  disease  entity, asbestosis,  results from the inhala-
tion of asbestos fibers and  is  a  chronic,  progressive pneumoconiosis.   It is
characterized by  fibrosis of the  lung parenchyma and  produces  shortness of
breath as the primary symptom.  Asbestos has accounted for numerous cases of
occupational  disablement  during  life as well as  a considerable  number of
deaths among  worker  groups.   In groups exposed  at  lower concentrations such
as the families of workers,  there is less  incapacitation and although asbes-
tosis can occur, deaths have not been reported (Anderson, et al.  1976).
         Extrapulmonary  chronic  effects  reported  include  "asbestos  corns"
from the penetration of asbestos  fibers  into the skin.  NO chronic nonmalig-
nant gastrointestinal effects have been reported.
V.   AQUATIC TOXICITY
     Pertinent  data  concerning the  effects  of asbestos  to either  fresh-
water or marine organisms were not located in the available literature.
                                   I a

-------
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the  human  health nor  the  aquatic criteria derived  by  U.S.  EPA
(1979), which are summarized  below,  have gone through the  process of public
review;  therefore,   there   is  a  possibility  that  these   criteria  will  be
changed.
     A.  Human
         The  current Occupational  Safety and Health Administration  (OSHA)
standard for an  8-hour  time-weighted average  (TWA)  occupational  exposure to
asbestos is  2 fibers longer  than  5 microns in length per  milliliter  of air
(2f/ml  or  2,000,000 f/m ).   Peak  exposures of up to 10 f/ml  are permitted
for no  more  than 10 minutes  (Fed.  Reg.,  1972).   This  standard  has been in
effect  since July  1,  1976,  when it replaced an earlier  one of 5 f/ml (TWA).
Great Britain also has  a value  of  2 f/ml as the accepted level,  below wnich
no  controls  are  required  (BOHS,   1968).   The  British standard, in  fact,
served as a guide for the OSHA standard (NIOSH, 1972).
         The British  standard was  developed  specifically  to  prevent  asbes-
tosis  among  working populations;  data  were  felt  to be lacking  that  would
allow  for  determination  of  a  standard   for  cancer  (BOHS,  1968).   Unfor-
tunately, among  occupational  groups,  cancer is  the primary cause of  excess
death  for workers  (see  "Carcinogenicity"  section)  with  three-fourths or more
of asbestos-related  deaths  caused  from malignancy.   This   fact has  led OSHA
to  propose  a  lower TWA  standard  of 0.5  f/ml (500,000   f/m3)  (Fed.  Reg.,
1975).   The  National Institute  for Occupational  Safety  and Health  (NIOSH),
in their criteria document  for  the  hearings  on a  new standard, have proposed
a value of 0.1 f/ml (NIOSH, 1977).  In  the discussion of the NIOSH proposal,
it was  stated that the  value  was selected on the  basis of  the sensitivity of
analytical techniques  using  optical  microscopy and that  0.1  f/ml may  not
neces

-------
sarily protect  against cancer.   Recognition that  no information exists that
would define  a  threshold for asbestos  carcinogenesis was  also  contained in
the preamble  of the OSHA proposal.   The existing  standard in Great Britain
has been questioned  by Peto (1978),  who estimates  that  asbestos disease may
cause the  death of  10 percent  of workers exposed  at 2 f/ml  for  a working
lifetime.
         The  existing  federal standard  for asbestos  emissions  into the en-
vironment  prohibits "visible  emissions"  (U.S.  EPA, 1975).   No  numerical
value was specified  because of difficulty  in monitoring  ambient air asbestos
concentrations in the  ambient air  or  in  stack emissions.  Some local govern-
ment  agencies,  however,  may have numerical  standards  (e.g.,  New  York,  27
ng/m ).
         No standards  for asbestos in  foods  or beverages  exist even though
the use  of  filtration  of such products  through asbestos filters has  been a
common practice  in  past years.   Asbestos  filtration,  however,  is prohibited
or limited for human drugs  (U.S.  FDA,  1976).
         The  draft   recommended  water  quality criterion  for  asbestos  par-
ticles (U.S.  EPA,  1979) is  derived  from  the  substantial  data  which exists
for the  increased  incidence of  peritoneal  mesothelioma  and gastrointestinal
tract cancer  in  humans exposed  occupationally  to  asbestos.   This derivation
assumes  that  much  or  all of this increased  disease  incidence  is  caused by
fibers ingested following  clearance  from  the  respiratory  tract.   Several
studies  allow the  association of approximate  airborne  fiber concentrations
to which individuals were  exposed with  observed excess peritoneal  and  gas-
trointestinal cancer.   All   of the inhaled asbestos is  assumed  to  be even-
tually cleared from the respiratory tract and ingested.

-------
         The draft criterion calculated  to-keep the individual lifetime can-
cer  risk below  10~ ,   is  300,000  fibers  of  all  sizes/liter.   The  corres-
ponding  mass concentration  for  chrysotile  asbestos  is approximately  0.05
ug/1.  This  criterion has  not  yet gone through the process of public review;
therefore, there is a possibility that the criterion may be changed.
     B.  Aqustic
         Because no data  are  available on the  aquatic toxicity  of asbestos,
the U.S. EPA (1979) derived no aquatic criteria.

-------
                             ASBESTOS

                            REFERENCES


Anderson,  H.A.,  at  al.    197t>.   Household-contact  asbestos neo-
plastic risk.  Ann. N.Y. Acad. Sci.  271: 311.

Berry, G.,  et al.   1972.   Combined effect  of  asoestos exposure
and  smoking  on  mortality  from  lung cancer  in  factory workers.
Lancet  2: 476.

Brain, J.D.,  and P.A. Volberg.   1974.   Models  of lung retention
based on ICRP task group report.  Arch.  Environ. Health  28:  1.

British  Occupational Hygiene  Society.    1968.    Hygiene standard
for chrysotile asbestos dust.  Ann. Occup. Hyg.  11: 47.

Chamberlain, M.  and  E.M.  Tarmy.   1977.   Asbestos ana glass  fibres
in bacterial mutation tests.  Mutat. Res.  43: 159.

Cook, P.M. and G.F. Olson.  1979.  Ingested mineral fibers:  Elimi-
nation in human urine.  Science  204: 195.

Cooper,  R.C.  and W.C.  Cooper.   1.978.   Public  health  aspects of
asbestos  fibers  in  drinking water.   Jour. Am.  Water  Works  Assoc.
72: 338.

Cooper,  R.C.,  et al.  1978.   Asbestos  in  domestic water supplies
for  five California counties.   Prog.  rep.   for  period April 25,
1977 to June 30, 1978.  EPA Contract No. R804366-02.

Cooper, R.C.,  et al.   1979.   Asbestos  in  domestic water supplies
for five California  counties.   Part  II  EHS Puol. No.  79-1,  School
of Public Health, Univ. Calif. Berkeley,  pp. 247.

Cunningham,  H.M. and  R.D.  Pontefract.    1971.    Asoestos   fioers
in beverages and drinking water.  Nature (Lond.)  232: 332.

Cunningham,  H.M. and  R.D.  Pontefract.    1973.    Asbestos   fibers
in beverages,  drinking water  and  tissues: their  passage  through
the  intestinal wall and movement through  the body.   Jour.  Assoc.
Off. Analyt. Chem.  56: 97b.

Cunningham,  H.M.,   et  al.-   1976.   Quantitative  relationship of
fecal  asbestos  to  asbestos  exposure.    Jour.   Toxicol.  Environ.
Health  1: 377.

Cunningham,  H.M.,   et  al.   1977.   Chronic  effects of ingested
asbestos in rats.  Arch. Environ. Contam. Toxicol.  6: 507.

Davis, J.M.G.,  et al.   1978.   Mass  and number of  fioers   itt the
pathogenesis of  asbestos-related  lung disease in rats.   Br.  Jour.
Can.  37: o73.

-------
Donna,  A.    1970.    Tumori  sperimentali  da  amiano  di crisotilo,
crocidolite  e  amosite   in  ratto  Sprague-Dawley.   Med.  Lavoro.
61: 1.

Elmes,  P.O.  ana M.J.C.  Simpson.   1971.   Insulation  workers in
Belfast.  III. Mortality 1940-66.  Br. Jour.  Ind. Med.  23: 226.

Enterline, P.E.  ana V.  Henaerson.   1973.   Type of  asbestos and
respiratory  cancer  in   the  asbestos  industry.   Arch.  Environ.
Health.  27:  312.

Federal Register.   1972.   Standard  for exposure to asbestos dust.
Title  29,  Chap. XVII,  Part  1910-Occupational Safety  and Health
Standards.  June 7, Washington, D.C.  37: 11318.

Federal  Register.    1975.    Occupational exposure  to  asbestos;
notice of proposed rulemaking.  Oct. 9, Washington, D.C.  49:  197.

Gibel, W., et  al.   1976.  Tierexperimentelle  untersuchungen  uber
eine  kanzerogene  wirkung  von  asbestfiltermaterial   nach  oraler
aufnahme.  Arch. Geschwulstforsch.  46: 437.

Gross,  P., et al.    1967.   Experimental•asbestosis:  The develop-
ment of lung cancer  in  rats with pulmonary deposits  of chrysotile
asbestos dust.  Arch. Environ. Health  15: 343.

Gross, P., et al.   1974.   Ingested  mineral  fibres.   Do they pene-
trate tissue  or cause cancer?  Arch. Environ. Health  29: 341.

Hammond,  E.G.,  et  al.   1979.    Cigarette  smoking  and  mortality
among  U.S.  asbestos  insulation  workers.    Ann.  N.Y.  Acaa.   Sci.
(In press; .

Henderson, V.I.  and  P.E.  Enterline.    1979.    Asbestos  exposure
factors  associated  with  excess  cancer  and   respiratory  disease
mortality.  Ann. N.Y. Acad. Sci.  (In press).

IARC Monographs  on  the  Evaluation of Carcinogenic Risk  of Chemi-
cals to Man.   1977.  Asoestos.  Vol. 14.

Jacobs, R., et  al.   1978.   Light and  electron microscope studies
of  the  rat  digestive  tract   following  prolonged and short-term
ingestion of  chrysotile asbestos.  Br. Jour.  Exp. Path.  59: 443.

Kay, G.  1973.   Ontario  intensifies  search for  asbestos in drinking
water.  Water Pollut. Control  9: 33.

Kogan, P.M.,  et al.   1972.  The  cancer mortality rate among workers
of asbestos industry of the Urals.  Gig. i Sanit.  37: 29.
                                                            *
Langer, A.M.,  et al.  1973.    Identification of  asbestos  in human
tissues.  Jour. Occup.  Med  15: 287.

-------
Levy,  B.S.,   et  al.   1976.    Investigating  possible  effects of
asbestos  in  city water:    Surveillance  of gastrointestinal cancer
incidence in Duluth, Minn.  Am. Jour. Epidemiol.  103:  362.

Lindell,  K.V.    1972.    Biological effects  of  asbestos.    Int.
Agency Res. Cancer, Lyon, France.

Maltoni, G. and C.  Annoscia.  1974.  Mesotheliomas in rats following
the  intraperitoneal injection of  crocidolite.   In;  W.  Davis and
C.  Maltoni,  eds.   Advances  in tumour prevention,  detection and
characterization.   Vol.  1.  Characterization  of   human  tumours.
Excerpta Medica,  Amsterdam.

Mason, T.J.,  et  al.  1974.   Asbestos-like  fibers  in Duluth water
supply.   Relation  to  cancer  mortality.    Jour. Am.  Med.  Assoc.
228: 1019.
                                            v
McDonald,  J.C.  and O.K.  Liddell.   1979.  Mortality in Canadian
miners and millers exposed to  chrysotile,   Ann. N.Y.  Acad.   Sci.
(In press).

Millette, J.   1979.  Health  Effects  Res. Lab.  (Personal communi-
cation) .

National  Institute of  Occupational  Safety  and  Health.    1972.
Criteria  for  a  recommended  standard...Occupational  exposure to
asbestos.  DHEW  (NIOSH)  Pb. No. 72-10267.

Natioal  Institute  of  Occupational  Safety and Health.    1977.
Revised  recommended asbestos  standard.    DHEW (NIOSH)  Pub.  No.
77-169.

Newhouse,  M.L.  and G.  Berry.   1979.   Patterns of disease among
long-term  asbestos workers  in  the  United Kingdom.   Ann.   N.Y.
Acaa. Sci. (In press).

Newhouse,  M.L.  and H.  Thomson.   1965.   Mesothelioma  of  pleura
and peritoneum following  exposure to  asbestos  in the London area.
Br. Jour. Ind. Med.  22:  261.

Nicholson, W.J.    1971.   Measurement of  asbestos  in amDient  air.
Final  report, Contract  CPA  70-92.   Natl.  Air  Pollut.  Control
Admin.

Nicholson, W.J.  and F.L. Pundsack.   1973.  Asoestos in the envi-
ronment.  Page 126 jLn_ P. Bogovski, et al. eds.   Biological effects
of  asoestos.   IARC Sci.  Publ. No.  8.    Int.   Agency Res.  Cancer,
Lyon, France.

Nicholson,  W.J.,  et  al.    1971.    AsDestos air pollution  in New
York City.   Page 136  _in H.M. England and W.T.  Barry, eds.  »Proc.
Second Clean Air Cong. Academic Press, New York.

Nicholson,  W.J.,  et  al.    1975.    Asbestos contamination  of  the
air  in  puolic buildings.  Final  report,  Contract  No.  63-U^-iJ
-------
Nicholson, W.J.,  et  al.   1979.   Mortality experience of asbestos
factory  workers:  Effect of   differing   intensities  of  asbestos
exposure.  Environ. Res.   (In press).

Peto, J.  1978. The hygiene standard for asbestos.  Lancet 8062: 484.

Pooley, F.DI   1973.   Mesothelioma  in relation  to exposure.  Page
222  iji P.  Bogovski,  et al.  eds.   Biological  effects  of asbestos.
IARC Sci. Publ. No. 8.  Int. Agency Res. Cancer, Lyon, France.

Pott,  F.  and  K.H.  Friedrichs.    1972.    Tumoren  der  ratte nach
i.p.-injektion faserformiger staube.  Naturwissenschaften.  59: 318.

Pott, F., et al.  1976.  Ergebnisse aus tierversuchen zur kanzero-
genen  wirkung  faserformiger staube  und  ihre deutung  im hinolick
auf  die  tumorentstehung  beim menschen.   Zbl. Bakt.  Hyg.,  I Abt.
orig.  B.  162: 467.

Reeves, A.L., et al.  1971.   Experimental  asbestos carcinogenesis.
Environ.  Res.  4: 496.

Reeves, A.L., et al.   1974.  Inhalation carcinogenesis from various
forms of asbestos.  Environ. Res.  8: 178.

Sebastien, P.,  et al.  1976.  Les pollutions atmospheriques urbanies
par  1'asbeste.  Rev. franc.  Mai. resp.  4: 51.

Seidman,  H., et al.  1979.  Long-term observation following short-
term employment  in  an amosite  asbestos factory.   Ann.  N.Y. Acad.
Sci. (In press).

Selikoff, I.J.  1976.   Lung  cancer  and mesothelioma during prospec-
tive surveillance of  1249 asbestos insulation workers,  1963-1974.
Ann. N.Y. Acad.  Sci.  271:  448.

Selikoff,  I.J.,  et  al.   1968.    Asbestos exposure,   smoking  and
neoplasia.  Jour. Am. Med, Assoc.  204: 106.

Selikoff,  I.J.,  et  al.   1979.   Mortality experience of insulation
workers  in  the United States  and  Canada,  1943-1977.   Ann.  N.Y.
Acad. Sci.  (In press).

Sincock,   A.M.    1977.   Ir±  vitro chromosomal effects  of  asoestos
and  other  materials.   In. Origins of human  cancer.   Cold  Spring
Harbour,  1976.

Sincock,   A.M.  and M. Seabright.   1975.   Induction of  chromosome
changes in Chinese  hamster  cells by exposure  to asbestos fibers.
Nature (Lond.)  257: 5o.

Smith, W.E.  ana D.D.  Hubert.    i974.   The intrapleural  rou"te  as
a means for  estimating carcinogenicity.   Pages  92-101 in_ E. Karbe
and  J.F.  Park,  eas.   Experimental  lung  cancer.   Springer-Verlag,
Berlin.  92-101.

-------
Speil, S. and J.P. Leineweber.  1969.  Asbestos minerals in modern
technology.  Environ. Res.  2: 166.

Stanton, M.F.    1973.   Some  etiological considerations  of fibre
carcinogenesis.  Page 28y  .in  P.  Bogovski,  et al.  eds.   Biological
effects  of  asnestos.   Int. Agency Res.  Cancer.   IARC  Sci. Publ.
No. 8.

Stanton, M.F.  and C. Wrench.   1972.  Mechanisms  of mesothelioma
induction  with asbestos  and  fibrous glass.   Jour. Natl.  Cancer
Inst.  48:  797.

U.S.  EPA.   1975.   National emission standards  for hazardous air
pollutants.  Fed. Reg. 40:48291.

U.S.  EPA.   1976.  Quarterly  report  of  the Environmental Research
Laboratory - Duluth.  October-December, 1976.  p. 5.

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

U.S.  Food  and  Drug Administration.   1976,   Current good manufac-
turing practice for finished Pharmaceuticals.  Fed. Reg.  41:  16933.

Wagner,  J.C.,  et  al.   1960.    Diffuse  pleural mesothelioma and
asbestos exposure  in  the  north western Cape  Province.   Br. Jour.
Ind. Med.  17: 260.

Wagner,  J.C.,  et al.   1973.   Mesotheliomata in rats after  inocu-
lation with asbestos and other materials.  Br. Jour.  Cancer 28:  173.

Wagner,  J.C.,  et al.   1974.   The  effects  of the  inhalation of
asbestos in rats.  Br. Jour. Cancer  29: 252.

Wagner,  J.C.,  et al.  1977.   Studies of  the carcinogenic  effect
of  fibre  glass  of  different diameters  following  intrapleural
inoculation in experimental animals.  In Natl. Inst. Occup.  Safety
Health.    Symp.  Occup. Exposure  to Fibrous  Glass.   University
of Maryland, 1977.  (in press).

-------
                                    No. 13
             Barium
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.   20460

          APRIL 30, 1980
        /3-y

-------
                          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.

-------
                                BARIUM
SUMMARY

     Water-soluble barium compounds are highly toxic to man.  Fish and lower
species of marine organisms have been  shown to bioaccumulate barium.  The con-
centration of barium in sea water ranges around 20 ug/L, while that of drinking
water averages about 6 ug/L.
     Soluble barium salts have a high  acute toxicity.  Small amounts of barium
can accumulate in the skeleton of humans and animals.  Barium salts are strong
muscle stimulants:  acute intoxication generally results in uncontrolled
contractions followed by partial or complete paralysis.  Cardiac disturbances
including arrythmias can also occur.   Barium dusts are irritant  to nose,
throat and eyes.  Baritosis (pneumoconiosis) occurs following chronic
inhalation of (fine) barium dusts.  Barium sulfate used in barium enemas,
swallows and artificial orthopedic bones can result in tissue injury following
solubilization of the barium sulfate and/or soluble impurities.  Potassium
acts as an antagonist for barium induced cellular disturbances.  The TWA
for exposure to soluble barium compounds is 0.5 mg/m .

I.  INTRODUCTION        .                            . .

     Barium (Ba; atomic weight 137.34) is a yellowish-white metal of the alkaline
earth group.  It is relatively soft and ductile and may be worked readily.
Barium has a melting point of 729 C and a boiling point of 1640 C; its density
is 3.51 g/cm3 (Kunesh 1978).
     Barium characteristically forms divalent compounds.  At room temperature,
it combines readily and exothermically with oxygen and the halogens.  It reacts
vigorously with water to form barium hydroxide, Ba(OH)_ (Kunesh 1978).
     Barium occurs in nature chiefly as barite, crude BaSO^, and as witherite,
a form of BaCO,, both of which are highly insoluble salts.  Only barite is
mined in this country (Kirkpatrick 1978).
     A review of the production range  (includes importation) statistics for
barium (CAS. No. 7440-39-3) which  are listed  in  the initial  TSCA  Inventory,
(U.S. EPA 1979) has shown that between 100,000 and 900,000 pounds of this
chemical were produced/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 (40 CFR 710).

-------
C.  Environmental Occurrence
     The flow of barium in the United States has been traced for the year 1969,
during which time consumption of barium totaled 1.87 billion pounds.  It was
estimated that 30.8 million pounds of barium were emitted to the atmosphere.
Nearly 18 percent of the emissions resulted from the processing of barite, more
than 28 percent from chemical production, 26 percent from the combustion of
coal, and 23 percent from the manufacture of miscellaneous end products
(U.S. EPA  1972).
     The concentration of barium in sea water is generally accepted as about
20 ug/L, with lower concentrations in the surface waters than at greater depths.
Barium ions are generally removed from solution quite rapidly by adsorption,
sedimentation and precipitation (U.S. EPA  1973).  Concentrations of barium in
this country's drinking water supplies generally range from less than 0.6 ug/L
to about 10 ug/L, although a few midwestern and western states have had upper
limits of 100 to 300 ug/L (U.S. EPA  1976).
     Due to the common use of barite as a weighting agent in drilling muds,
the resultant contamination of sediments near drilling sites was studied.  The
average content of barium in benthic sediments from the Southern California Bight
was 637 parts per million (ppm), with a range from 43 to 1899 ppm.  This area
includes active drilling sites where barium contamination is expected.  The
concentration values were compared with the average 879 ppm barium found in
mainland intertidal sediments and the 388 ppm determined in the channel island
intertidal sediments.  The lower barium content of the island sediments was
attributed to the volcanic soil of the islands; however, the higher barium
concentration of the mainland could not be traced to either natural or anthro-
pogenic origin.  Due to variations in soil sources it is questionable whether
barium concentrations determined elsewhere could be used as reference values for
this study (Chow  1978).
     In two studies correlating trace metal concentrations in the environment
with that in scalp hair of the inhabitants, barium was measured in the house
dust collected in four communities.  Geometric mean values of barium determined
in house dust samples from the New York City area were as follows:  65.2 ug Ba/g
dust in Riverhead, 137.6 ug/g in Queens, and 312.4 ug/g in the Bronx (USEPA, 1978b)
The geometric mean value for barium measured in house dust in Ridgewood, New
Jersey was 330.0 ug/g  (U.S. EPA 1978c).
                               /3-V

-------
                   Barium and its compounds are used industrially as weighting agents in
              oil and gas well drilling muds; as coloring agents in glass, ceramics, paint,
              and pigments; as filler in rubber; and as  antismoking agents  in diesel
              fuel (U.S. EPA 1972; NAPCA 1969).  In medicine, barium sulfate is used as
              an x-ray contrast medium because of its extreme insolubility and its ability to
              absorb x-rays (Kirkpatrick 1978; U.S. EPA 1978a).

              II.  EXPOSURE                                          :•••_

                   A.  Environmental Fate
                   Due  to  the high reactivity of barium, it is not found in its elemental
              state in the environment.  In sea water, the naturally present sulfate and
              carbonate tend to precipitate any water-soluble barium components.  Thus, the
              sediment usually has a higher concentration of barium than its corresponding
              water source (Guthrie 1979) .

                   B.  Bioconcentration
                   Due to the toxicity of soluble barium salts to man, the bioaccumulation
V
[             of the element has been a concern.  Barium can be concentrated in goldfish by
;      .        a factor of 150.  Concentration factors for barium listed in one study are
;              17,000 in phytoplankton, 900 in zooplankton, and 8 in fish muscle (U.S. EPA 1973).
i
I              Thus, ingestion of fish by man can be a source of barium exposure.
j.                  Another study conducted on various species of marine organisms produced the
•              following results (Guthrie  1979):  Barnacles bioaccumulated  about
I              five times greater concentration of barium than was in the water, while oysters
!              and clams contained concentrations of the element similar to that present in
i              the water.  Crabs and polychaetes were also analyzed for barium and were found
I              to contain a significantly smaller quantity than that present in the sediment
i              on which they dwell.  However, no significant differences were noted between
i              the concentration of barium in the two organisms and the concentrations in
              the water column.
I                   In man, studies have been conducted to determine a correlation between barium
I              in the environment, measured as house dust, and the concentration of barium found
              in scalp hair of the inhabitants.  A significant positive correlation has been
              determined between the geometric mean concentrations of the element in house dust
':              and hair.  Other covariants of significant value measured in the studies were sex,
;              hair length, and, in children less than 16 years old, age (U.S. EPA 1978b; U.S.
'              EPA 1978c).

-------
Ill.  PHARMACOKINETICS                            ,,.
     Soluble barium is retained by muscle tissue for about 30 hours, after
which the amount of retained barium decreases slowly (NAPCA 1969) .  Small
amounts of barium become irreversibly deposited in the skeleton.  However,
the acceptance level is limited, as quantitative analysis of human bone
reveals no accumulation of barium from birth to death.... Barium levels
averaged 7 ug/g ashed bone.  Very little barium is retained by the liver,
kidneys, or spleen, and practically none by the brain, heart, or hair.
Transient high concentrations are seen in the liver with lesser amounts in
lung and spleen following acute experimental dosing.
     Barium administered orally or intraperitoneally as Bad. to weanling
male rats at doses of 1, 5, 25, or 125 mg/kg was taken up rapidly by the
soft tissues (30 mins), showed slow uptake by the skeleton (2 hrs) and was
excreted primarily in the feces (Clary and Tardiff, 1974) .  No retention
data were reported.
                                                      133
     Pulmonary clearance rates of inhaled radioactive    Ba salts, ranged from
                                                              11
several hours for the soluble BaCl. to hundreds of days for Ba   in fused
clay .  Large amounts of barium were excreted in the feces; a lesser amount
was excreted in the urine.  Although BaSO, is "Insoluble" in water, 50% of
133
   BaSO, dissolved in a simulated biological fluid within 2-3 days, indicating
that solubilization is relatively rapid.

IV.  HEALTH EFFECTS

A.  Carcinogenicity
     Bronchogenic carcinoma developed in rats injected with radioactive   S
(unspecified dose) labelled barium sulfate (Patty 1963).  BaSO^ powder (particle
size undefined) injected intrapleurally in female and male mice produced a
mesothelioma in only 1 out of 30 animals.  No other pathological lesions were
investigated or reported.  Saline controls (32) resulted in no mesotheliomas.
Barium sulfate had an oncogenie potency similar to that of glass powder and
                                                                      •
aluminum oxide.  It therefore appears likely that the observed tumor was due
to foreign-body-oncogenesis (Wagner).

-------
B.  Acute and  Chronic Toxicity
     The soluble  salts  of barium are highly  toxic when  ingested.  Barium chloride
and barium  carbonate, two of  the soluble compounds, have been  reported to
cause  toxic symptoms of a severe but usually nonfatal degree.  Seven grams of
barium chloride  (^4.5  g Ba)  taken orally produced severe abdominal pain and
near-collapse, but not  death  (NAPCA 1969).   However, Patty  (1963) indicates
800 to 900   rag of barium chloride (550-600  mg Ba) to be a  fatal, human dose.
Few cases of industrial poisoning from soluble barium salts have  been reported.
Most of these  have been cases of accidental  ingestion (NAPCA 1969).
     Ingested  soluble barium  compounds produce a strong stimulating effect on
all muscles of the body.  The effect on the  heart muscle is manifested by
irregular contractions  followed  by arrest of systolic action.  Gastrointes-
tinal  effects  include vomiting and diarrhea.  Central nervous  system effects
observed include  violent tonic and clonic spasms followed in some cases by
paralysis (NAPCA  1969).
     Death  resulting from barium exposure may occur in a few hours or a few
days,  depending on the  dose and  solubility of the barium compound.  A death
attributed  to  barium oxide poisoning has been reported.  However, the usual
effect of exposure to dusts and  fumes of barium oxide, barium  sulfide, and
barium carbonate  is irritation of eyes, nose, throat and the skin (NAPCA 1969).
     Some of the  BaSO,  used in orthopedic bone cements has  been shown to escape
into surrounding  tissues (Rae 1977) .  Mouse  peritoneal macrophages exposed to
barium sulfate (10 particles.of  unspecified  size/macrophage) for  periods up
to 144 hours showed a marked cytoplasmic vacuolization.  Following cessation
of exposure only  partial recovery occurred.  No cell membrane  damage was
observed (Rae  1977).  The use of  barium sulfate in barium swallows and
enemas \resulted in severe toxic ""affects on rupture of  the intestinal tract
(Gardiner and  Miller 1973, Bayer  et al. 1974).
       Inhalation  of barium compounds is known to cause a benign respiratory
 affliction (pneumoconiosis) called baritosis, which has been  reported in
I workers exposed  to finely divided barium sulfate in Italy, in barite miners
 in the United States,  Germany,  and Czechoslovakia, and among  workers exposed
 to barium  oxide.  Generally, baritosis produces no symptoms of emphysema or
 bronchitis, and  lung function tests show no respiratory incapacity, although
 some  afflicted workers complain of dyspnea  upon exertion.  In the majority
 of cases nodulation disappears  if exposure  to the barium compound is stopped
 (NAPCA 1969).  Aspirated BaSO,  can result in granulomas of the lung and other
 sites in man  (Patty 1963) .

-------
    Suicidal ingestion of a facial depilatory containing  15.8  g  of  BaS
resulted In paralysis of head, neck, arms,  and trunk as well as  respiratory
                                                   ''.';.
paralysis.  Therapy with MgSO,, saline and  potassium resulted  in recovery
within 24 hours (Gould et al. 1973).
    Acute oral toxicity values for barium carbonate were:  mouse LD = 200 mg/
kg; rat LD =» 50-200 mg/kg, LD5Q = 1480 + 340 mg/kg; rabbit ID  =  170-300 mg/kg.
For barium chloride oral toxicity values were:  mouse LD  = 7-14  mg/kg; rat
LD = 355-533 mg/kg; rabbit LD = 170 mg/kg;  dog LD = 90 mg/kg.  For  barium
flouride the acute oral LD for guinea pigs  was 350 mg/kg  (NAPCA  1969).

C.  Other Relevant Information

    Potassium acts as an in vitro antagonist of barium.   Cardiac effects
such as arrythmias exerted by barium are also reversed rapidly by potassium.
Barium induces hypokalemia apparently by promoting a shift of  potassium
from plasma into cells.  The prolongation of action-potentials and  depolariza-
tion of smooth and skeletal muscle by barium are thought  to  be due  to
barium induced decreases in potassium conductance.  In addition,, barium can
replace sodium to produce and/or prolong action potentials and can  also
substitute for calcium in neurosecretory processes as described  below (Peach 1975)
    Barium chloride has been shown to cause arterial contractions in
                                                                       _4
in vitro preparations of human digital arteries at concentrations of  10   to
10~  M (Jauernig and Moulds 1978).  This activity was approximately 40 to 50
fold more than that of potassium chloride.   At Bad- concentrations above 10~  M
contractions developed very slowly.  The action of BaCl_  was inhibited by
                                                      ^         _2
veraparmil, a calcium antagonist, at BaCl_  contractions below  10   M.
                                   /3-r

-------
V.  AQUATIC TOXICITY

     According to an EPA report, experimental data indicate that  in  frtsh
and marine waters, the soluble barium concentration would need  to exceed
50 mg/L before toxicity to aquatic life would be expected (U.S. EPA  1976).
Furthermore, in most natural waters,  sufficient sulfate  or carbonate is present
to precipitate barium in the water to a virtually insoluble,  non-toxic
compound.
     Soluble barium salts, however,  are quite toxic.  It has  been reported
that 10 to 15 mg/L of barium chloride (9.9 mg/L Ba)  was   lethal to an aquatic
plant and two species of snails (species and origin unspecified). Bioassay
with this same barium salt showed the LCqf. for Coho Salmon to be  158 mg/L
(104 mg/L Ba)  (U.S. EPA 1973).

VI.  GUIDELINES

A.  Human, Health

     The OSHA Time Weighted Average for exposure to barium (soluble  compound)
is 0.5 mg/rn3 (29 CFR 1910:1000).

B.  Aquatic

     There is no established criterion for barium in the aquatic  environment.
The U.S. EPA (1973) suggests, however, that concentrations of barium equal
to or exceeding 1.0 mg/L constitute a hazard in the marine environment, and
levels less than 0.5 mg/L present minimal risk of deleterious effects.
                             a-f

-------
                                 References
Bayer HP, Buhler F and Ostermeyer J, 1974.  On the distribution of interstitial
and parenteral administered barium sulfate in the organism.  Z. Rechtsmedizin
74:  207-215 (1974).  (Ger.)

Chow T, Earl J, Reeds J, Hansen N, land Orphan V, 1978.  Barium content of marine
sediments near drilling sites:  A potent pollutant indicator.   Marine Pollution
Bulletin.  9:97-99.

Clary JJ,.and Tardiff RG, 1974.  The absorption, distribution and excretion of
orally administered 133-Bad., in weanling male rats.  Toxicol. Appl.  Pharmacol.
27:139.

Gardiner H and Miller RE, 1973.  Barium peritonities.  Am. J.  Surgery 125:350-352.

Gould DB, Sortell MB and Lupariello AD.  1973.  Barium sulfide poisoning.  Arch.
Jut. Med. 132:891-894.

Guthrie RK, Ernst M, Cherry D, Murray H, 1979.  Biomagnification of heavy metals
by organisms in a marine microcosm.  Bull. Environm. Contam. Toxicol. 21:53-61.

Jauernig RA and Moulds RFJ.  1978.  A human arterial preparation for  studying the
effects of vasoactive-agents.  Circ. Res. 42:363-358.

Kirkpatrick T. 1978.  Sarium Compounds In. Kirk-Othmer1s Encyclopedia  of
Chemical Technology, 3rd edition.  John Wiley and Sons, Inc.  New York. 3:463-479.

Kunesh CJ.  1978.  Barium In Kirk-Othmer's Encyclopedia of Chemical Technology,
3rd edition.  John Wiley and Sons, Inc.  New York.  3:458-463.

NAPCA.  1969.  Air Pollution Aspects of Barium and Its Compounds.  National
Air Pollution Control Administration.  PB  188 083.

Patty FA, Ed.  1963.  Industrial Hygiene and Toxicology.  Vol II.  Toxicology.
2nd Edition.  Interscience Publishers, New York;  pp. 998-1002.

Peach MJ.  1975.  Cations:  Calcium, Magnesium, Barium, Lithium and Ammonium.
In:  The Pharmaceutical Basis of Therapeutics.  Goodman LS and Oilman A, Eds.
MacMillan Publishing Co., Inc.  New York, pp. 791.

Rae.T, 1977.  Tolerance of mouse macrophages in vitro to barium sulfate used in
orthopedic bone cement.  Biomed.  Mater. Res.  11:839-646.

U.S. Dept, of Labor.  General Industry Standards Table Z-l.  29 CFR 1910:1000.

U.S. EPA 1972.  National Inventory of Sources and Emissions - Barium, Baron,
Copper, Selenium, and Zinc  1969-Barium Section I.  PB 210 676.
                                                                     9
U.S. EPA 1973.  Water Quality Criteria  1972.  EPA-R-373-033.

-------
                                    No.  14
         Benzal Chloride

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

          APRIL 30,  1980
           a-/

-------
                                       No.  14
          Benzal Chloride

  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.

-------
                                BENZAL CHLORIDE
                                    Summary

     Benzal chloride  has  been reported to induce papillomas, carcinomas, and
leukemia in mice.  Details of this work were not available for assessment.
     Mutagenic  effects of  benzal chloride  exposure  have  been  reported in
Salmonella, Bacillus,  and £_._ coll.
     There is no  available  information on the teratogenic or adverse repro-
ductive effects of the compound.

-------
I.   INTRODUCTION
     Benzal  chloride,  CAS registry number  98-87-3,  is a  fuming,  highly re-
fractive,  colorless liquid.   It  is  made  by free  radical  chlorination  of
toluene  and has  the following  physical  and chemical  properties  (Windholz,
1976; Verschueren, 1977):

              Formula:                   C7H6C12
              Molecular Weight:          161.03
              Melting Point:             -16°C
              Boiling Point:             207°C
              Density:                   1.25614
              Vapor Pressure:            0.3 torr ® 20°C
              Solubility:                alcohol, ether
                                         insoluble in water
     Benzal chloride is  used almost exclusively for the manufacture  of ben-
zaldehyde.  It can  also  be used to prepare  cinnamic  acid  and benzoyl chlor-
ide (Sidi, 1971).
II.  EXPOSURE
     A.   Water
          Benzal chloride  is  converted  to benzaldehyde  and hydrochloric acid
on contact with water (Sidi, 1971).
     B.   Food
          Pertinent data could not be located in the available literature.
     C.   Inhalation
          It is likely that  the  only  source  of benzal chloride in  the air  is
production  facilities.   The  compound  will   hydrolyze  in moist  air to  give
benzaldehyde and  hydrochloric acid.   Inhaled benzal chloride will  probably
produce effects similar to those of inhaled  hydrogen chloride.
                                                                       »
     D.   Dermal
          Benzal chloride is irritating to the skin (Sidi,  1971).

-------
 III. PHARMACOKINETICS
     Pertinent  data on the pharmacokinetics of  benzal  chloride could not be
 located  in the  available literature.
 IV.  EFFECTS
     A.   Carcinogenicity
          In  a study  of Matsushita,  et al.  (1975)  benzal  chloride,  along
 with several  other compounds, was found  to  induce carcinomas,  leukemia, and
 papillomas in mice.  The details of  the study were not available, but benzal
                                                  \
 chloride was  shown to  possess a  longer  latency  period  than benzotrichloride
 before the onset of harmful effects.
     8.   Mutagenicity
          Yasuo, et al.  (1978) tested the mutagenicity of several compounds
 including benzal chloride  in microbial assay systems which  include the rec-
 assay  using  Bacillus subtilis,  the  reversion assay  using E_._  coli,  and the
 Ames assay using  Salmonella  typhimurium, with  or without metabolic activa-
 tion.  Benzal chloride was  positive  in the  rsc-assay without activation and
 in  the reversion  assays  using  S^ typhimurium  and §_._ coli with  metabolic
 activation.
     C.   Teratogenicity, Other Reproductive Effects and Chronic Toxicity
          Pertinent data could not be located in the available literature.
     D.   Acute Toxicity
          The oral  LD^'s  for mice and  rats exposed to benzal chloride are
2,462 mg/kg and 3,249 mg/kg, respectively (NIOSH, 1978).
V.   AQUATIC TOXICITY
     Pertinent  aquatic toxicity  data could  not  be located in  the  available
literature.

-------
VI.  EXISTING GUIDELINES AND STANDARDS
     There are no  existing  guidelines or standards  for  exposure to benzal
chloride.
                                  IV-<

-------
                                  REFERENCES


Matsushito, H., et al.  1975.  Carcinogenicities of the related compounds  in
benzoyl chloride production.  49th Annual Meeting Japan Ind. Hyg. Soc.,  Sap-
pro, Japan,  p. 252.

National  Institute  for Occupational Safety and  Health.   1978.   Registry  of
Toxic Effects of Chemical Substances.   NIOSH,  OHEW Publ. No.  79-100.

Sidi, H.  1971.  Benzyl Chloride, Benzal Chloride and Benzotrichloride.  In;
Kirk-Othmer Encyclopedia of Chemical Technology,  2nd ed.  Vol. 5, John Wiley
and Sons, New York.   p. 281.

Verschueren, K.  1977.  Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York.   p.  127.

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

Yasuo, K.,  et  al.  1978.   Mutagenicity of benzotrichloride and related  com-
pounds.  Mutation Research  58:  143.
                             >¥-7

-------
                                    No. 15
             Benzene
  Health  and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON,' D.C.   20460

          APRIL 30, 1980
         is-i

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

-------
                       SPECIAL NOTATION









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



benzene and has found sufficient evidence to indicate that



this compound is carcinogenic.
                          IS-*

-------
                                    BENZENE -
                                    Summary

     Benzene  is a  widely  used  chemical.   Chronic  exposure  to it  causes
hematological  abnormalities.    Benzene  is  not  mutagenic  to  bacteria,  but
recent evidence  shows  it. to be carcinogenic, in animals.   Also,  benzene has
been shown to  be leukemogenic  in humans.  There is  suggestive evidence that
benzene may be teratogenic and may cause reduced fertility.
     Benzene has been shown to  be acutely toxic to  aquatic organisms  over a
concentration  range of  5,800  to 495,000 pg/l.   The  marine fish striped bass
was the most sensitive species tested.

-------
                                    BENZENE .
I.  INTRODUCTION
     This profile is based on  the  draft Ambient Water Quality Criteria Docu-
ment for Benzene (U.S.  EPA, 1979).
     Benzene  (Benzol CgHg;  molecular  weight  78.1)  is  a  volatile,  color-
less,  liquid hydrocarbon  produced principally  from  coal  tar distillation,
from petroleum  by catalytic  reforming  of light naphthas, and  in  coal pro-
cessing and coal coking operations (Weast, 1972; Ayers  and Muder, 1964; U.S.
EPA, 1976a).   Benzene has a  boiling point  of -80.10C,  a melting  point of
5.5°C,   a.  water  solubility  of  1,780  mg/1  at  25°C,  and  a  density  of
0.87865  g/ml  at 20°C.   The  broad  utility  spectrum of benzene  includes its
use  as:   an intermediate  for synthesis in  the chemical  and pharmaceutical
industries, a  thinner  for lacquer,  a degreasing and cleaning agent,  a sol-
vent in  the  rubber  industry, an antiknock  fuel additive,  a general solvent
in  laboratories  and in the  preparation and  use of inks  in the graphic arts
industries.
     Current production of benzene in the U.S.  is over 4 million metric tons
annually,  and  its  use  is expected to  increase when  additional production
facilities become available (Fick,  1976).
II.  EXPOSURE
     A.  Water
         A  report  by  the  National  Cancer   Institute  (1977)  noted benzene
levels of  0.1. to 0.3  ppb in  four U.S. city drinking water  supplies.   One
measurement  from a  groundwater  well in Jacksonville,  Florida showed levels
higher than 100 ppb.  One  possible source of benzene  in the aquatic environ-
                                                                      »
ment is  from cyclings  between the  atmosphere  and water  (U.S.  EPA, 1976b).
Concentrations  of   benzene   upstream  and    downstream   from   five  benzene

-------
production or consumption plants ranged  from  less  than 1.0 to 13.0 ppb,  with
an average of 4.0 ppb (U.S.  EPA,  1977a).
     B.  Food
         Benzene  has been  detected  in  various  food categories:   fruits,
nuts,  vegetables,  dairy products,  meat,  fish,  poultry,  eggs,  and  several
beverages  (Natl.  Cancer  Inst.,   1977).    NCI  estimated  that an  individual
might  ingest  as  much as 250  ug/day from  these  foods.  The U.S.  EPA  (1979)
has  estimated the weighted  average bioconcentration  factor of benzene  for
the  edible  portion  of fish and  shellfish consumed by  Americans to be  6.9.
This estimate is based on the octanol/water partition coefficient of benzene.
     C.  Inhalation
         The respiratory route is the major source of human exposure to ben-
zene, and much of this exposure  is  by  way of gasoline  vapors  and  automotive
emissions.  American gasolines contain, an  average  of  0.8 percent benzene (by
weight) (Goldstein,  1977a), and  automotive exhausts contain an  average  of 4
percent benzene  (by weight)  (Howard and  Durkin,  1974).   Concentrations  cf
benzene in the ambient air of gas stations have  been found to be  0.3  to 2.4
ppm  (Natl.  Acad.  Sci/Natl.  Res.   Council,  1977).   Lonneman and  coworkers.
(1968) measured  an average concentration  of 0.015  ppm  in Los Angeles  air
with  a maximum of  0.057 ppm.   The rural background  level for benzene  has
been reported as 0.017 ppb (Cleland  and Kingsbury,  1977).
III. PHARMACOKINETICS
     A.  Absorption
         The  respiratory  absorption of  benzene  by humans  has been  measured
several times .and found to be 40 to 50 percent retained on  exposures  to  110
ppm  or less  (Srbova,  et al.  1950;  Teisinger, at al.  1952;  Hunter  and Blair,
1972; Nomiyama and Nomiyama,  1974).  Absorption was  slightly less  efficient,
                                 Iff

-------
28  to  34  percent,  on  exposure  to  6,000  ppm  (Duvoir,  et  al.  1946).
Deichmann, et al. (1963) demonstrated  that  rats  exposed  to benzene (44 to 47
ppm)  for  long periods  of time maintained  blood benzene  levels  of approxi-
mately 4.25 mg/1.
     B.  Distribution
         Free  benzene  accumulates  in  lipid  tissue  such  as  fat  and  bone
marrow, and  benzene metabolites accumulate  in liver tissue  and  bone marrow
(U.S. EPA, 1977b).
     C.  Metabolism
         Benzene is metabolized by  the mixed-function oxidase system to pro-
duce the highly  reactive  arene  oxide  (Rusch, et al.  1977).   Arene oxide can
spontaneously rearrange to  form phenol,, undergo enzymatic hydration followed
by  dehydrogenation  to  form catechol  or a  glutathione  derivative,  or  bind
covalently  with  cellular macromolecules.   Evidence  has accumulated  that a
metabolite of benzene is  responsible  for benzene  toxicity,  in light  of the
fact  that  a protection  from benzene  toxicity is afforded  by  inhibitors of
benzene metabolism  (Nomiyama,  1964;  Andrews,  et  al.  1977).  The specific
metabolite  that  produces  benzene toxicity  has not yet  been identified, but
likely candidates are benzene oxide,  catechol, and hydroquinone,  or the cor-
responding semiquinones (U.S. EPA, 1977b).
     0.  Excretion
         Phenol  measurement  (free  plus combined) of  the  urine  of human vol-
unteers indicated that 50 to 87 percent of  the retained  benzene was excreted
as phenol (Hunter and Blair,  1972).   The highest concentration of phenol was
found  in the  urine  within  about 3  hours  .from  termination  of  exposure.
Elimination via  the lungs was no more than 12 percent of the  retained 'dose.

-------
IV.  EFFECTS
     A.  Carcinogenicity
         On subcutaneous,  dermal,  oral, and inhalation  exposure  of rats and
mice  to  benzene, animal  experiments have  failed to  support the  view that
benzene  is leukemogenic  (U.S.  EPA,  1979).   Recent evidence  suggests, how-
ever,  that benzene  is an  animal  carcinogen  (Maltoni and  Scarnato,   1579).
The evidence  that  benzene is a leukemogen  for man is  convincing and has re-
cently been reviewed  by  the Natl.  Acad. Sci./Natl.  Res.  Coun. (1976), Natl.
Inst.  Occup.  Safety and  Health  (1977), and U.S.'- EPA  (1977b).  Vigliani and
Saita  (1964)  calculated  a 20-fold higher  risk of acute  leukemia in workers
in  northern  Italy  exposed to benzene.  In some studies of  acute leukemia
where  benzene exposure levels have been  reported,  the  concentrations have
generally been above  100  ppm  (Aksoy, et al. 1972, 1974a,b, 1976a,b; Vigliani
and Fourni, 1976;  Vigliani and  Saita,  1964; Kinoshita,  et al. 1965; Sellyei
and  Kelemen,  1971).   However,  other  studies  have  shown an  association  of
leukemic evidence to benzene levels  less than  100 ppm  (Infante et al., 1977;
Ott et al., 1978).
     8.  Mutagenicity
         Benzene    has    not    shown    mutagenic    activity    in    the
Salmonella/microsome in vitro bioassay  (Lyon,  1975;  Shahin,  1977; Simmon,  et
al. 1977).
     C.  Teratogenicity
         With rats  exposed to 100  to 2,200 ppm benzene during days  6 to 15
of  gestation  some  skeletal deformities  were  observed  in their  offspring
(Amer. Pet.  Inst.,  1978).  Pregnant mice  given  single  subcutaneous  injec-
tions  of  benzene (3 ml/kg) on  days 11 to  15  of  gestation  produced .fetuses

-------
with cleft palates, agnathia, and microagnathia, when  delivered  by  caesarean
section on day 19 (Watanabe and  Yashida,  1970).
     D.  Other Reproductive Effects
         Gofmekler (1968) found complete absence of pregnancy  in female  rats
exposed continuously to 209.7 ppm benzene for 10 to 15 days  prior to  impreg-
nation.  One  of ten  rats exposed to  19.8 ppm  exhibited  resorption of  em-
bryos.  The number of offspring per female exhibited an  inverse  relationship
to benzene exposure levels from  0.3 to 209.7  ppm.
     E.  Chronic Toxicity
         In humans,  pancytopenia  (reduction of  blood erythrocytes,  leuko-
cytes, and platelets)  has clearly been  related  to chronic  benzene  exposure
(Browning,  1965;  Goldstein,  1977b;  Intl.  Labour Off.,  1968;  Snyder  and
Kocsis, 1975)..   Also,  impairment of  the immunological  system has  been  re-
ported with  chronic benzene  exposure  (Lange,  et  al.  1973a; Smolik, et  al.
1973).  Wolf,  et  al.  (1956) reported  that  the  no-effect  level for  blood
changes in rats,  guinea pigs,. and rabbits was below  88 ppm in  the air  when
the animals were exposed for 7 hours per day  for  up to  269  days.
     F.  Other Relevant Information
         In rabbits and rats  injected subcutaneously with  0.2  mg/kg/day  ben-
zene, the  frequency of  bone marrow mitosis with chromosomal aberrations  in-
creased  from  5.9  percent  to 57.8  percent after an  average  of  18  weeks
(Kissling and  Speck,  1971;.  Dobrokhotov,  1972).    In patients  with  benzene
induced  aplastic  anemia,   lymphocyte   chromosome damage,  i.e.,   abnormal
karyo-type and deletion of chromosomal material, has been  found  (Pollini  and
Cdlombi,  1964).
                                   is-f

-------
V.   AQUATIC TOXICITY
     A.  Acute
         Acute  toxicity  values  for  freshwater  fish  are  represented  by
96-hour  static  LC5Q  values  of  20,000  to 22,490  ug/1  for  the  bluegill,
Lepomis macrochirus, to  386,000 ug/1  for the mosquitofish, Gambusia affinis,.
with goldfish,  Carassius auratus, fathead  minnows,  Pimephales promelas, and	
guppies, Poecilia reticulatius, being  somewhat  more  resistant than the blue-
gill (U.S.  EPA,  1979).  Only  one study was available  for the acute effects
of  benzene to  freshwater  invertebrates.   A  48^hour  static  LC^  value  of
203,000 jug/1  was obtained  for the  cladoceran  Daphnia magna.   LCeg values
for marine fish were  reported as 5,800 and 10,900  ug/1 for  striped  bass,
Morone  saxatilis.  and  20,000 to 25,000 ^ig/1  for  Pacific  herring,  Clupea
pallasi, and  anchovy,  Engraulis  mordax, larvae.  Marine  invertebrates were
much more  resistant with LC^ values of 27,000, 108,000,  and 450,000 ^ig/1
reported  for  grass  shrimp,  Palaemonetes  pugio,  dungeness  crab,  Cancer
tnaqister,  and  the  copepod,  Tiqricopus californicus.  respectively (U.S. EPA,
1979).
     8.  Chronic Toxicity
         The only chronic toxicity  test conducted on an aquatic species was
performed  on  the freshwater  cladoceran, Daphnia  magna.   There  were  no ob-
served effects  to these organisms at concentrations  as high as 98,000 ug/1.
Pertinent  information  of the chronic effects  of benzene  on  marine  fish and
invertebrates could not be located in the available literature.
     C.  Plant Effects
         A  concentration of 525,000 jug/1 was  responsible for a  50 percent
reduction  in  ceil numbers  at 48-hours  for the  freshwater  algae,  Chlorella
vulqaris,  while  marine plants were  reported as having  growth inhibition at

-------
concentrations  ranging   from  20,000  to • 100,000  /jg/1   for  the  diatom,
Skeletonema costatum, with the dinoflagellate,  Amohidinium  carterae,  and the
algae, Cricosohaera  carterae,  being intermediate  in  sensitivity with effec-
tive concentrations of 50,000 jug/1.
     D.  Residues
         A bioconcentration  factor of 24  was  obtained for organisms  with a
lipid content of 8 percent.
VI..  EXISTING GUIDELINES AND STANDARDS
     Neither  the   human  health  nor  aquatic  criteria  derived  by U.S.  EPA
(1979) which  are  summarized below  have  gone through  the process  of public
review;  therefore,  there is  a  possibility  that  these  criteria will  be
changed.
     A.  Human
         Existing  air standards  for occupational.exposure to benzene include
10 -ppm,  an  emergency  temporary  level of 1 ppm by  the  U.S.  Occupational
Safety and Health  Administration (Natl.   Inst.  Occup. Safety  Health,  1974,
1977), and 25  ppm  by  the  American Conference  of Governmental   Industrial
Hygienists  (ACGIH, 1971).   Based on  human  epidemiology data,  and  using a.
modified "one-hit" model,  the  EPA (1979)  has estimated levels  of benzene in
ambient water which will result in specified risk levels of human cancer:

Exposure Assumptions           Risk Levels and Corresponding Draft Criteria
     (per day)
                               0            10-7        10-6         10-5
2 liters of drinking water     0          0.15 jug/1   1.5 pg/1      15 pg/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and        0          2.5jug/l    25 pg/1      250 /jg/1
shellfish only.

-------
     8.  Aquatic
         Criterion  for  the  protection of  freshwater  organisms  have  been
drafted at 3,100 ug/1 as a  24-hour  average concentration not to exceed 7,000
jjg/1.  For marine  organisms criterion have been drafted as a 24-hour average
concentration of 920 pg/1 not to exceed 2,100 ug/1.

-------
                                    BENZENE .
                                  REFERENCES
ACGIH.   1971.   Threshold limit values.   American Conference of Governmental
Industrial Hygienists.  Cincinnati, Ohio.
Aksoy, M., et  al.   1972.   Acute leukemia due to chronic exposure to benzene.
Am. Jour. Med.  52: 160.
Aksoy,  M.,   et al.   1974a.   Acute leukemia  in  two  generations  following
chronic exposure to benzene..  Hum. Hered.  24: 70.
Aksoy, M.,  et al.  1974b.   Leukemia in  shoe  workers exposed chronically to
benzene.  Blood  44: 837.
                                                 ».
Aksoy, M.,  et  al.   1976a.  Combination  of genetic factors and chronic expo-
sure to benzene in the aetiology of leukemia.  Hum. Hered.  26: 149.
Aksoy, M..,  et al.  1976b.   Types of leukemia  in chronic benzene poisoning.
A study in- thirty-four patients.  Acta Haematologica  55: 65.
American  Petroleum Institute.    1978.   Table . 6  in  Submission  to Environ.
Health Comm. of the Sci.  Advis. Board,  U.S.  Environ.  Prot. Agency.   Jan. 13,
1978.
Andrews,. L.S., et al.   1977... Biochem. Jour.  26:  293.
Ayers, G.W.,  and R.E.  Muder.   1964.   Kirk-Othmer encyclopedia  of chemical
technology.  2nd ed.  John Wiley and Sons, Inc., New  York.
Browning, E.   1965.   Benzene.   In:  Toxicity  and metabolism  of industrial
solvents.  Elsevier Publishing Co., Amsterdam.
Cleland,  J.G., and G.L.  Kingsbury.   1977.   Multimedia, environmental goals
for  environmental  assessment.    EPA  600/7-77-136.    U.S.  Environ.  Prot.
Agency, Washington, O.C.
Oeichmann, W.B.,  et al.   1963.   The hemopoietic  tissue  toxicity of benzene
vapors.  Toxicol. Appl. Pharmacol.  5: 201.
Dobrokhotov,  v.B.   1972.   The mutagenic influence  of benzene  and  toluene
under experimental conditions.  Gig. Sanit.  37: 36.
Duvoir, M.R.,  et  al.   1946.  The significance  of benzene in the bone marrow
in the course of.benzene blood.diseases.  Arch. Mai.  Prof.  7: 77.
Fick,  J.E.   1976.. To 1985:  U.S.  benzene  supply/demand.   Hydrocarbon Pro-
cessing.  55: 127.
Gofmekler, V.A.   1968.   Effect in embryonic development  of benzene and for-
maldehyde.  Hyg. Sanit.  33: 327.

-------
Goldstein,  B.D.   1977a.   Introduction  (Benzene toxicity:  Critical review).
Jour. Toxicol. Environ. Health Suppl.  2: 1.

Goldstein,  G.D.   1977b.  Hematotoxicity in  humans.   Jour.  Toxicol. Environ.
Health Suppl.  2: 69.

Howard,  P.H., and  P.R.  Durkin.   1974.   Sources  of  contamination,  ambient
levels,  and  fate of benzene  in  the environment.   EPA  560/5-75-005.   U.S.
Environ. Prot. Agency, Washington, O.C.

Hunter,  C.G., and  0.  Blair.   1972.   Benzene:   Pharmakokinetic  studies  in
man.  Ann. Occup. Hyg.  15: 193.

Infante, P.I., et al.  1977.  Leukemia in benzene workers.  Lancet.  2: 76.

International Labour  Office.   1968.   Benzene:  Uses,  toxic effects,  substi-
tutes.  Occup. Safety Health Ser.,  Geneva.      v

Kinoshita,  Y., et al..  1965.  A  case of myelogenous  leukemia.   Jour.  Japan
Haematol. Soe.  1965: 85.

Kissling, M.,  and B. Speck.   1971.   Chromosomal aberrations in experimental
benzene intoxication.  Helv. Med.  Acta.   36: 59.

Lange, A.,  et al.   1973.   Serum  immunoglobulin levels in workers exposed to
benzene, toluene and xylene.  Int. Arch. Arbeitsmed.  31: 37.

Lonneman, W.A.,  et  al.   1968.   Aromatic  hydrocarbons in  the  atmosphere  of
the Los Angeles basin.  Environ. Sci. Technol.  2:  1017.

Lyon,  J.P.    1975.    Mutagenicity   studies  with   benzene.   Ph.D.  thesis.
University of California.

Maltoni, C. and C. Scarnato.  1979.   LaMedicina del Lavoro.  70(5): 352.

National Academy  of Sciences/National  Research  Council.   1976.   Health  ef-
fects of benzene: A review.  Natl. Acad. Sci., Washington, D.C.

National  Academy of  Sciences/National  Research Council.   1977.   Drinking
water and health.  Natl. Acad. Sci., Washington, D.C.

National Cancer  Institute.   1977.  On  occurrence,  metabolism,  and toxicity
including  reported  carcinogenicity  of   benzene.   Summary  rep.   Washington,
D.C.

National Institute of Occupational Safety  and Health.   1974.  Criteria for a
recommended standard.   Occupational  exposure  to benzene.  U.S.  Dep.  Health
Edu. Welfare, Washington, O.C.

National.Institute of Occupational Safety  and Health.   1977.  Revised* recom-
mendation  for an occupational exposure standard  for  benzene.    U.S.  Dept.
Health Edu. Welfare, Washington, D.C.
                                  ff-'f '

-------
Nomiyama,. K.   1964.   Experimental  studies on benzene poisoning.  Bull. Tokyo
Med. Dental Univ.  11: 297.

Nomiyama,  K.,  and  H. Nomiyama.   1974a.   Respiratory retention,  uptake and
excretion of organic  solvents in man.  Int. Arch. Arbertsmed.  32: 75.

Ott, M.G., et  al.   1978.   Mortality among individuals occupationally exposed
to benzene.  Arch.. Environ. Health.  33: 3.

Pollini, G., and R.  Colombi.   1964.   Lymphocyte chromosome damage in benzene
blood dyscrasia.  Med. Lav.  55: 641.

Rusch,  G.M.,   et  al.   1977.   Benzene, metabolism.   Jour.  Toxicol.  Environ.
Health Suppl.  2: 23.

Sellyei,  M.,  and E.  Kelemen.   1971.  Chromosome  study  in a  case of granu-
locytic  leukemia with  "Pelgerisation' 7  years 'after benzene pancytopenia.
Eur. Jour. Cancer  7: 83.

Shahin,  M.M.'   1977.   Unpublished  results.   The  University  of  Alberta,
Canada.  Cited in Mutat. Res.  47: 75.

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

Smolik, R., et al.   1973.   Serum complement level in workers exposed to ben-
zene, toluene and xylene.  Int.. Arch. Arbeitsmed.  31: 243.

Snyder,  R.,  and J.J. Kocsis.   1975.   Current  concepts  of  chronic benzene
toxicity.  CRC Crit.  Rev. Toxicol.  3: 265.

Srbova, J., et al.   1950.  Absorption and elimination  of inhaled benzene in
man.  Arch. Ind. Hyg.  2: 1.

Teisinger, J.,  et  al.   1952.   The  metabolism of benzene  in man.  Procovni
Lekarstvi  4: 175.

U.S. EPA.  1976a.  Health effects  of benzene: A review.   U.S. Environ. Prot.
Agency, Washington, D.C.

U.S. EPA.   1976b.    Air  pollution  assessment  of benzene.  Contract  No.  EPA
68-02-1495.  Mitre Corp.

U.S. EPA.   1977a.   Sampling in  vicinity  of benzene  production and consump-
tion facilities.  Preliminary  report to Off.  Tox.  Subst.  Battelle-Columbus
Laboratories.

U.S. EPA.   1977b.    Benzene  health effects assessment.   U.S.  Envirorv Prot.
Agency, Washington, D.C.

U.S. EPA.   1978.   Environmental sources of benzene  exposure: source contri-
bution factors.  Contract No. 68-01-4635, Mitre Corp.

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

Vigliani, E.G.,  and A. Forni.   1976.   Benzene and  leukemia.   Environ. Res.
11: 122.

Vigliani, E.G.,  and- G.  Saita.   1964.   Benzene  and leukemia.   New England
Jour. Med.  271: 872.

Watanabe, G.I.,  and S. Yoshida.   1970.   The teratogenic  effects of benzene
in pregnant mice.  Act. Med. Biol.  19: 285.

Weast, R.C.   1972.   Handbook of chemistry  and  physics.   The Chemical Rubber
Co., Cleveland, Ohio.

Wolf, M.A.,  et al.  1956.   Toxicological  studies of certain  alkylated ben-
zenes and benzene.  Arch. Ind. Health  14: 387.

-------
                                    No. 16
            Benzldlne


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

          APRIL 30, 1980
           16-1

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

-------
                       SPECIAL NOTATION


U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
benzidine and has found sufficient evidence to indicate that
this compound is carcinogenic.

-------
                            BENZIDINE



                             Summary



     Benzidine is a known carcinogen and has been linked to an  in-



creased incidence of  bladder  cancer in humans  and  to cancers  and



tumors in experimental animals.   Benzidine  is mutagenic in  the Ames



assay and gives positive results in a test measuring DNA synthesis



inhibition in HeLa cells.



     Pertinent data could  not be located in --the available litera-



ture concerning  the toxic  effects of benzidine to  aquatic organ-



isms.

-------
                            BENZIDINE
I.    INTRODUCTION
     Benzidine  (4,4'-diaminobiphenyl)  is  an  aromatic  amine  with
a molecular weight of 184.24.  It exists at environmental tempera-
ture  as  a  grayish-yellow,   white,  or  reddish-gray  crystalline
powder.   Its melting  point   is  128°C,  and its  boiling  point  is
400°C.   Benzidine's  amino  groups  have  pKa  values  of  4.66  and
3.57  (Weast,  1972).   Two and one-half  liter's of cold  water  will
dissolve 1  g of benzidine, and  its  solubility  increases as water
temperatures  rise..   Dissolution  into   organic  solvents  greatly
increases solubility.   Benzidine is easily converted  to and  from
its. salt.  Diazotization reactions involving benzidine will result
in  colored  compounds  which   are  used  as  dyes  in  industry (U.S.
EPA, 1979} .
II.  EXPOSURE
     A.   Water
          Residential  water   supplies could  be  contaminated  with
benzidine and its derivatives if the industrial effluent contain-
ing these chemicals  were  discharged into water  supplies, however,
to date U.S. EPA (1979) finds no reports of such contamination.
     B.   Pood
          While- food may become contaminated with benzidine due to
poor industrial, hygiene,. U.S.  EPA (1979)  reports that the ingestion
of contaminated food.is not a real, contribution to benzidine toxi-
city.
                        16-S

-------
          The U.S.  EPA  (1979)  has  estimated a  weighted average
bioconcentration factor (BCF)  of 50  for benzidine, on octanol/water
partition coefficients and other factors.
     C.   Inhalation
          Due to poor  industrial  hygiene and the use of open sys-
tems in the early days of the chemical and dye industries, inhala-
tion was formerly a principal route of entry  for benzidine and  its
derivatives into the body.  At present workers wear respirators  and
protective  clothing  to  avoid  exposure  when cleaning  equipment
(Haley, 1975).
     0.   Dermal
          Skin absorption is.  the most important route for entry of
benzidine into the  body.   Intact  skin  is easily penetrated by  the
powdery benzidine base and  is penetrated less readily by 3,3'-di-
methoxybenzidine and  3,3.'-dichlorobenzidine.   High  environmental
air temperatures and  humidity increase  skin absorption  of benzi-
dine,1  3,3'-dimethoxybenzidine,  3,3'-dichlorobenzidine,  and  3,3'-
dimethylbenzidine (U.S. EPA,  1979).
III. PHARMACOKINETICS
     A.   Absorption and Distribution
          Benzidine is rapidly .absorbed  into the bodies of intra-
veneously  injected  rats,  with  maximum concentrations  of  free
and bound benzidine occurring at  two and  three hours, respectively.
The highest concentration of benzidine  was found  in  the  blood
followed by the  liver,  kidney, spleen, heart, and  lung (Soloimskaya,
1968) .   Four  hours  after rats received intraperitoneal injections
of  100  mg  benzidine/kg,  high concentrations  of  the  compound were
found  in  the stomach,  stomach  contents,   and   small  intestine;

-------
12 hours  after  administration,  benzidine  was found  in  the small
intestine and  its  contents.   Benzidine  levels in  the  liver,  the
target  organ  for  toxicity  in  the  rat,  remained  relatively high
and constant throughout the 12-hour period.  The conjugated material,
indicative  of   the  presence  of  metabolites,  was  high  in urine
and  tissues at  12  hours  (Baker and  Deighton,  1953) .    In rats
given 20  rag of 3,3 '-dimethylbenzidine subcutaneously once a week
for eight weeks, amines  were concentrated  in  the  Zymbal's gland,
followed  by the  kidney, omentum,  spleen,  «nd  liver  (Pliss  and
Zabezhinsky, 1970).
     B.    Metabolism and Excretion
          The urine of humans exposed to  benzidine  contained a num-
ber of metabolites:  N-hydroxyacetylamino benzidine,  3-hydroxyben-
zidine,   4-amino-4-oxybiphenyl,  and  mono-  and  diacetylbenzidine
(Engelbertz and Babel,.  1953;  Troll,  et  al.  1963;  Sciarini  and
Meigs,  1961; Vigliani  and  Barsotti, 1962).  Benzidine metabolites
in other  species  generally  differ  considerably  from  those   in
humans,   although  3-hydroxybenzidine and its conjugation products
are common  to both animals and humans  (Haley,  1975).
          The  half-life  of  benzidine in  blood  was  68  hours  for
the rat  and 88 hours  for  the dog.   Rats,  dogs,  and monkeys  ex-
creted  97,  96,  and  83  percent,   respectively,  within  one week
of an  0.2  rag/kg dose  of  benzidine.    The  respective  excretion
rates  for  3,3'-dichlorobenzidine  were  98,  97,   88.5  percent.
Dogs and monkeys excreted free benzidine  in the urine  and dichloro-
                                                              •
benzidine  in   the  bile  while  rats excreted  both  compounds  via
the bile  (Kellner, et al. 1973).

-------
          Workers  exposed  to  benzidine,  who perspire  freely and
have wet skin, contain a higher  concentration of benzidine in the
urine (U.S. EPA, 1979).                                    •        •
IV.  EFFECTS
     A.    Carcinogenicity
          Benzidine is a proven human carcinogen.  Its primary site
of tumor induction is the urinary bladder  (U.S.  EPA, 1979).
          Workers exposed to benzidine have a carcinogenicity risk
14 times higher than that of  the  unexposed  population  (Case, et al.
1954).   The incidence of bladder  tumors  in humans resulting from
occupational exposures to aromatic  amines  (benzidine) was  first re-
searched in Germany in 1895.   In  the  United States,  the  first cases
of this condition were: diagnosed in  1931 and reported in  1934.
          A number of studies document the  high  incidence of blad-
der  tumors in  workers  exposed  to  benzidine  and  other  aromatic
amines  (Gehrman,  1936;  Case, et al.  1954; Scott, 1952;  Deichmann
and  Gerarde,  1969;  Hamblin,  1963; Rye,  et al.  1970;  Int. Agency
Res. Cancer,  1972;  Riches,  1972;  Sax,  1975;  Zavon,  et al.  1973;
Mancuso and El-Attar, 1966, 1967; Kuzelova, et al. 1969;  Billiard-
Duchesne,  1960;  Vigliani and Barsotti, 1962;  Forni,  et  al.  1972;
Tsuchiya, et al.  1975; Goldwater,  et al.  1965).   Initial exposure
concentration, exposure  duration,  and years of  survival  following
exposure as well  as work habits  and  personal hygiene are involved
in the development of carcinomas where benzidine appears  to be im-
plicated (Rye, et al. 1970).
          Benzidine  has  also  produced   carcinogenic   effects  or
                                                              »
tumors  in  the  mouse  (hepatoma,  lymphoma),  the  rat  (hepatoma,

-------
carcinoma of  the  Zymbal's gland, adenocarcinoma, sarcoma, mammary
gland  carcinoma),  the  hamster  (hepatoma, liver  carcinoma,  chol-
angioma),  the  rabbit  (bladder  tumor,  gall  bladder  tumor)  and
the dog (bladder tumor)  (Haley, 1975).
          At present, there is no evidence indicating  that 3,3'-di-
methylbenzidine,  3,3'-dimethoxybenzidine, or  3,3'-dichlorobenzi-
dine are human bladder carcinogens  (Rye,  et al. 1970).
     B.   Mutagenicity
          In  the  Ames test, benzidine  is mutagenic to Salmonella
typhimurium strains  TA1537, TA1538,  and TA98.   Benzidine produces
positive  results  in  a DNA synthesis inhibition test  using HeLa
cells  (Ames, et al.  1973;  McCann, et al. 1975;  Garner,  et al.  1975;
U.S. EPA, 1978; U.S. EPA, 1979).
     C.   Teratogenicity
          No teratogenic effects of benzidine have been  reported  in
humans.  Mammary gland tumors  and lung adenomas occurred in progeny
of  female mice  that received  8 to 10 mg  of 3,3'-dimethylbenzidine
in.  the  last week  of pregnancy.   The tumors may have  resulted from
transplacental transmission of the chemical or from  its  transfer  to
neonates in milk from dosed mothers  (Golub, et al.  1974).
     D.   Other Reprodutive Effects
          Pertinent  data could  not  be  located   in  the available
literature.
     E.   Chronic Toxicity
          Glomerulonephritis  and  nephrotic syndrome were produced
in  Sprague-Dawley rats  fed 0.043 percent  N,N' -diacetylbenzidin-e,  a
metabolite  of  benzidine, for  at  least  two months (Harman,  et al.
1952; Harman, 1971).  Glomerulonephritis also  developed  in rats fed

                                if

-------
benzidine (Christopher and Jairam,  1970),  and  in rats receiving in-
jections either 100 mg  subcutaneously or  100 or  200  mg intraper-
tioneally of N,N'-diacetylbenzidine.   The severity of the lesions
in the later study was dose-related (Bremner and Tange, 1966).
          Mice fed 0.01 and 0.08 percent benzidine dihydrochloride
exhibited decreased carcass, liver, and kidney  weights, increased
spleen and  thymus weights,  cloudy  swelling  of the liver,  vacuolar
degeneration of the renal  tubules, and hyperplasia of the myeloid
elements in the bone marrow and  of  the lymphoid cells in the spleen
                                            \
and thymic  cortex.  There was  a dose dependent weight loss  of 20
percent in males and 7 percent in females  (Rao,  et al. 1971).
     P.   Other Relevant Information
          Dermatitis,   involving  both  benzidine  and  its  dimethyl
derivative, has .been reported in workers in the benzidine dyestuff
industry.   Individual sensitivity  played  a large  role in the  de-
velopment of this condition (Schwartz, et  al. 1947).
V.   AQUATIC TOXICITY
     Pertinent data could  not be  located  in the available litera-
ture concerning the toxic effects of benzidine  to aquatic organisms.
VI.  EXISTING GUIDELINES AND STANDARDS
     Both  the  human  health and  aquatic  criteria  derived  by  U.S.
EPA (1979), which are summarized below, have  not  yet gone through
the process of public  review;  therefore,  there  is  a possibility
that these criteria may be changed.
A.   Human
                                                             •
          The  ambient water concentration  standard  for benzidine
is  zero,  due  to  potential  carcinogenic  effects  of  exposure  to
                             16-10

-------
benzidine by ingestion of water  and contaminated aquatic organisms.
U.S. EPA  may set  standards at  an  interim  target  risk  level in
the  range  of IQ~^,  10,  or  10   with  respective  corresponding'
criteria of 1.67 x 10~3 ug/1, 1.67 x 10~4, and 1.67 x 10~5 ug/1.
     B.   Aquatic
          Criteria  for  the protection  of  freshwater  or  marine
aquatic organisms were not drafted, due to a lack of toxicological
evidence (U.S. EPA, 1979).
                             It'll

-------
                                BENZIDINE

                                REFERENCES

Ames, B. et al.  1973-  Carcinogens are mutagens:  A simple test system
combining liver homogenates for activation and bacteria for detection.
Proc. Natl. Acad. Sci. 70: 2281

Baker, R.K.,  and J.G. Deighton.  1953.  The metabolism of benzidine in
the rat.  Cancer Res. 13:  529.

Billiard-Buchesne, J.L.   1960.  Cas Francais de tumeurs professionelles
de la vessie.  Acta Unio  Int. Contra Cancruzn (Belgium) 16:  284.

Bremner, D.A., and J. D.  Tange.  1966.  Renal and neoplastic lesions
after injection of N,N'-diacetylbenzidine.  Arch. Pathol. 81:   146.

Case, R.A.M., et al.  1954.  Tumours of the urinary bladder in workmen
engaged in the manufacture and use of certain dyestuff intermediates in
the British chemical  industry:  Part I.   The role of aniline, benzidine,
alpha-naphthylamine and beta-naphthylamine.  Br. Jour. Ind. Med. 11:  75.

Christopher,  K.J., and B.T. Jairam.  1970.  Benzidine
poisoning in white rats.  Sci. Cult. (India) 36:  511.

Deichmann, W.B., and  H.W. Gerarde.  1969.  Toxicology of drugs  and chemicals.
Academic Press, New York.

Englebertz, P., and E. Babel.   1953.  Nachweis von benzidin und seinen
umwand. lungs produkten im harn und in organteilen.  Zentr. Arbeitsmed.
Arbeitsschutz 3:  161.

Forni, A., et al.  1972.  Urinary cytology in workers exposed to carcinogenic
aromatic amines:  A six-year study.  Acta Cytol. 16:  142.

Garner, et al.  1975-  Testing of some benzidine anologies for  microsomal
activation to bacterial mutagens.  Cancer Let. 1:  39-

Gehrman, G.H.  1936.  Papilloma and carcinoma of the bladder in dye workers.
Jour. Am. Med. Assoc.  107:   1436.

Goldwater, L.J., et al.   1965.  Bladder tumors in a coal tar dye plant.
Arch. Environ. Health 11:  814.

Golub, N.I.,  et al.   1974.  Oncogenic action of some nitrogen compounds
on the progeny of experimental mice.  Bull. Exp. Biol. Med. (USSR) 78:
1402.

Haley, T.J.  1975.  Benzidine revisited:  A review of the literature and
problems associated with  the use of benzidine and its congeners.  Clin.
Toxicol.  8:  13.

-------
Hamblin, D.O.  1963-  Aromatic nitro and amino compounds.  Page 2105 in
D.W. Fassett and D.D. Irish, eds.  Industrial hygiene and toxicology.
Vol. II.  Interscience Publishers, New York.

Harman, J.W.  1971.  Chronic glomerulonephritis and the nephrotic syndrome
induced in rats with M,N'-diacetylbenzidine.  Jour. Pathol. (Scotland)
104:  119.

Harraan, J.W., et al.  1952.  Chronic glomerulonephritis and nephrotic
syndrome induced in rats by M,N'-diacetylbenzidine.  Am. Jour. Pathol.
28:   529.

International Agency for Research on Cancer.  1972.  IARC monographs on
the evaluation of carcinogenic risk of chemicals to man.  Vol. I.  Lyon,
France.
                                                ^
Kellner, H .M., et al.  1973-  Animal, studies on the kinetics of
benzidine and 3,3'-dichlorobenzidine.  Arch. Toxicol. (West Germany)
31:   61.

Kuzelova, M., et al.  1969-  Sledovani pracovniku zamestnanych pri
vyrobe benzidinu.  Prac. Lek.  (Czechoslovika) 21:  310.

Mancuso, T.F., and A.A. El-Attar.  1966.  Cohort studies of workers
exposed to. betanaphthylamine and benzidine.  Ind. Med. Surg. 35:  571.

Mancuso, T.F., and A.A. El-Attar.  1967.  Cohort study of workers exposed
to betanaphthylamine and benzidine.  Jour.. Occup. Med. 9:  277.

McCann, J.,  et al.   1975.  Detection of carcinogens as. mutagens in the
Salmonella/microsome test:  Assay of 300 chemicals.  Proc. Natl. Acad.
Sci. 72:  5135.

Pliss, G.B., and M.A. Zabezhinsky.  1970.  Carcinogenic properties of
orthotolidine (3,3'-dimethylbenzidine).  Jour. Natl. Cancer Inst. 45:  283-

Rao, K.V.N., et al.  1971.  Subacute toxicity of benzidine in the young
adult mice.  Fed. Proc'. Am. Soc. Exp. Biol. 30:  344.

Riches, E.   1972.  Industrial cancers.  Nurs. Mirror (Great Br.) 134:  21.

Rye, W.A., et al.  1970.  Facts and myths concerning aromatic diamine
curing agents.  Jour. Occup. Med.  12:  211.

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

Schwartz, L. , et al..  1947.  Dermatitis in synthetic dye manufacture.
Page 268 in  Occupational diseases  of the skin.  Lea and Febiger, Philadelphia,
Pa.

-------
Sciarini, L.J., and J.W. Meigs.  1961.  The biotransformation of benzidine.
II.  Studies in mouse and man.  Arch. Environ. Health 2:  423.

Scott, T.S.  1952.  The incidence of bladder tumours in a dyestuffs  factory.
Br. Jour. Ind.  Med. 9:  127.

Soloimskaya, E.A.  1968.  The distribution of benzidine in rat organs and
its effect on the peripheral blood.  Vopr.. Onkol. (USSR) 14:  51.

Troll, W., et al.  1963-  N-hydroxy acetyl amino compounds, urinary  metabolites
of aromatic amines in man.  Proc. Am. Assoc. Cancer Res.  4:  68.

Tsuchiya, K., et al.  1975.  An epidemiological study of occupational
bladder tumours in the dye industry of Japan.  Br. Jour. Ind. Med. 32:
203.

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

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

Vigliani, E.G., and M. Barsotti.  1962.  Environmental tumors of the
bladder in some. Italian dyestuff factories.  Acta Unio Int. Contra Cancrum
(Belgium) 18:  669.

Weast, R.C., ed.  1972.  Handbood of chemistry and physics.  53rd ed. CRC
Press, Cleveland, Ohio.

Zavon, M.R., et al.  1973-  Benzidine exposure as a cause of bladder
tumors. Arch. Environ. Health 27:  1.

-------
                                     No.  17
         Benz(a)anthracene


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

          APRIL 30, 1980
         17-1

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

-------
                       SPECIAL NOTATION










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



benz(a)anthracene and has found sufficient evidence to indi-



cate that this compound is carcinogenic.

-------
                      BENZ(a)ANTHRACZNS
                           SUMMARY
     Benz(a)anthracene is a member of the polycyclic  aro-
matic hydrocarbons  (PAH)  class.  Although the PAH  class
contains several,well-known potent carcinogens,  benz(a)an-
thracene displays only weak carcinogenic activity.  Benz(a)-
anthracene apparently does not display remarkable  acute
or chronic toxicity other than the capability to induce
tumors on the skin of mice.  Although exposure  to  benz(a)-
anthracene in the environment occurs in conjunc'tion with
exposure to other PAH, it is not known how  these compounds
may interact in human systems.  Furthermore, the specific
effects of benz(a)anthracene in humans are  not  known.
     The only toxicity data for any of the  polycyclic aro-
matic hydrocarbons is an 87 percent mortality of freshwater
fish exposed to 1,000 ug/1 benz(a)anthracene for six  months.

-------
 I.    INTRODUCTION
      This profile is based primarily on the Ambient Water
 Quality Criteria Document for Polynuclear Aromatic Hydrocar-
 bons (U.S.  EPA,  1979a)  and the Multimedia Health Assessment
 Document for Polycyclic Organic Matter (U.S.  EPA, 1979b).
      Benz(a)anthracene  (CngH,-) is °ns °f the family of
 polycyclic aromatic hydrocarbons (PAH) formed as a result
 of  incomplete combustion of organic material.  Benz(a)anthra-
 cene has the following  physical/chemical properties (U.S.
 EPA, 1979b):
               Melting  point:      159.5-160.5°C
               Boiling  Point:      400°C    _?
               Vapor Pressue:      1.10  x 10    torr
      PAH, including benz(a)anthracene, are ubiquitous in
 the environment, being  found in ambient air,  food, water,
 soils,  and sediment (U.S.  EPA, 1979b) .  The PAH class con-
 tains a number of potent carcinogens (e.g., benzo(a)pyrene),
 weak carcinogens (e.g.,  benz(a)anthracene), and cocarcino-
 gens (e.g.,  fluoranthene), as well as numerous non-carcino-
 gens (U.S.  EPA,  1979b).
      PAH which contain  more than three rings  (such as benz(a)-
 anthracene)  are  relatively stable in the environment, and
 may be  transported in air  and water by adsorption to particu-
 late matter.  However,  biodegradation and chemical treatment
 are effective in eliminating most PAE in the  environment.
      The reader  is referred to the PAH Hazard Profile for
•a more  general discussion  of PAH (U.S. EPA, 1979c).
                         17-S

-------
II.  EXPOSURE
     A.   Water
          Benz(a)anthracene  levels  in  surface  waters  or
drinking water have not  been reported.   However,  the  concen-
tration of six representative PAH  (net  including  benz(a)-
anthracene)  in U.S. drinking water  averaged  13.5  ng/1 (Basu
and Saxena,  1977, 1978).
    - B.   Food
          Benz(a)anthracene  has been detected  in  a  wide
variety of foods  including margarine  (up to  29.5  ppb), smoked
fish (up to  1.7 ppb), yeast  (up to  2C3  ppb) , and  cooked
or smoked meat (up to 33.0 ppb)  (U.S. EPA,  1979a).  The
total intake of all types of PAH through the diet has been
estimated at 1.6  to 16 jag/day  (U.S. EPA, 1979b) .  The U.S.
EPA (1979a)  has estimated the bioconcer.tration  factor for
benz(a)anthracene to be  3,100 for the edible portions of
fish and shellfish consumed  by Americans.  This estimate
is based on  the octanol/water partition coefficient of benz-
(a)anthracene.
     C.    Inhalation
          Benz(a)anthracene  has been repeatedly detected
in ambient air at concentrations ranging from  0.18  to 4.5.
ng/m3" (U.S. EPA, 1979a) .  Thus, the hacan daily intake of
benz(a)anthracene by inhalation of  anbient air may  ber in
the range of 3.42 to 87.4 ng, assuming  that a  human breathes
19 m  of air per day.

-------
III. PHARMACOKINETICS
     There are no data available concerning the pharraaco-
kinetics of benz(a)anthracene, or other PAH,  in humans.
Nevertheless, it is possible to make limited  assumptions
based on the results of animal research conducted with sev-
eral PAH, particularly benzo(a)pyrene.
     A.   Absorption
          The absorption of benz(a)anthracene  in humans
has not been studied.  However, it is known (U.S. EPA, 1979a)
that, as a class, PAH are well-absorbed across the respira-
tory and gastrointestinal epithelia.  In particular, benz(a)-
anthracene was reported to be readily transported across
the gastrointestinal mucosa (Rees, et al., 1971).  The high
lipid solubility of compounds in the PAH class supports
this observation.
     B.   Distribution
          The distribution of benz(a)anthracene in mammals
has not been studied.  However, it is known (U.S. EPA, 1979a)
that other PAH are widely distributed throughout the body
following their absorption in experimental rodents.  Rela-
tive to other tissues, PAH tend to localize in body fat
and fatty tissues (e.g., breast).
     C.   Metabolism
          Benz(a)anthracene, like other PAH,  is metabolized
by the microsomal mixed-function oxidase enzyme system in
mammals (U.S. EPA, 1979b).  Metabolic attack on one or more
                                                          •
of the aromatic double bonds leads to the formation of phenols

-------
and  isomeric dihydcodiols by  the  intermediate  formation
of reactive epoxides.  Dihydrodiols are further metabolized
by microsomal mixed-function  oxidases to yield diol epoxides,
compounds which are known to  be biologically reactive  inter-
mediates for certain PAH.  Removal of activated intermediates
by conjugation with glutathione or glucuronic acid, or by
further metabolism to tetrahydrotetrols, is a key step in
protecting the organism from  toxic interaction with cell
macromolecules.                           v
     D.   Excretion
          The: excretion of benz (a) anthracene by'mammals
has  not been studied.  However, the excretion of closely
related PAH is rapid  and occurs mainly via the feces  (U.S.
EPA, 1979a).  Elimination in  the bile may account for a
significant percentage of administered PAH.  However, the
rate of disappearance of various PAH from the body  and
the  principal routes of excretion are influenced both by
the  structure of the parent compound and the route of admini-
stration (U.S. EPA, 1979a).   It is unlikely that PAH will
accumulate in the body with chronic low-level exposures.
IV..  EFFECTS
     A.   Carcinogenicity
          Benz(a)anthracene is recognized as a weak carcino-
gen  in mammals (U.S. EPA, 1979a,b).  It is a tumor initiator
on- the skin of mice, but failed to yield significant results
in the strain A mouse pulmonary tumor bioassay system.
                              *
                            IT-?

-------
     B.   Mutagenicity
          Benz(a)anthracene has shown weak rnutagenic activity
in several test  system, including Ames Salmonella  assay,
somatic cells  in culture, and sister chromatid exchange
in Chinese hamster cells  (U.S. EPA, 1979b) ..
     C.   Teratbgenicity
          Pertinent data could not be located in the avail-
able literature  concerning the possible  teratogenicity of
benz(a)anthracene.  Other related PAH are  apparently not
significantly  teratogenic in mammals  (U.S. EPA, 1979a).
     D.   Other  Reproductive Effects
          Pertinent data could not be located in the avail-
able literature.
     E.   Chronic Toxicity
          The chronic toxicity of benz(a)anthracene has
not been extensively studied.  The repeated injection of
benz(a)anthracene in mice for 40 weeks (total dose, 10 rag.)
had little apparent effect on longevity  or organ weights
(U.S.  EPA, 1979b).
V.   AQUATIC TOXICITY
     A.   Acute
          Pertinent data could not be located in the avail-
able information.
     B.   Chronic
          No standard chronic toxicity data have been pre-
sented on freshwater or marine species.  The only  toxicity'
data available for benz(a)anthracene for fish is an 87 per-

-------
cent mortality on  the  freshwater  bluecill sunfish,  Lepomis
macrochirus, exposed to  1,000 ^ig/1  fcr  six months  (Brown,
et al., 1975).
     C.   Plant Effects
          Pertinent data could not  be located  in the  avail-
able information.
VI.  EXISTING GUIDELINES AND STANDARE3
     Neither the human nor  the aquatic  criteria  derived
by U.S. EPA  (1979a), which  are summarized below, have gone
through the process of review; therefore, there  is  a  pos-
sibility that these criteria will be changed.
     A.   Human
          There are no established  exposure criteria  for
benz(a)anthracene.  However, PAH  as a class are  regulated
by several authorities.  The World  Health Organization (1970)
has recommended that the concentration  of PAH  in drinking
water  (measured as  the total of fluorsn.thene,  benzo(g,h,i)-
perylene, benzo(b)fluoranthene, benzc(>)fluoranthene, indeno-
(l,2,3-cd)pyrene,  and benzo(a)pyrene) not to exceed 0.2
•ug/1.  Occupational exposure criteria have been  established
for coke oven emissions, coal tar products,  and  coal  tar
pitch volatiles, all of which contain large amounts of PAH
including benz(a)anthracene  (U.S. EPA,  1979a)..
          The U.S'i- EPA (1979a) draft recommended criteria
for PAH in. water are based  upon the ex-rapolation of  animal.
carcinogenicity data for benzo (a) pyrsr.s and dibenz (a, h) anthra-
cene.

-------
     B.   Aquatic



          Data were insufficient to propose criteria for



freshwater or marine environments.

-------
                               8ENZ(a)ANTHRACENE

                                  REFERENCES
Basu, O.K.,  and J. Saxena.   1977.   Analysis of raw  and drinking water sam-
ples  for polynuclear  aromatic  hydrocarbons.   EPA PO  No.  CA-7-2999-A,  and
CA-8-2275-B.  Expo. Evalu. Branch, HERL, Cincinnati, Ohio.

Basu,  O.K.,  and  J.  Saxena.   1978.   Polynuclear  aromatic  hydrocarbons  in
selected  U.S.  drinking waters  and  their  raw  water  sources.   Environ. Sci.
Technol.  12: 795.

Brown, E.R., et al.   1975.   Tumors  in fish caught in polluted waters: possi-
ble explanations.   Comparative  Leukemia Res.   1973.   Leukemogenesis.  Univ.
Tokyo Press/Karger, Basel,  pp.  47-57.                   v

Rees, E.O., et al.  1971.   A study  of the mechanism of  intestinal absorption
of benzo(a)pyrene.  Biochem. Biophys. Act.  225: 96.

U.S.  EPA.   1979a.   Polynuclear Aromatic  Hydrocarbons:  Ambient Water Quality
Criteria   (Draft), '

U.S.  EPA.   1979b.   Multimedia health assessment document for polycyclic or-
ganic matter.   Prepared under "contract by J.  Santodonato,  et al.,  Syracuse
Research Corp.

U.S.  EPA.   1979c.  EnvironmentaT"Criteria  and 'Assessment  Office.   Polynu-
clear Aromatic Hydrocarbons: Hazard Profile   (Draft).

World. Health  Organization.   1970.   European  standards  fcr  drinking water.
2nd. ed.j Geneva.

-------
                                      No. 18
        Benzo(b)£luo ranthene


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION


U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
benzo(b)fluoranthene and has found sufficient evidence to
indicate that this compound is carcinogenic.

-------
                    BEN ZO(b)FLUORANTHEN E
                           SUMMARY
     Benzo(b)fluoranthene is a member of the polycyclic  aro-
matic hydrocarbon (PAH) class.  Numerous compounds  in  the  PAH
class are well known for their carcinogenic effects  in ani-
mals.  Benzo(b)fluoranthene is carcinogenic to the  skin  of
mice and produces sarcomas when injected in mice.   Very
little is known concerning the non-carcinogenic effects  pro-
duced by chronic exposure to benzo(b)fluoranthene.   Although
exposure to benzo(b)fluoranthene in  the environment  occurs in
conjunction with exposure to other PAH, it is not known  how
these compounds may interact in human systems.  Furthermore,
the specific effects of benzo(b)fluoranthene in humans are
not known.
     Standard acute or chronic toxicity testing for  aquatic
organisms has not been found in the  available literature.
                            >*-
-------
                     BEN ZO(b)FLUORANTHEN E



 I. '  INTRODUCTION



      This profile is based primarily on the Ambient Water



 Quality Criteria Document for Polynuclear Aromatic Hydrocar-



 bons (U.S. EPA, 1979a) and the Multimedia Health Assessment



 Document for Polycyclic Organic. Matter (U.S. EPA, 1979b).



      Benzo(b)fluoranthene (C2QH12^ is one of the family



 of polycyclic aromatic hydrocarbons (PAH) formed as a  result



 of incomplete combustion of organic material.  Its physical/



 chemical properties have not been well-characterized,  other



 than a reported melting point of 167°C (U.S. EPA, 1979b) .



      PAH, including benzo(b)fluoranthene, are ubiquitous in



 the environment, being found in ambient air, food, water,



 soils, and sediment (U.S. EPA, 1979b).  The PAH class  con-



 tains a number of potent carcinogens (e.g., benzo(a)pyrene),



 moderately active carcinogens (e..g., benzo(b)f luoranthene) ,



 weak carcinogens (e.g., benz(a)anthracene), and cocarcinogens



 (e.g., fluoranthene), as well as numerous noncarcinogens



 (U.S. EPA, 1979b) .



      PAH which contain more than three rings (such as  benzo-



 (b)fluoranthene) are relatively stable in the environment and



 may be transported in air and water by adsorption to particu-



• lar matter.  However, biodegradation and chemical treatment



 are effective in eliminating most PAH in the environment.



 Refer to. the PAH Hazard Profile (U.S. EPA, 1979c) for  a more



 general treatment of PAH.

-------
II.  EXPOSURE

     A.   Water

          In a monitoring survey of U.S. drinking water,  Basu

and Saxena (1977, 1978) were unable to detect benzo(b)fluor-

anthene.  However, the concentration of six  representative
                       *
PAH (fluoranthene, benzo(a)pyrene, benzo(g h i)perylene,

benzo(j)fluoranthene, benzo(k)fluoranthene,  indeno(l,2,3-cd)

pyrene) averaged 13.5 ng/1.

     B.   Food

          Levels of benzo(b)fluoranthene have not been re-

ported  for food.  However,  the total intake .of all  types  of

PAH through the diet has.. been estimated at 1.6 to 16  ug/day

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

weighted average bioconcentration factor of  benzo(b)fluor-

anthene to be 6,800 for the edible portion of fish  and shell-

fish consumed by Americans.  This estimate is based on the

octanol/water partition coefficient of benzo(b)fluoranthene.

     C.   Inhalation

          Benzo(b)fluoranthene has been detected  in ambient

air at  concentrations ranging from 0.1 to 1.6 ng/m^ (Gordon

and Bryan, 1973).  Thus, the human daily intake of  benzo(b)-

fluoranthene by inhalation  of ambient air may be  in the range

of 1.9  to 30.4 ng, assuming that a human breathes 19  m^ of

air per day.

Ill. PHARMACOKINETICS

     Pertinent data could not be located in  the available

literature concerning the pharmacokinetics of benzo(b)fluor-

anthene, or other PAH, in humans.  Nevertheless,  it is pos-

-------
sible to make limited assumptions based on  the  results  of
animal research conducted with several PAH, particularly
benzo(a)pyrene.
     A.   Absorption
          The absorption of benzo(b)fluoranthene  in  humans  or
other animals has not been studied.  However, it  is  known
(U.S. EPA, 1979a) that, as a class, PAH are well-absorbed
across the respiratory and gastrointestinal epithelia.  The
high lipid solubility of compounds  in the PAH class  supports
                                          \
this observation.
     B.   Distribution
          The distribution of benzo(b)fluoranthene  in mammals
has not been studied.  However,  it  is known (U.S. EPA,  1979a)
that other PAH are widely distributed throughout  the body
following their absorption in experimental  rodents..  Relative
to other tissues, PAH tend to localize in body  fat  and  fatty
tissues (e.g., breast).
     C.   Metabolism
          The metabolism of benzo(b)fluoranthene  in  mammals
has not been studied.  Benzo(b)fluoranthene, like other PAH,
is most likely metabolized by the microsomal mixed-function
oxidase enzyme system in mammals (U.S. EPA, 1979b).  Meta-
bolic attack, on one or more of the  aromatic double  bonds
leads to the formation of phenols and isomeric  dihydrodiols
by the intermediate formation of reactive epoxides.  Dihydro-
diols are further metabolized by microsomal mixed-function •
oxidases to yield diol epoxides, compounds  which  are known  to
be biologically reactive intermediates for  certain  PAH.  Re-
moval of activated intermediates by conjugation with gluta-

-------
thione or glucuronic acid, or by further metabolism  to  tetra-
hydrotetrols, is a key step in protecting  the organism  from
toxic interaction with cell macromolecules.
     D.   Excretion
          The excretion of benzo(b)fluoranthene  by mammals
has not been studied.  However, the excretion of  closely  re-
lated PAH is rapid and occurs mainly via the feces  (U.S.  EPA,
1979a).  Elimination in the bile may account for  a signifi-
cant percentage of administered PAH.  It is unlikely that PAH
                                         «.
will accumulate in the body with chronic low-level exposures.
IV.  EFFECTS
     A.   Carcinogenicity
          Benzo(b)fluoranthene is  regarded as a  moderately
active carcinogen (U.S. EPA, 1979b).  It is carcinogenic  by
skin painting on mice, and by subcutaneous injection in mice
(U.S. EPA, 1979b; LaVoie, et al. 1979).  The sarcomagenic
potency of benzo(b)fluoranthene is similar to that of benzo-
(a)pyrene (Buu-Hoi, 1964).
     B.   Mutagenicity
          Benzo(b)fluoranthene is  mutagenic in the Ames Sal-
monella assay in the presence of a microsomal activating  sys-
tem  (LaVoie, et al. 1979).  It is  also positive  in  the  induc-
tion of sister-chromatid exchanges by intraperitoneal injec-
tion in Chinese hamsters (U.S. EPA, 1979b).
     C.   Teratogenicity
          Pertinent data could not be located in  the litera-
ture available concerning the possible teratogenicity of

-------
benzo(b)fluoranthene.  Other related PAH are apparently  not



significantly teratogenic in mammals (U.S.  EPA, 1979a).



     D.   Other Reproductive Effects



          Pertinent information could not be located  in  the



available literature.



     E.   Chronic Toxicity



          Published data are not available regarding  the  non-



carcinogenic chronic effects of benzo(b)fluoranthene.  It  is



known, however, that exposure to carcinogenic PAH may produce



widespread tissue damage as well as selective destruction  of



proliferating tissues (e.g., hematopoietic and lyraphoid  sys-



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



V.   AQUATIC TOXICITY



     Pertinent information could not be located  in the avail-



able literature.



VI.  EXISTING GUIDELINES AND STANDARDS



     A.   Human



          There are no established exposure criteria  for



benzo(b)fluoranthene.  However, PAH as a class are regulated



by several authorities.  The World Health Organization has



recommended that the concentration of PAH in drinking water



(measured as the total of fluoranthene, benzo(g,h,ijperylene,



benzo(b)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)'



pyrene, and benzo(a)pyrene) not exceed 0.2 ug/1.  Occupa-



tional exposure criteria have been established for coke oven



emissions, coal tar products, and coal tar pitch volatiles/



all of which contain large amounts of PAH including benzo(b)-



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

-------
          The tJ.S. EPA (1979a') draft recommended  criteria  for



PAH in water are based upon the extrapolation of  animal  car-



cinogenicity data for benzo(a)pyrene and dibenzc(a,h)anthra-



cene.



     B.   Aquatic



          The criteria for freshwater and marine  life  have



not been drafted (U.S. EPA, 1979a).

-------
                             BENZO(b)R_UORANTHENE

                                  REFERENCES
Basu, O.K.  and 0.  Saxena.   1977.  Analysis  of raw and  drinking  water sam-
ples  for polynuclear  aromatic  hydrocarbons.   U.S.  Environ.  Prot.  Agency,
P.O. No. CA-7-2999-A.  Exposure Evaluation Branch, HERL, Cincinnati, Ohio.

Basu,  O.K.  and  J.  Saxena.   1978.   Polynuclear  aromatic  hydrocarbons  in
selected U.S.  drinking waters  and their  raw water sources.   Environ. Sci.
Technol.  12: 795.

Buu-Hoi,  N.P.    1964.    New  developments  in  chemical  carcinogenesis  by
polycyclic  hydrocarbons  and  related  heterocycles:  A  review.   Cancer Res.
24: 1511.
                                                    v
Gordon,  R.J.  and R.J. Bryan.   1973.   Patterns of airborne  polynuclear hy-
drocarbon concentrations  at four Los Angeles sites.  Environ.  Sci. Technol.
7: 1050.

La Voie, E., et al.   1979.   A  comparison of the mutagenicity, tumor-initiat-
ing activity and  complete carcinogenicity of polynuclear aromatic hydrocar-
bons..  In: Polynuclear Aromatic  Hydrocarbons, P.W.  Jones and P.  Leber  (eds.)
Ann Arbor Science Publishers, Inc.

U.S. EPA.   1979a.   Polynuclear Aromatic  Hydrocarbons:  Ambient  Water Quality
Criteria.  (Draft)

U.S. EPA.   1979b.   Multimedia health assessment  document for polycyclic or-
ganic matter.   Prepared  under contract  by J.  Santodonato,  et  al., Syracuse
Research Corp.

U.S. EPA.   1979c.   Environmental Criteria and Assessment Office.  Polynucle-
ar Aromatic Hydrocarbons: Hazard Profile.  (Draft)

World Health Organization.  1970.   European Standards  for Drinking Water. 2nd
ed., Geneva.

-------
                                       No.  19
           Benzo(a)pyrene


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION










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



benzo(a)pyrene and has found sufficient evidence to indicate



that this compound is carcinogenic.

-------
                                 BENZO(a)PYRENE
                                    Summary
      The first chemicals  shown to be  involved in  the  development of cancsr
 belong to the polynuclear aromatic hydrocarbons  (PAH)  class.  Benzo(a)pyrene
 is the  most  widely recognized  and extensively  studied of  all  carcinogenic
 PAH.   It  is  among the  most potent  animal carcinogens known   and produces
 tumors in virtually all species by all routes of administration.
      Since humans  are  never exposed to  only  benzo(a)pyrene  in  the environ-
-ment, it  is  not  possible  to attribute  human  cancers  solely  to exposure to
 benzo(a)pyrene.   However," numerous  epidemiologic studies  support  the belief
 that  carcinogenic PAH,  including benzo(a)pyrene,  are also human carcinogens.
      Measured steady-state  bioconcentration  factors are  not available  for
 freshwater or saltwater aquatic  species  exposed  to benzo(a)pyrene.  Standard
 toxicity data for freshwater and  saltwater aquatic  life  have  not  been  re-
 ported.

-------
I.   INTRODUCTION
     This profile  is based  on the  Ambient  Water Quality  Criteria Document
for Polynuclear  Aromatic Hydrocarbons  (U.S.  EPA,  1979a) and  the Multimedia
Health Assessment Document for Polycyclic Organic Matter  (U.S. EPA,  1979b).
     Benzo(a)pyrene  (C^cf1!^  ^s  one  °^ the  ^i^7 °^  polynuclear aromat-
ic hydrocarbons  (PAH) formed as a result of incomplete combustion of organic
material.   Its  physical and chemical properties have  not  been well-charac-
terized,  other  than a  reported melting  point of 178.8-179.3°C  and a  vapor
pressure of..5.49 x 10"9 mm Hg  (U.S. EPA, 1979b). '•
     PAH, including benzo(a)pyrene,  are ubiquitous  in the environment,  being
found  in ambient  air,  food,  water,   soils  and sediment (U.S.  EPA, 1979a).
The  PAH class  contains a  number of  potent  carcinogens  (e.g.,  benzo(a)py-
rene), moderately  active carcinogens  (e.g., benzo(b)fluoranthene),  weak car-
cinogens  (e.g.,  benz(a)anthracene),  and  cocarcinogens  (e.g.,  fluoranthene),
as well as numerous noncarcinogens (U.S. EPA,  1975a).
     PAH  which  contain more than three  rings (such as  benzo(a)pyrene)  are
                                                                           i
relatively  stable in  the  environment  and  may be  transported in air  and
water  by adsorption  to  particulate  matter.   However,  biodegradation  and
chemical treatment are effective  in eliminating most PAH  in the environment.
II.  EXPOSURE
     A.  Water
         Basu and Saxena  (1977,  1978) have  monitored  various United States
drinking  water  supplies for the  presence of  PAH,  including  benzo(a)pyrene.
They reported that the  average level of benzo(a)pyrene in drinking  water  was
0.55 nanograms/liter.   This would result  in  a human daily  intaks  of benzo-
(a)pyrene from water of about  0.0011 jjg.

-------
            ••' V
     B.  Food
         Benzo(a)pyrene  has been  detected  in a  wide  variety  of  foods  by
numerous investigators  (U.S.  EPA,  1979a).   Benzo(a)pyrene  levels are  espe-
cially high' in cooked or  smoked meats, where  in  certain cases (i.e.,  char-
coal-broiled  steak)  concentrations  as  high as  50  ppb have  been  reported
(Lijinsky and Ross,  1967).   It  has been estimated (U.S. EPA,  1979b)  that the
daily  dietary  intake of benzo(a)pyrene  is about  0.16  to 1.6 ug, and  total
PAH intake  is about 1.6  to 16 ug.   The U.S.  EPA  (1979a)  has estimated  the
weighted average, bioconcentration  factor for benzo(a)pyrene  to  be 6,800  for
the edible portions  of  fish and shellfish consumed by Americans.   This  esti-
mate is based-on the octanol/water partition coefficient for  benzo(a)pyrene.
     C.  Inhalation
         Benzo(a)pyrene  levels  have been  routinely  monitored in  the  ambient
atmosphere  for  many  years.  The average  urban-rural ambient benzo(a)pyrene
concentration  in the United  States has  been estimated  at  0.5 nanograms/m
(U.S. EPA, 1979a).   Thus, the human daily intake of benzo(a)pyrene by  inhala-
tion of  ambient air is  about  9.5 nanograms,  assuming  that  a human  breathes
about 19 m  of air per day.
III. PHARMACOKINETICS
     Pertinent  data  could  not  be  found in.  available  literature  concerning
the pharmacokinetics of  benzo(a)pyrene,  or other  PAH,  in humans.  Neverthe-
less,  it is  possible  to make  limited assumptions  based on  the  results  of
animal research conducted with several PAH, particularly benzo(a)pyrene.
     A.  Absorption
         Toxicity data indicate  that,  as a class,  PAH are capable of  passage
across epithelial membranes (Smyth,  et al.  1962).   In  particular, benzo(a)-
pyrene was  reported  to be  readily transported across  the  intestinal mucosa

-------
(Rees, et al.  1971)  and the respiratory  membranes (Kotin, et al. 1969; Vai-
niok, et al. 1976).
     8.  Distribution
         Benzo(a)pyrene becomes  localized in a  wide  variety of body tissues
following its absorption  (Kotin,  et  al.  1969).  Due  to  its high lipid  solu-
bility,  benzo(a)pyrene localizes  primarily  in body  fat  and  fatty tissues
(e.g., breast) (Schlede, et al. 1970a,b).
     C.  Metabolism
                                           »
         The  metabolism  of  benzo(a)pyrene  in  mammals  has been  studied  in
great detail  (U.S.  EPA, 1979a).  8enzo(a)pyrene,  like  other PAH, is metabo-
lized  by the- microsomal  mixed function  oxidase  enzyme  system  in mammals
(U.S. EPA,  1979b).   Metabolic  attack  on one or more of  the  aromatic  rings
leads to  the  formation of phenols and isomeric dihydrodiols by the interme-
diate formation  of  reactive epoxides.  Dihydrodiols  are further metabolized
by  microsomal mixed  function  oxidases  to  yield diol  epoxides,  compounds
which  are known  to be  ultimate carcinogens  for  certain PAH.   Removal  of
activated intermediates by conjugation with glutathione or glucuronic  acid,
or by  further metabolism to tetrahydrotetrols,  is a key step in protecting
the organism  from toxic interaction with cell macromolecules.
     0.  Excretion
         The  excretion of benzo(a)pyrene  by mammals has been studied by sev-
eral  groups  of investigators.   In  general, the  excretion of benzo(a)pyrene
and  related  PAH  is rapid, and  occurs  mainly via the feces (U.S. EPA, I979a;
Schlede, et al.  1970a,b).   Elimination in the bile may  account for a signi-
ficant percentage of administered PAH.  It is unlikely that PAH will accumu-
late in the body as  a  result of chronic low-level  exposures.

-------
IV.  EFFECTS
     A.  Carcinogenicity
         The  carcinogenic activity  of  benzo(a)pyrene was  first  recognized
decades ago, and since that time  it  has  become a laboratory standard  for  the
production  of experimental  tumors which  resemble human  carcinomas in ani-
mals.  The  carcinogenic  activity  of benzo(a)pyrene  is distinguished by sev-
eral remarkable  features:  (1) it  is among the  most potent animal carcino-
gens known,  producing tumors  by  single  exposures to microgram quantities;
(2)  it acts  both  at the  site of application and at  organs  distant to  the
site of  absorption;  and (3)  its Carcinogenicity  has been  demonstrated  in
nearly every  tissue and  species  tested, regardless  of the route  of  admini-
stration (U.S. EPA, 1979a).
         Oral  administration  of   benzo(a)pyrene  to   rodents  can  result   in
tumors of  the forestomach, mammary  gland, ovary,  lung,  liver,  and lymphoid
and  hematopoietic  tissues (U.S. EPA,  1979a).   Exposure to benzo(a)pyrene  by
intratracheal instillation in  rodents  can also be an  effective means  of pro-
ducing respiratory  tract tumors  (Feron,  et al.  1973).   In addition, benzo-
(a)pyrene has remarkable  potency  for  the induction of skin tumors  in  mice  by
direct dermal application (U.S. EPA, 1979a).
         Numerous epidemiologic studies  support the belief that' carcinogenic
PAH, including  benzo(a)pyrene, are  responsible  for  the  production of human
cancers both  in  occupational  situations  and among tobacco smokers  (U.S. EPA,
1979b).
     B.  Mutagenicity
         Benzo(a)pyrene  gives  positive  results  in  nearly  all  mutagenicity
test systems  including the Ames  Salmonella assay, cultured  Chinese  hamster
cells, the  sister-chromatid exchange  test,  and  the  induction of ONA repair
synthesis (U.S. EPA, 1979a).

-------
     C.  Teratogenicity and Other Reproductive Effects
         Only limited  data are available  regarding the  teratogenic effects
of benzo(a)pyrene or other PAH  in  animals.   8enzo(a)pyrene had little effect
on fertility or the developing  embryo  in several mammalian and non-mammalian
species (Rigdon and Rennels,  1964;  Rigdon and Neal, 1965).
     0.  Chronic Toxicity
         As long  ago  as 1937,  investigators knew  that  carcinogenic PAH such
as benzo(a)pyrene produced systemic  toxicity as manifested by  an inhibition
of body  growth  in rats  and  mice  (Haddow,  et  al... 1937).  The  target organs
affected  by chronic  administration  of  carcinogenic  PAH are  diverse,  due
partly to  extensive  distribution  in the body  and also  to the  selective de-
struction  of  proliferating cells  (e.g.,  hematopoietic and lymphoid system,
intestinal epithelium, testis) (Philips,  et al. 1973).
V.   AQUATIC TOXICITY
     Pertinent data could not be located in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the  human health nor the aquatic criteria  derived  by U.S. EPA
(1979a),  which are summarized below, have gone through  the process of public
review;  therefore,   there is  a  possibility  that  these criteria will  be
changed.
     A.  Human
         There are no  established  exposure  standards specifically for benzo-
(a)pyrene.  However,  PAH as  a  class  are  regulated by  several authorities.
The World  Health  Organization (1970)  has recommended that the  concentration
of PAH in  drinking water  (measured as  the  total of fluoranthene,  benzo(g,h,-
i)perylene,  benzo(b)fluoranthene,  benzo(k)fluoranthene,  indeno(l,2,3-cd)py-
rene, and  benzo(a)pyrene) not exceed  0.2  ug/1.  Occupational  exposure  cri-
                                    19-?

-------
teria have been  established  for coke oven emissions,  coal tar products, and
coal tar pitch volatiles,  all  of which contain large amounts of PAH in water
based upon the  extrapolation of animal carcinogenicity  data for benzo(a)py-
rene and  dibenz(a,h)anthracene.  Levels for each  compound are derived which
will result  in  specified risk  levels of human cancer as  shown  in the table
below:
                              BaP
Exposure Assumptions          Risk Levels and Corresponding Draft Criteria
     (per day):-    '
                              0       ID-7          10-*        10-5
2 liters of drinking water    0       0.097         0.97         9.7
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish                   0.44          4.45        44.46
and shellfish only.
Exoosure Assumotions
(per day)
2 liters of drinking water
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish
and shellfish only.
DBA
Risk
0
0

Levels and
1C-7
0.43
1.96
Corresoonding
10-6
4.3
19.6
Draft Criteria
10-5
43
196
     8   Aquatic
         Guidelines are  not  available for benzo(a)pyrene in aquatic environ-
ments.

-------
                          BENZO(A)PYRENE

                            REFERENCES


Basu,  O.K., -and J.  Saxena. 1977.   Analysis of  raw  and drinking
water samples for polynuclear  aromatic  hydrocarbons.   EPA P.O.  No.
CA-7-2999-A, and CA-8-2275-B,  Expo.  Evalu.  Branch, HERL., Cincin-
nati.

Basu, O.K., and J.  Saxena. 1978.   Polynuclear aromatic hydrocarbons
in  selected O.S.  drinking waters  and  their  raw  water sources.
Environ. 3ci. Technol.  12: 795.                          ...  .  . ..

Feron, V.J., et al. 1973.   Dose-response correlation for  the  induc-
tion of respiratory  tract tumors  in  Syrian  golden hamsters by in-
tratracheal instillations of benzo(a)pyrene.  Europ. Jour. Cancer.
9: 387.

Haddow, A., et -al.  1937.   The  influence of certain carcinogenic and
other hydrocarbons on body  growth in the rat.  Proc.  Royal Soc. B.
122: 477.
Kotin, P., et al.  1969.   Distribution retention and  elimination of
C  -3, 4-benzopyrene after a<
Nat!. Cancer Inst.  23: 541.
 T ;T
C  -3, 4-benzopyrene after administration to mice and rats.  Jour.
Lijinsky,  W.,  and  A.E.  Ross.  1967.    Production  of carcinogenic
polynuclear  hydrocarbons' in  the  cooking of  food.    Food Cosmet.
Toxicol.  5: 343.                              (

Philips, F.S. et al., 1973.   In vivo cytotoxicity of  polycyclic hy-
drocarbons.   In:  Pharmacology anathe  future of man.   Proc. 5th
Intl. Congr. PKarmacology, 1972, San Francisco.  2:  75.

Rees, E.G., et al.   1971.   A study of the mechanism of  intestinal
absorption of benzo(a)pyrene.  Biochem. Biophys.  Act.   255:  96.

Rigdon, R.H., and J.  Neal.   1965.   Effects of feeding benzo(a)py-
rene  on  fertility,  embryos,  and young  mice.   Jour.  Natl. Cancer.
Inst.  32: 297.

Rigdon,  R.H.,  and  E.G.  Rennels.   1964.   Effect  of  feeding benzo-
pyrene on reproduction in the  rat.  Experientia.  20: 1291.

Schlede, E.,  et  al.   1970a.   Stimulatory effect of  benzo(a)pyrene
and phenobarbital pretreatment on  the  biliary excretion of benzo-
(a)pyrene metabolites in the  rat.   Cancer Res.   30:  2398.

Schlede,  E. ,  et al.   1970b.   Effect  of enzyme  induction on' the
metabolism and tissue distribution  of benzo(a)pyrene.  Cancer Res.
30: 2893.
                                If-At

-------
Smyth, H.F., et al.   1962.  Range - finding toxicity data:  List  II.
Am. Ind. Hyg. Jour.  23: 95.

U.S.  EPA.    1979a.   Polynuclear  Aromatic Hydrocarbons:   Ambient
Water Quality Criteria.  (Draft).

U.S. EPA.  1979b.  Multimedia Health Assessment Document  for Poly-
cyclic Organic Matter.   Prepared  under  contract by J. Santodonato
et al., Syracuse Research Corporation.

Vainioh, et  al.  1976.   The  fate  of intracheally installed benzo-
(a)pyrene in the isolated perfused rat lung of both  control and  20-
methylcholanthrene pretreated.  Res.  Commun. Chem. Path.  Pharmacol.
13: 259.

World Health Organization.  1970.  European standards for  drinking
water.  2nd  ed.  Revised.  Geneva.

-------
                                     tto. 20
          Benzotrlchlorlde
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON,  D.C.  20460

           APRIL 30,  1980
          -ft.0-/

-------
                          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.

-------
                                BENZOTRICHLORIDE
                                    Summary

      Benzotrichloride  has  been shown to  be  mutagenic in a  number  of micro-
bial  tests  with and without  metabolic  activation..  One study  has  described
the carcinogenicity  of benzotrichloride  in  mice.  The  lowest  concentration
producing a  lethal effect d-C^g) has been reported at 125 ppm for  rats  in-
haling  benzotxichloride  for   four  hours.   Pertinent  data  for  the  toxic
effects to aquatic organisms were not found in the available  literature.
                                  10 -3

-------
 I.    INTRODUCTION
      Benzotrichloride (CAS registry  number 98-07-7),  is a colorless,  oily,
 fuming  liquid.   It. is  made by  the  free radical  chlorination  of  boiling
 toluene  (Sidi,  1964;  Windholz,  1976).   Benzotrichloride  has  the  following
 physical and chemical properties  (Windholz, 1976; Sidi,  1964):
                   Formula:
                                         0
                   Molecular Weight:    155.48
                   Melting Point:       -5°c
                   Boiling Point:       220. 8°C
                   Density:             1.375620
                                              4
                   Solubility:          alcohol, ether, benzene,
                                         insoluble in water
     Benzotrichloride  is  used  extensively  in  the dye  industry  for  the
production of Malachite  green,  Rosamine,  Quinoline red, and Alizarine yellow
A.  It can also be used to produce ethyl orthobenzoate  (Sidi, 1964).
II.  EXPOSURE
     A.   water
          Benzotrichloride decompose in the presence of water to benzoic and
hydrochloric acids (Windholz, 1976).
     B.   Food
          Pertinent data were not found in the available literature.
     C.   Inhalation
          Pertinent  data were  not  found in  the available  literature;  how-
ever,  significant exposure  could occur  in  the  workplace   from  accidental
spills.   Benzotrichloride decomposes  in moist  air to  benzoic and  hydro-
chloric acids (Windholz,  1976).
     0.   Dermal
          Benzotrichloride is irritating to  the skin (Windholz,  1976).

-------
 III.  PHARMACOKINETICS
      Pertinent pharmacokinetic data were not found in the available
 literature.
 IV.   EFFECTS
      A.   Carcinogenicity
          In  a  study by  Matsushito and  coworkers (1975),  benzotrichloride
 was  found to  Induce  carcinomas,  leukemia, and papillcmas  in mice.  The  de-
 tails of  the study were not available for assessment.
      B.   Mutagenicity
          Yasuq,  et  al.  (1978) tested  the mutagenicity of several  compounds
 including benzotrichloride in microbial  systems such  as the rec-assay  using
 Bacillus  subtilis, reversion  assays using £._ coii, and the Ames assay  using
 Salmonella  typhimuriunv,   with or  without  metabolic  activation.   Benzo-
 trichloride was positive  for mutagenicity  in  the rec-assay  and  was highly
 positive  on certain  strains of §_._ coli and S._ typhimurium  in the  reversion
 i
 assay  with metabolic activation,   without  metabolic  activation,  however,
 benzotrichloride was  only weakly positive in  the latter  assay.
     C.   Teratogenicity, Reproductive Effects, and Chronic Toxicity
          Pertinent data were not  found  in the available literature.
     0.   Acute Toxicity
          The  lowest lethal  concentration d-CLQ)  for  rats  inhaling  benzo-
 trichloride is 125 ppm for four hours (Smyth, et al. 1951).
          Benzotrichloride was severely  irritating to  the  skin of rabbits
that  received  dermal  applications of 10  mg  for 24 hours and to the eyes of
rabbits that received instillations of 50 ug to the eye  (Smyth, et al. 1951).

-------
V.   AQUATIC TOXICITY
     Pertinent data were not found in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     Existing'.quidelines and standards were not found in the available
literature.

-------
                                  REFERENCES
Matsushitot H., et al.  1975.  Carcincgenicities of the related compounds in
benzoyl  chloride production.   49th  Annu.   Meeting  Japan  Ind.  Hyg.  Soc.,
Sappro, Japan,  p. 252.

Sidi,  H.   196A.  Benzyl  chloride,  benzal  chloride,  benzotrichloride.   In:
Xirk-Qthmer Encyclopedia of  Chemical  Technology.   John Wiley  and Sons,  New
York, p. 281.

Smyth,  H.F.,  et  al.   1951.   Range finding toxicity data:   List IV.  Amer.
Med. Assoc. Arch, of Ind.  Health.   4:  119.

winohoiz,  M.   (ed.)   1976.   Merck Index,  9th  ed.   Merck  and  Co.,  Inc.,
Rahvray, NJ.

Yasuo, K., et  al.   1978.   Mutagenicity  of benzotrichloride and related com-
pounds.  Mutat. Res.  58:  143.
                               20-?

-------
                                       No.  21
          Benzyl Chloride


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

           APRIL 30, 1980

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

-------
                                BENZYL CHLORIDE
                                    Summary

     Benzyl chloride has  been shown to produce carcinogenic effects in  rats
following subcutaneous  administration  and in mice  following  intraperitoneal
administration.
     Weak mutagenic.  activity  of the  compound has  been  demonstrated in the
Ames Salmonella assay and in £._ coll.
     There is  no available information  on  the possible  teratogenic or ad-
verse reproductive effects of  benzyl chloride.
     Inhibition of cell multiplication in the alga, Microcystis aeruginosa,
started at 30 mg/1.  Concentrations of 10 mg/1  and 17 mg/1 caused paralysis
in two species of fish.
                                   aj-3

-------
 I.    INTRODUCTION
      Benzyl  chloride (alpha-chlorotoluene),  CAS Registry number 100-44-7, is
 a colorless-to-light yellow,  clear,  lachrymatory liquid and is made by free-
 radical  (photochemical)  chlorination of tolene (Hawley, 1971; Austin, 1974).
 It  has  the  following  physical and  chemical properties  (Windholz,  et  al.
 1976; Hawley, 1971; Weast, 1972):
                  Formula:
               .   Molecular Weight:        126.59
                  Melting Point:           -43°c
                  Boiling Point:           179°C
                  Density:                 Itl002!
                  Solubility:              Miscible in alcohol, chloroform,
                                             ether; insoluble in water
                  Production:              approximately 89 million Ibs.  1977
                                             (NIOSH, 1977)
                                                                      i
     Benzyl chloride is a moderately volatile compound  with a vapor pressure
of  1  mm Hg  at  22°C  (NIOSH,  1978).   The compound  decomposes  relatively
slowly in water with a 15-hour half-life of pH 7 (25°C)  (NIOSH, 1978).
     Benzyl chloride is used to make benzaldehyde  through additional  chlori-
nation and  hydrolysis, but  modest amounts  are also used as a  benzylating
agent  for benzyl  benzoate,  n-butyl benzyl  phthalate,  benzyl ethyl aniline,
benzyl cellulose,  components of  dyes and  perfumes-,  and  for production  of
phenylacetic acid by benzyl  cyanide (Austin,  1974).
II.  EXPOSURE
     A.   water
          Gruber  (1975)  reports  that  no  benzyl  chloride  enters  the water
from production.
                                   a'-/

-------
     8.   Food
          Pertinent data could not be  located  in  the  available  literature.
     C.   Inhalation
          Pertinent  data were  not  found  in  the  available literature; how-
ever,-  benzyl chloride is  used exclusively  as  a chemical  intermediate  in
manufacturing and  exposure  and is most  likely limited to the workplace.   As
such, the level of exposure is reported  to be  less than 1 ppm (NIOSH,  1978).
     0.   Dermal
                                            »
          Pertinent data could not be  located  in the  available literature.
III. PHARMACOKINETICS
     A.   Absorption and Distribution
          Pertinent data could not be  located  in the  available literature.
     8.   Metabolism and Excretion
          The major excretion product  following ingestion of benzyl chloride
is a cysteine conjugate,•benzylmercapturic  acid (Stekol,  1938,  1939; Witter,
1944; Barnes, et al. 1959; Knight and  Young, 1958).
          Bray, et al.  (1958) administered  benzyl chloride  at 200 mg/kg body
weight orally to  rabbits.   Urine collected for 24 hours  showed 86.4 percent
of the administered dose in the  soluble  fraction,  with 49 percent as benzyl-
mercapturic acid, 20 percent as  a  glycine conjugate,  0.4 percent as glucosi-
duronic acid, and 17 percent as  unconjugated  benzoic  acid.   Maitrya and vyas
(1970) found 30  percent of the  total  oral dose of benzyl chloride to be ex-
creted by rats as hippuric acid.
          Knight  and  Young  (1958)   found that benzyl chloride  is converted
directly to benzyl mercapturic acid, unlike  related compounds such as chlor-
inated benzenes, which form acid-labile precursors.

-------
          Barnes,  et al.  (1959)  found that 27 percent of the  total oral dose
 of benzyl chloride  administered  to rats was  excreted as benzyl  mercapturic
 acid.  This  value  compares  with  49 percent excreted in rabbits  (Bray,  et al.
 1958) and 4  percent  in guinea pigs  (Bray, et al.  1959).
          Several  studies have indicated  that glutathione is  the source  of
.the thiol   groups  for   mercapturic  acid  formation  from  benzyl  chloride
 (Bames,  et al. 1959;  Simkin and  White,  1957;  Anderson and  Mosher,  1951;
•Waelsch  and Rittenberg,  1942;  Bray,  et al.  1969; Beck, et  al. 1964).   The
 turnover  rate  of  glutathione in  the  liver was  found to  be  49 mg/100 g  of
 liver per hour (Simkin and White,  1957).  An  in vitro study  by Suga, et  al.
 (1966) revealed  that conjugation with glutathione can occur  both  enzymatic-
ally and  non-«nzymatically in rat  liver* preparations.  The enzymic  conjuga-
tion has  also  been observed in  human liver preparations  (Soyland and Chas-
seaud, 1969).
 IV.  EFFECTS
     A.   Carcinogenicity
          Benzyl chloride was  reviewed by  IARC  (1976) and found  to be car-
cinogenic in rats.  Oruckrey,  et al.  (1970) injected  14 rats subcutaneously
with benzyl  chloride at  2.1 g/kg body weight (total  dose)  and 8 rats with
3.9 gAg body  weight (total dose) during 51 weeks.   Injection site  sarcomas
were noted  in  three  of the rats  receiving the lower  dose and six receiving
the higher  dose;  most  of  the  tumors had  metastasized to  the lungs.   The
vehicle of administration, arachis oil,  did not produce local  tumors.
          Poirier,  et al.  (1975)  administered intraperitoneal  injections of
benzyl chloride  in tricaprylin to three groups of 20  male and female A/Hes-
                                                                        *
ton mice, three  times per  week  for  eight  weeks, with  total  doses  of 0.6,
1.5, and  2.0 g/kg  body weight.   After  24 weeks, all  survivors  were killed;

-------
 lung tumors  occurred in  4/15,  7/16,  and 2/8  surviving mice  in the  three
 groups,  respectively.   The average  number  of tumors  per mouse was  0.26,
 0.50,  and  0.25,  respectively.   The incidence of tumors  in mice  receiving the
 benzyl  chloride was  not significantly different  from  the  results  recorded
 for  untreated mice on the  tricaprylin-vehicle treated mice.
     B.    Mutagenicity
           McCann, et  al. (1975a,b) found  benzyl chloride to be weakly  muta-
 genic  (less  than 0.10 revertants/nanomole) when tested using the Ames  assay
 (Salmonella/microsomal activation).
        .   Rosenkranz  and Poirier (1978),  in  a  National Cancer Institute  re-
 port, found  benzyl chloride to be marginally mutagenic  in  the Ames assay at
 doses of 5 ul and 10  pi/plate without activation.  Microsomal activation  had
 an inactivating  effect on  benzyl chloride.  The investigators also evaluated
 the  DMA-modifying activity in  bacterial systems using Escherichia coli pol A
 mutants.   A  dose of 10 ul benzyl chloride, produced  a  positive mutagenic  ef-
 fect.
           Benzyl  chloride  was found to be non-mutagenic in  the Ames Salmo-
nella microsomal assay  by  Simmon (1579).  The compound was  mutagenic when
exposure was by vapor phase in a dessicator.
     C.    Teratogenicity, Other Reproductive Effects and Chronic Toxicity
           Pertinent data could not be located in the available literature.
     D.   Acute Toxicity
          A  number of studies have been  conducted on the acute toxicity of
benzyl chloride  vapor to animals  and  were reviewed  in a criteria  document
prepared by  NIOSH (1978).   Respiratory tract inflammation and  secondary in-
fections were observed  in  mice exposed  to  390 mg/nP  (LC5Q)  for two  tiours
and  rats   exposed  to  740  mg/m^  (LC5Q)  for  two  hours  (Mikhailova,  1965).
                                      It
                                      re*
                                  J/-7

-------
 Rabbits exposed  to  480  mg/m3  of benzyl  chloride for  eight hours/day  for
 six days suffered mild eye and nasal irritation by  the sixth day,  while cats
 exposed to the same  regimen suffered a  loss  of appetite in  addition  to  eye
 and respiratory  tract irritation  (Wolf,  1912).    Death  of  a dog  occurred
 within  24  hours  of  exposure to  1,900  mg/nv5  of  benzyl  chloride  for  eight
 hours.   Corneal  turbidity  and  irritation  of  the  ocular,  respiratory,  and
 oral mucosa were  observed before death  (Schutte,  1915).  Mikhailova  (1965)
 observed hepatic  changes  and necrosis of the kidney in rats  and mice exposed
 to  benzyl  chloride at 100 mg/m^.
           Landsteiner and Jacobs- (1936) investigated  the  sensitizing proper-
 ties of benzyl chloride to guinea pigs.  Benzyl chloride, in a saline  solu-
 tion (0.01 mg/animal)  was  injected  intracutaneously  twice  per week for  12
 weeks.   Two weeks later,  re-exposure  revealed that  benzyl  chloride  had  a
 sensitizing effect.
           Occupational exposures to  benzyl chloride  have been  reported  by
 several investigators (Wolf,  1912;  Schutte, 1915;  Mikhailova, 1971;  Katz  and
'Talbert,  1930; Watrous,  1947).   Lacrimination, conjunctivitis,  and  irrita-
 tion of the respiratory tract and eyes have been reported following  exposure
 to  benzyl  chloride vapor levels ranging from 6 to  8  mg/m3 for five minutes
 to  brief exposure at  23,600 mg/m3.   Although  no cases were reported in  the
 literature,  liquid benzyl  chloride  has  the  potential  for  skin   irritation
 based on its release  of hydrochloric acid upon hydrolysis.   The odor thresh-
 old  and nasal  irritation thresholds for  benzyl chloride  are 0.21  to 0.24
 mg/m3  and  180  mg/nr5,  respectively  (Katz  and  Talbert,  1930;  Leonardos,   et
 al.  1969).

-------
 V.    AQUATIC  TOXICITY
      A.   Acute  and  Chronic  Toxicity
          Pertinent  data could not be  located  in  the available literature.
      8.  • Plant  Effects
          Inhibition of  cell multiplication in Microcystis  aeruqinosa  start-
 ed at 30 mg/1 (Bringmann and Kuhn, 1976).
      C.   Residues
          Pertinent  data could not be  located  in  the available literature.
      0.   Other  Relevant Information
          Hiatt,  et  al.  (1953)  found  that l.Q mg/1 of benzyl chloride pro-
 duced no irritant response in marine fish,  but 10 mg/1 caused a slight irri-
 tant  activity.   This compound  caused paralysis in the fish  Trutta iridea and
 Cvprinus  carpio  at  concentrations  of  10 mg/1  and  17  mg/1,  respectively
 (Meinck, et al.  1970),.
 VI.   EXISTING GUIDELINES AND STANDARDS
      A.   Human
          The  American Conference of  Governmental .and Industrial Hygienists
 (ACGIH, 1977)  recommends an occupational  exposure  limit of 1 ppm (5 mg/m^)
 for benzyl chloride.  The  U.S.  federal standard  promulgated by  OSHA is also
 1 ppm (TWA)  (29  CFR  1910.1000).  NIQSH  recommends  an environmental exposure
 limit of 5 mq/mj as a ceiling value for a 15-minute exposure (NIOSH,  1978).
     3.   Aquatic
          NO  guidelines  to protect fish and saltwater organisms from benzyl
chloride toxicity  have been established because of  the  lack  of  available
data.

-------
                                   REFERENCES
 American Conference of Governmental Industrial Hygienists.   1977.   Threshold
 Limit Values  for Chemical  Substances and  Physical Agents  in the  Workroom
 Environment.   Cincinnati,  Ohio.

 Anderson,  E.I. and  W.A.  Mosher.   1551.   Incorporation of  S35 from  
-------
 Katz,  S.H.  and E.J.  Talbert.   1930.   Intensities of  odors and  irritating
 effects  of warning  agents for  inflammable  and poisonous  gases,  Paper  480.
 U.S. Department of Commerce, Bureau of Mines.   37 pp.

 Knight,  R.H. and L.  Young.   1558.  Biochemical studies of  toxic  agents —
 II. The  occurrence of premercapturic acids.  Biochem.  Jour.   70: 111.
         •-.. •
 Landsteiner, k. and  J. Jacobs.  1936.   Studies on  the sensitization of  ani-
 mals with simple chemical  compounds, II.  Jour. Exp. Med.  64: 625.

 Leonardos,  G.,  et al.  1969.    Odor  threshold determinations of  53 odorant
 chemicals.  Jour. Air Pollut. Control Assoc.  29: 91.

 Maitrya, B.B. and C.R. Vyas.   1970.   Studies on conjugation of organic  com-
 pounds in the rat.  Ind. Jour. Biochem.  7: 284.

 McCarm,  a.,  et  al.   1975a.  Detection of carcinogens  as mutagens ~ Bacter-
 ial tester strains  with  R  factor plasmids.   Proc.  Natl.  Acad.  Sci.,  USA.
 72: 979.

 McCann,  J.,  et  al.   1975b. Detection of carcinogens as mutagens in the  Sal-
 monella/microsome test —  Assay  of 300  chemicals.   Proc. Natl.  Acad.  Sea..,
 USA.  72: 5D5.

 Meinck, f.., et  al.  1970.  Les eaux residuaires industrielles.

 Mikhailova,  T.v.   1965.   Comparative toxicity of  chloride derivatives of
 toluene — Benzyl  chloride,  benzal  chloride  and  benzotrichloride.    Fed.
 Proc.  (Trans. Suppl.)  24: T877.

 Mikhailova,   T.V.     1971.   Benzyl   chloride  In:   ILQ   Encyclopedia   of
Occupational  Health  and  Safety,  Vol.   1.    Geneva,   International  Labour
Office: 169.

National  Institute  for Occupational  Safety  and Health.   1977.   Information
 profiles on  potential occupational hazards,  benzyl chloride.  OHEW,  210-77-
 0120.

 National Institute  for Occupational  Safety and Health.   1978.   Criteria for
 a  Recommended  Standard...Occupational  Exposure to Benzyl  Chloride.   OHEY*
 78-182.

 Poirier, L.A.,  et al.  1975.   Bioassay of alkyl halides and nucleotide base
 analogs by pulmonary tumor response to strain A mice.   Cancer Res.   35:  1411.

Rosenkranz, H.S. and  L.A.  Poirier.  1978.  An  evaluation of the  mutagenicity
 and DMA-modifying activity in microbial  systems of  carcinogens and noncarci-
nogens. . Unpublished  report from  U.S. Oept. of Health, Education and Wel-
 fare,  Public Health  Service,  National Institute of Health,  National  Cancer
 Institute.  56 pp.
                                                                        »
Schutte,  H.   1915.    Tests with benzyl  and  benzal chloride.   Dissertation
 translated  from German.  Wurzburg.  Royal Bavarian Julius-iMaximilians  uni-
 versity, Franz Staudenraus Book Printing.  27 pp.
                                  3.1- H

-------
 Simkin,  J.L.  and  K. White.   1957.  The  formation  of hippuric  acid — The
 influence  of  benzoate administration  on  tissue glycine  levels.   Biochem.
 Jour.  65: 574.

 Simmon,  V.F.  1979.   In_ vitro  mutagenicity assays  of chemical  carcinogens
 and  related  .compounds with  Salmonella typhimurium.  Jour. Natl. Cancer  Inst.
 62:  893.

 Stekol,  J.A.   1938.   Studies on the mercapturic acid synthesis in animals —
 IX.  Jour. aid. Chem.  124:  129.

 Stekol,  J.A.   1939.   Studies on the mercapturic acid synthesis in animals —
 XII.  The detoxification  of  benzyl  chloride,  benzyl  alcohol, benzaldehyde,
 and  S-benzyl  homocysteine   in  the  rabbit  and  rat.   Jour.  Biol.   Chem.
 128: 199.

 Suga,  T.,  et al.  1966.  Studies on mercapturic  acids,  effect of some aro-
 matic compounds on the  level of glutathione and  the  activity of  glutathion-
 ase  in the rat.  Jour. Biochem.  59: 209.

 Waelsch, H.  and  0.  Rittenberg.  1942.  Glutathione —  II.  The metabolism of
 glutathione  studied  with isotopic ammonia  and glutamic acid.   Jour. Biol.
 Chem.  144: 53.

 watrous, R.M.   1947.   Health hazards  of  the pharmaceutical  industry.    Br.
 Jour. 'Ind. Med.  4: 111.

 Weast, R.C.   1972.   Handbook of Chemistry  and Physics, 53rd ed.  Chemical
 Rubber Company, Cleveland, Ohio.

 Windholz, M., et al.  1976.   Merck Index,  9th ed.  Merck and Co., Inc., Rah-
way, New Jersey.

Witter,  R.F.  1944.   The  metabolism of  monobromobenzene, benzene,  benzyl
chloride and related  compounds  in  the rabbit.   Ann  Arbor,  University  of
Michigan, University  Microfilms,  Dissertation.   1-7, 32-35,  37-66,  93,  197,
 113-118,  126-138.

Wolf, w.  1912.  Concerning the Effect of Benzyl  Chloride  and Benzal Chlor-
ide on the Animal Organisms.   Translation  of dissertation from German, Wurz-
burg, Royal  Bavarian  Julius-Maximilians university.  Franz Staudenraus Book
Printing, 25 pp.

-------
                                      No. 22
             Beryllium


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION


U.S. SPA's Carcinogen Assessment Group (GAG) has evaluated
beryllium and has found sufficient evidence to indicate
that this compound is carcinogenic.

-------
                          BERYLLIUM

                           SUMMARY




     Beryllium was shown to be carcinogenic in three animal

species, producing cancers of the lung and bone when admin-

istered by injection, inhalation, or intratracheal  instilla-

tion.  Ingestion of beryllium has failed to produce cancers

in animalsf possibly due to its poor gastrointestinal absorp-

tion.  Several'epidemiology studies support the hypothesis
                            •
that beryllium is a human carcinogen.

     Beryllium is toxic to freshwater organisms at concentra-

tions as low as 5.3 pg/1.  Pertintent data for marine or-

ganisms were not found in the available literature  (U.S.

EPA, 1979).

-------
                           BERYLLIUM
. I .    INTRODUCTION
      This  profile is primarily based upon the Ambient Water
 Quality Criteria Document for Beryllium (U.S. EPA, 1979).
 Recent comprehensive reviews on the hazards of beryllium
 have also  been prepared by the National Institute for Occupa-
 tional Safety and Health (NIOSH,  1972)  and the International
 Agency for Research on Cancer (IARC, 1972) .
      Beryllium (Be; atomic weight 9.01) is--a dark gray metal
 of  the al'kaline earth family.  Beryllium has the following
 physical-chemical properties (IARC, 1972)  :
                Boiling point:      2970°C
                Melting point:      1284 - 1300 C
                Hardness:           60 - 125
                Density:            1.84 - 1.85
                Solubility:         Soluble in acids and alkalis
 World production of beryllium was reported as approximately
 250 tons annually, but much more reaches  the environment
 as  emissions from .coal burning operations  (Tepper, 1972).
 Most common beryllium compounds are readily soluble in water.
 The hydroxide is soluble only to the extent of 2 rag/1 (Lange,
 1956).  Beryllium forms chemical compounds in which its
 valence is -t-2.  At acid pH, it behaves as a cation but forms
 anionic complexes at pH greater than 8 (Krejci and Scheel,
 1966) .  The major source of beryllium in  the environment
 is  the combustion of fossil fuels  (Tepper, 1972).  Beryl-
 lium enters the waterways through weathering of rocks and
 soils, through atmospheric fallout and through discharges
 from  industrial and municipal operations.
                               X.

-------
II.  EXPOSURE
   .  A.   Water
          Kopp and Kroner (1967) reported the results of
trace metal analyses of 1,577 drinking water samples.obtained
throughout the United States.  Beryllium was detected in
5.4 percent of the samples.  Concentrations ranged  from
0.01 to 1.22 ug/1, with a mean value of 0.19 ug/1.
     B.   Food
          Beryllium has been detected in a- variety  of vege-
tables, and in eggs, milk, nuts, bread, and baker's yeast
(Meehan and .Smythe, 1967; Petzow and Zorn, 1974).   Measured
levels of beryllium were generally in the range of  0.01
to 0.5 ppm.  Using the data for consumption and bioconcen-
tration for freshwater and saltwater fishes, mollusks, and
decapods, and the measured steady-state bioconcentration
factor (BCF) for beryllium in bluegills, the U.S. EPA  (1979)
has estimated a weighted average BCF.for beryllium  to be
19 for the edible portions of fish and shellfish consumed
by Americans.
     C.   Inhalation
          The detection of beryllium in air is infrequent
and usually in trace amounts.  In urban areas beryllium
levels may reach 0.008 ug/m , while  in rural areas  beryllium
concentrations have been measured at 0.00013 pg/m   (Tabor
and Warren, 1953; National Air Sampling Network, 1968).
At a beryllium extraction plant in Ohio, beryllium  concen- »
trations were generally around 2 ug/m"1 over a seven year
period (Breslin and Harris, 1959).

-------
III. PHARMACOKINETICS
     Ingested beryllium is poorly absorbed within  the  gastro-
intestinal tract, presumably due to solubility problems
in the alimentary canal (HyslopT et al.  1943; Reeves,  1965).
When inhaled, soluble beryllium compounds are rapidly  re-
moved from the lung, whereas insoluble beryllium compounds
can remain in the lung indefinitely (Van Cleave and Kaylor,
1955; Wagner, et al. 1969; Sprince, et al. 1976).  When
parenterally administered, beryllium  is  di-stributed to all
tissues, although it shows preferential  accumulation  in
bone, followed by spleen, liver, kidney  and muscle (Van
Cleave and Kaylor, 1955; Crowley, et  al. 1949; Klemperer,
et al. 1952; Kaylor and Van Cleave, 1953; Spencer, et  al.
1972).  Absorbed beryllium tends to be either excreted in
the urine or deposited in kidneys and bone  (Scott, et  al.
1950).  Once deposited in the  skeleton,  beryllium  is  removed
very slowly, with half-lives of .elimination reported  to
be 1,210, 890, 1,770 and 1,270 days in mice, rats, monkeys,
and dogs, respectively (Furchner, et  al.  1973).
IV.  EFFECTS
     A.   Carcinogenicity
          Beryllium was shown  to be carcinogenic in three
animal species.  Intravenous injection of beryllium,  zinc
beryllium silicate, and beryllium phosphate produced  osteo-
sarcomas in the rabbit (Gardner and Heslington, 1946;  Dutra
                                                            #
and Largent, 1950; Komitowski, 1969;  Fodor, 1971;  IARC,
1972).  Inhalation and intratracheal  instillation  of  beryl-

-------
lium compounds have produced lung cancers in the rat and
monkey (Vorwald and Reeves, 1959; Vorwald, et al. 1966;
Reeves, et al. 1967).  Ingestion of beryllium by rats and
mice has failed to induce tumors, possibly due to the poor
absorption of beryllium from the gastrointestinal tract.
          Several epidemiological studies have failed to
establish a clear association between beryllium exposure
and cancer development (Stoeckle, et al. 1969; Mancuso,
1970; Niemoller, 1963).  However, other recent studies sup-
port the hypothesis that beryllium is a human carcinogen
(Berg and Burbank, 1972; Wagoner, et al. 1978; Discher,
1978) .
     B.   Mutagenicity
          Pertinent data were not found in the available
literature.
     C.   Teratogenicity
          Beryllium has been implicated as a teratogen in
snails (Raven and Sprok, 1953) and has inhibited limb re-
generation in the salamander, Amblystoma punctatum  (Thorton,
1950).
     D.   Other Reproductive Effects
          Pertinent data were not found in the available
literature.
     E.   Chronic Toxicity
          Chronic beryllium inhalation in humans produces
a progressive, systemic disease which may follow the ces-
sation of exposure by as long as five years  (Tapper, et

-------
al. 1961; Hardy and Stoeckle, 1959).  Symptoms  include  pneu-
monitis with cough, chest pain, and general weakness.   Sy-
stemic effects include right heart  enlargement  with  cardiac
failure, enlargement of liver and spleen, cyanosis,  digital
clubbing, and kidney stones  (Hall,  et al. 1959).  Chronic
beryllium disease can be produced in rats and monkeys by
inhalation of beryllium sulfate at  35 pg/m   (Schepers,  et
al. 1957; Vorwald, et al. 1966).
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
                                        •
          Acute toxicity data for beryllium for  freshwater
fishes are taken from 22 static and 5 flow-through bioassays,
all 96 hours in duration.  U.S. EPA (1979) presents  the
most sensitive species, the guppy Poecilia reticulata,  with
LC^Q values ranging from 71  to 17,500 jag/1.  The data re-
flect that the toxicity of beryllium to  freshwater fish
is decreased in hard water.  This has also been confirmed
by U.S. EPA (1979) in the fathead minnow, Pimephales prome-
las, with LC^g values ranging from  82 to 11,000  ug/1.   Acute
toxicity for aquatic invertebrates  provides two 48-hour
LCen values of 7,900 and 2,500 ug/1, with water  hardness
values of 180 and 200 jig/1 as CaCo^.  The source of  these
invertebrate studies is the  same for chronic freshwater
studies.  No data for acute  toxicity to marine  species  was
found in the available literature.

-------
     B.   Chronic Toxicity
          No chronic tests for freshwater fish were  found
in the available literature.  The clacioceran, Daphnia maqna,
was the only- freshwater species tested for chronic effects;
chronic values of less than 36 ug/1 and 5.3 ug/1 were ob-
tained by the U.S. EPA (1979).  No chronic data for  marine
species of fish or invertebrates was found in the available
literature.
     C.   Plant Effects                    \
          The only plant study available reveals that the
green algae, Chlorella vannieli, displayed growth inhibition
at a concentration of 100,000 ug/1 (U.S. EPA, 197*).
     D.   Residues
          Exposure of the bluegill for 28 days produced
a bioconcentration factor of 19 (U.S.  EPA, 1978).   No other
data was found in the available literature.
     E.   Other Relevant Information
          The only marine data presented showed reduced
alkaline phosphatase activity in the mummichog, Fundulus
heteroclitus, at concentrations as low as 9 ug/1.  A tera-
togenic response was observed by Evola-Maltese  (1957) in
sea urchin embryos at concentrations of 9.010 ug/1.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          The present standard for occupational exposure
to beryllium prescribes an 8-hour time-weignted average

-------
of 2.0 ug/m  with a ceiling concentration of 5.0 pg/ra  .
This is the same value recommended by the American Confer-
ence of Governmental Industrial Hygienists  (1977).  The
National Institute for Occupational Safety  and Health  (NIOSH,
1972) recommends that occupational exposure to beryllium
and its compounds not exceed 1 pg/m   (8-hour time-weighted
average) with a ceiling limit of 5 ug/m   (measured over
a 15 minute sampling period).
          National Emission Standards for Hazardous Air
Pollutants set their criterion as not more  than  10 g in
24 hours or emissions which result in maximum outplant con-
centrations of 0.01 pg/m  , 30-day average  (U.S.  EPA, 1977).
          Based on animal bioassay data for beryllium  to
which the linear model was applied, the U.S. EPA (1979)
has estimated levels of beryllium in  ambient water which
will result in carcinogenic risk for  humans.  As a result
of the public comments received, additional review and re-
evaluation of the data base is required before a final cri-
terion level can be recommended.
     B.   Aquatic
          The U.S. EPA proposed a water quality  standard
of 11 pg/1 for the protection of aquatic  life in soft  fresh-
water; 1,100 pg/1 for the protection  of aquatic  life in
hard freshwater; and 100 pg/1 for continuous irrigation
on all soils, except 500 mg/1 for irrigation on  neutral
to alkaline lime-textured soils  (U.S. EPA,  1977).

-------
          The National Academy of Science/National Academy
of Engineering  (1973) Water Quality Criteria  recommendation
for marine aquatic life is: hazard level - 1.5 ug/1; minimal
risk of deleterious effects - 0.1 mg/1; and application
factor - 0.01 (applied to 96-hour LC^n) •  Their recommenda-
tion for irrigation water is: 0.10 mg/1 for continuous use
on all soils.
          The U.S. EPA (1979) has derived a draft criterion
for beryllium to protect freshwater aquatic organisms.
The 24-hour average concentration in ug/1 is  dependent on
water hardness and is derived by the following equation:
               ££ 3 e(1.24 In (hardness) - 6.65)

The concentration not to be exceeded at any time is:
               _,   a (1.24 In (hardness) - 1.46)
               CJ\ — e
No draft criterion was derived for marine organisms  (U.S.
SPA, 1979).         '

-------
                          BERYLLIUM   .

                          REFERENCES

American Conference of Governmental Industrial Hygienists
1977.  Threshold limit values for chemical substances  in
workroom ai;r adopted by ACGIH for 1977.  ACGIH, P.O. Box
1937, Cincinnati, Ohio 45201.

Berg, J.W., and F. Burbank.  1972.  Correlations between
carcinogenic trace metals in water supply and cancer mor-
tality.  Ann. N.Y. Acad. Sci.  199: 249.

Breslin, A.J., and W.B. Harris.  1959.  Health protection
in beryllium facilities.  Summary of ten years of experience.
AMA Arch Ind. Health  19: 596.

Crowley, J.F., et al.  1949.  Metabolism of carrier-free
radioberyllium in the rat.  Jour. Biol. Chem.  177: 975.

Discher, D.P.  1978.  Letter to w.H. Foege, Director,  Center
for Disease Control HEW  (published in BNA Occupational Safety
and Health Reporter) 8: 853.

Dutra, F.R., and F.J. Largent.  1950.  Osteosarcoma induced
by beryllium oxide.  Am. Jour. Pathol.  26: 197.

Evola-Maltese, C.  1957.  -Effects of beryllium on the  develop-
ment and alkaline phosphatase activity of Paracentrotus
embryos.  Acta Embryol. Morphol. Sxp. 1: 143.

Fodor, J.  1971.  Histogenesis of bone tumors induced  by
beryllium.  Magyar Onkol.  15: 180.

Furchner, J.E., et al.  1973.  Comparative metabolism  of
radionucleotides in mammals.  VIII: Retention of beryllium
in the mouse, rat, monkey, and dog.  Health Physics  24:
293.

Gardner, L. U., and H.F. Heslington.  1946.  Osteo-sarcoma
from intravenous beryllium compounds in rabbits.  Fed. Proc.
5: 221.

Hall, T.C., et al.  1959.  Case data from the beryllium
registry.  AMA Arch. Ind. Health  19:100.

Hardy, H.L., and J.D. Stoeckle.  1959.  Beryllium disease.
Jour. Chron. Dis.  9: 152.

Hyslop, F., et al.  1943.  The toxicology of beryllium.
U.S. Pub. Health Serv. Natl. Inst. Health Bull.  181.

IARC.  1972.  Monographs on  the evaluation of carcinogenic
risk of chemicals to man.  Beryllium: 1: 17.

-------
Kaylor, C.T.,  and C.D. Van Cleave.  1953.  Radiographic
visualization of the deposition of radioberyllium  in  the
rat.  Anat. Record  117: 467.

Klemperer, F.W., et al.  1952.  The fate of beryllium com-
pounds in 'the rat.  Arch, aiochem. Biophys.  41: 148.

Komitowski, D.  1969.  Morphogenesis of beryllium-induced
bone tumors.  Patol. Pol (suppl.)  1: 479.

Kopp, J.F., and R.C. Kroner.  1967.  A five year study of
trace metals in waters of the United States.  Fed. Water
Pollut. Control Admin., U.S. Dep. Inter., Cincinnati, Ohio.

Krejci, L.E.,  and L.D.  Scheel.  1966.  Ln H.E. Stokinger,
ed. Beryllium: Its industrial hygiene aspects.  Academic
Press, Inc., New York.

Lange, N.A. ed.  1956.  Lange's handbook of chemistry.
9th ed. Handbook Publishers, Inc., Sandusky, Ohio.

Mancuso, T.F.   1970.  Relation of duration of employment
and prior illness to respiratory cancer among beryllium
workers.  Environ. Res.  3: 251.

Meehan, W.R.,  and L.E. Smythe.  1967.  Occurrence  of beryl-
lium as a trace element in environmental materials.  Environ.
Sci. Technol.   1: 839.

National Academy of Sciences, National Academy of  Engineer-
ing.  1973.  Water quality criteria 1972.  A report.  Natl.
Acad.  of Sci., Washington, D.C.

National Air Sampling Network, Air Quality Data.   1968.
National Air Sampling Network, Durham, N.C., U.S.  Dep. Health
Education and Welfare, Pub. Health Serv.

National Institute of Occupational Safety and Health.  1972.
Criteria for a recommended standard... .Occupational exposure
to beryllium.   DHEW  (NIOSH) ?ubl. No. 72-10806.

Niemoller, H.K.  1963.  Delayed carcinoma induced  by beryl-
lium aerosol in man.  Int. Arch. Gewerbepthol. Gewerbehyg.
20: 18.

Petzow, G., and H. Zorn.  1S74.  Toxicology of beryllium-
containing materials.  Chemlxer Vig.  98: 236.

Raven, C.P., and N.S. Sprcn.<.  1953.  Action of beryllium
on the development of Limnaei stagnalis.  Chem. Abstr.
47: 6561.

-------
Reeves, A.L.  1965.  Absorption of beryllium from the gastro-
intestinal tract.  AMA Arch. Environ. Health  11: 209.

Reeves, A.L.,  et al.  1967.  Beryllium carcinogenesis. I.
Inhalation exposure of rats to beryllium sulfate aerosol.
Cancer Res..27: 439.

Schepers, G.W.H., et al.  1957.  The biological action of
inhaled beryllium sulfate.  A preliminary chronic toxicity
study in rats.  AMA Arch. Ind. Health  15: 32.
Scott, J.K., et al.  1950.  The effect of added carrier
on the distribution an<
Biol. Chem.  172: 291.
                                          	y—
on the distribution and excretion of soluble  Be. Jour.
Spencer, H.C., et al.  1972.  Toxicological evaluation of
beryllium motor exhaust products.  AMRL-TR-72-118.  Aero-
medical Res. Lao. Wright-Patterson AFB, Ohio.

Sprince, N.L., et al.  1^76.  Current  (1975) problems of
differentiating between beryllium disease and. sarcoidosis.

Stoeckle, J.D., et al.  1969.  Chronic beryllium disease:
Long-term follow-up of 60 cases and selective review of
the literature.  Am. Jour. Med.  46: 545.

Tabor, B.C., and W.V. Warren.  1958.  Distribution of cer-
tain metals in the atmosphere of some American cities.
Arch.  Ind. Health.  17: 145.

Tepper, L.3.  1972.  Beryllium.  CRC critical reviews in
toxicology.  1: 235.

Tepper, L.B., et al.  1961.  Toxicity of beryllium compounds.
Elsevier Publishing Co., New York.

Thornton, C.S.  1950.  Beryllium inhibition of regenerations.
Jour. Exp. Zool.  114: 305.

U.S. EPA.  1977.  Multimedia environmental goals for environ-
mental assessment.  Vol. II. MEG charts and background inform-
ation.  EPA-b0017-77-136b.  U.S. Environ. Prot.Agency.

U.S. EPA.  1978.  In-depth studies on health and environmental
impacts of selected water pollutants.  U.S. Environ. Prot.
Agency, Washington, D.C.

U.S. EPA.  1979.  Beryllium:  Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.

Van Cleave, C.D., and C.T. Kaylor.  1955.  Distribution,
retention and elimination of  Be in the rat after intratra-
cheal injection.  AMA Arch. Ind. Health  11: 375.

-------
Vorwald, A.J., and A.L. Reeves.  1959. ..Pathologic changes
induced by beryllium compounds.  AMA. Arch. Ind. Health
19: 190.

Vorwald, A.J., et al.  1966.  Experimental beryllium toxi-
cology,  in H.E. Stokinger, ed. Beryllium, its industrial
hygiene aspects.  Academic Press, New York.

Wagner, W.D., et al.  1969.  Comparative inhalation toxicity
of beryllium  ores bertranaite and beryl with production
of pulmonary tumors by beryl.  Toxicol. Appl. Pharmacol.
15: 10.

Wagoner, J.K., et al.  1978.  Beryllium: carcinogenicity
studies.  Science 201: 298.

-------
                                      No.  23
     Bis(2-chloroethoxy)raethane

  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.

-------
                          3IS(2-CHLOROETHOXY)METHANE
                                    Summary
     Pertinent data could not be  located in the available literature search-
es on  the  mutagenic,  carcinogenic, teratogenic, or  adverse  reproductive ef-
fects  of  bis(2-chloroethoxy)methane  (BCEXM)  in mammals.  A closely related
compound,  bis(2-chloroethoxy)ethane  (BCEXE) has been shown to  produce skin
tumors and injection site sarcomas in animal studies.
     Pertinent information  could,  not be located in  the  available literature
on bis(2-chloroethoxy)methane toxicity to aquatic organisms.

-------
                          BIS( 2-CHLOROETHOXY )METHANE
I.   INTRODUCTION
     This profile  is based  on the  Ambient Water  Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
     The Chloroalkyl ethers  are compounds in  which a hydrogen atom  in one  or
both of  the aliphatic  ether chains  are substituted  with chlorine.  Bis (2-
chloroethoxy)methane    (3CEXM,    dichloroethyl    formal,   C1CH2CH2-0-CH2-
             is  a  colorless  liquid  at  room  temperature  with a boiling
point  of  218. 1°C  and  a  specific  gravity  of  1.2339.    The  compound   is
slightly soluble in water but miscible with most organic solvents.
     The Chloroalkyl ethers have  a wide variety of industrial  uses in organ-
ic synthesis,  treatment  of textiles, the manufacture  of polymers and insec-
ticides, as  decreasing  agents  and solvents,  and  in  the  preparation of ion
exchange resins (U.S. EPA, 1979a).
     The Chloroalkyl  ethers,  like  BCEXM,  have  a  higher  stability  in water
than the alpha Chloroalkyl ethers, which decompose.   BCEXM is decomposed  by
mineral acids.
II.  EXPOSURE
     NO specific information  on exposure to BCEXM is  available.   The reader
is referred  to a  more general  treatment  of  chloroalkyl  ethers  (U.S.  EPA,
1979b).  3CEXM has been monitored  in  rubber  plant  effluents at  a maximum
level  of  140  mg/1  (Webb,  et   al.  1973).   Bis-l,2-(2-chloroethoxy)ethane
(BCEXE), a closely  related compound, has been  reported in drinking water at
a maximum  level of 0.03 ug/1 (U.S.  EPA,  1975).   Data on  levels  of  BCEXM in
foods was not found in the available literature.
     No bioaccumulation factor for BCEXM has been derived.

-------
III. PHARMACOKINETICS
     Pertinent  information  could not be  located  in the available  literature
on BCEXM.  The  reader is  referred  to a more general treatment of chloroalkyl
ethers. (U.sl EPA, 1979b).
IV.  EFFECTS
     A.  Carcinogenicity
         Pertinent information could not  be located in the available  litera-
ture on  carcinogenic effects  of BCEXM.   The reader  is  referred  to  a more
general  treatment  of chloroalkyl  ethers   (U.S. EPA,  I979b).  A closely re-
lated compound, BCEXE, has been  shown to  produce  skin tumors in mice  and in-
jection site sarcomas (Van Ouuren, et al.  1972).
     B.  Mutagenicity, Teratogenicity, Other  Reproductive  Effects and Chron-
         ic Toxicity
         Pertinent data could not  be located in the available literature for
BCEXM.
V.   AQUATIC TOXICITY
     Pertinent  information  could not be  located  in the available  literature
on the aquatic toxicity of BCEXM.
VI.  EXISTING GUIDELINES AND STANDARDS
     No standards or  recommended criteria exist  for  the  protection of human
health or aquatic organisms to bis(2-chloroethoxy)methane.

-------
                          3IS( 2-CHLOROETHOXY)METHANE

                                  RE
U.S. EPA.,  1975.   Preliminary assessment of  suspected carcinogens in drink-
ing water:'Interim report to Congress, Washington, O.C.

U.S.  EPA.   1979a.   Chloroalkyl  Ethers:   Ambient  Water Quality  Criteria.
(Draft)

U.S. EPA.   1979b.   Environmental Criteria  and Assessment  Office.   Chloro-
alkyl Ethers: Hazard Profile.  (Draft)

Van  Ouuren,  et  al.   1972.   Carcinogenicity  of haloethers.   II. Structure-
activity  relationships  of  analogs of  bis(chloromethyl)ether.   Jour.  Natl.
Cancer Inst.  48: 1431.

Webb, R.G., et al.   1973.   Current practice in GC-MS analysis of organics in
water.   Publ. EPA-R2-73-277.  U.S. Environ. Prat. Agency, Carvallis, Oregon.

-------
                                      No. 24
      Bi3<2-chloroethyl)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  infornation  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


bis(2-chloroethyl)ether and has found sufficient evidence to
                                             •

indicate that this compound is carcinogenic.

-------
                            BIS(2-CHLOROETHYL)ETHER
                                    Summary
     Oral  administration of bis(2-chloroethyl)ether  (BCEE) did  not produce
an increase  of  tumors in rats.  Male  mice  showed a  significant  increase in
hepatomas after  ingestion  of BCEE.  BCEE has also shown activity as a tumor
initiator for mouse skin.
     Testing  of BCEE  in  the  Ames1  Salmonella  assay,  in E^ cpli,  and in
Saccharomyces  cerevisiae  has  shown  that  this  compound  induces  mutagenic
effects.
     There is  no. available evidence  to  indicate that BCEE produces adverse
reproductive effects or teratogenic effects.
     The data  base for bis (2-chloroe thy Wether is limited  to  three studies.
The 96-hr  LC5Q value for  the  bluegill is reported to be over 600,000 ;jg/l.
Adverse chronic  effects  were not  observed  with the  fathead  minnow  at test
concentrations as  high as  19,000  jug/1.  A bioconcentration factor  of 11 \yas
observed during a 14-day  exposure  of bluegills.   The half-life was 4-7 days.
                                 ^t^-lf

-------
                            BIS( 2-CH.QRQETHYDETHER
I.   INTRODUCTION
     This  profile  is based  on the  Ambient Water Quality  Criteria Document
for Chloralkyl Ethers (U.S. EPA,  1979a).
     The chloroalkyl ethers are compounds in which a hydrogen atom  in one or
both of  the aliphatic  ether chains  are substituted with  chlorine.  8is(2-
chloroethyl)ether  (BCSE,  molecular  weight  143.01) is a  colorless liquid at
room temperature with  a  boiling  point  of 176-178°C  at 760  mm Hg,  and a-
                             •
density of 1.213.   The compound  is practically  insoluble  in water,  but is
miscible with most organic solvents  (U.S. EPA, 1979a).
     The chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic  synthesis,  in  textile treatment,  the manufacture of polymers
and insecticides,  as degreasing agents,  and in  the  preparation  of ion ex-;
change resins (U.S. EPA, 1979a).
     The B-substituted  chloroalkyl ethers, such,  as 3CEE,  are generally more
stable and hence  less  reactive  in aqueous  systems  than  the a-substituted
compounds  (U.S. EPA, 1979a).
     for additional  information regarding chloroalkyl ethers in general, the
reader is  referred  to the  EPA/ECAO  Hazard Profile  on Chloroalkyl  Ethers
(U.S.  EPA  1979b).

II.  EXPOSURE
     The B-chloroalkyl ethers  have been monitored in water.   Industrial dis-
charges from chemical plants involved  in the manufacture of glycol products,
rubber, and insecticides  may  contain high  levels  of  BCEE (U.S.  EPA, 1979a).
The highest concentration of SCEE  in drinking water  reported by  the U.S.* EPA

-------
(1975) is  Q.5 jjg/1.  There  is no evidence of  the occurrence of the  chloro-
alkyl  ethers  in the  atmosphere; human  exposure  appears  to  be confined  to
occupational settings.
     Human exposure to chloroalkyl  ethers  via ingestion  of food is  unknown
(U.S. EPA, 1979a).  The B-chloroalkyl ethers,  due to their  stability  and  low
water  solubility,  may have  a  high tendency to be bioaccumulated.  The U.S.
EPA  (1979a)  has estimated the weighted average  bioconcentration factor  for
BCEE  to  be  25 for  the  edible  portions of  fish and  shellfish consumed  by
Americans.   This  estimate  is  based  on  a  measured   steady-state  biocon-
centration factor using bluegills.
III. PHARMACOKINETICS
     A.  Absorption
         Experiments  with radiolabelled  8CEE  have  indicated that  the com-
pound  is  readily   absorbed  following  oral  administration  (Lingg,  et   al.
1978).   Information on inhalation or dermal absorption of chloroalkyl  ethers
is not available (U.S. EPA,  1979a).
     B.  Distribution
         Pertinent  information  on  the  distribution  of  BCEE  could  not   be
located in the literature.
     C.  Metabolism
         The biotransformation of BCEE in rats following oral administration
appears  to involve  cleavage  of the  ether  linkage and subsequent conjugation
with non-protein-free sulfhydryl  groups,  the  major route,  or with glucuronic
acid   (Lingg,   et   al.    1978).    Thiodiglycolic   acid   and    2-chloro-
ethanol-8-O-glucuronide were  identified  as urinary  metabolites of BCEE   in
rats.

-------
     0.  Excretion
         BCEE  administered  to rats  by  intubation was  eliminated  rapidly in
the  urine,  with  more than  60 percent  of the  compound excreted  within 24
hours (Uingg',,et al. 1978).
IV.  EFFECTS
     A.  Carcinogenicity
         SCEE  has shown activity  as a  tumor  initiator in  mouse  skin (U.S.
EPA, 1979a).   Preliminary  results  of an NCI study  indicate  that oral admin-
istration of  BCEE does  not produce an  increase in tumor incidence  in rats
(U.S. EPA,  1979a);  however,  mice  administered BCEE  by ingestion  showed a
significant increase in hepatomas (Innes, et al. 1969).
     B.  Mutagenicity
         Testing of  the chloroalkyl  ethers  in  the Ames1 Salmonella assay and.
in  E^  coll have  indicated that. BCEE  induces  mutagenic effects  (U.S.  EPA,
1979a).  BCEE  has also  shown mutagenic effects  in  Saccharomvces  cerevisiae
(Simmon, et  al.  1977), but  none  were  found  in the  heritable translocation
test for mice  (Jorgenson, et al.  1977).
     C.  Teratogenicity, Chronic Toxicity and other Reproductive Effects
         Pertinent information could not be located  in the  available liter-
ature.
     0.  Other Relevant Information
         Acute physiological  responses   of the  guinea  pig  to  inhalation of
high concentrations  of BCEE were congestion, emphysema, edema and  hemorrhage
of the  lungs (Shrenk,  et al.  1933).  Brief exposure of man to BCEE vapor, at
levels   260 ppm,  irritated  the  nasal  passages and eyes with profuse lacri-
mation.  Deep  inhalation produced nausea.   The highest concentration, with no
noticeable effect was 35 ppm (Shrenk, et al. 1933).
                                  A/-

-------
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         96-hr LC5Q  value for  the bluegill, Leoomis  macrochirus,  could not
be  determined, for bis(2-chloroethy1)ether  with  exposure  concentrations as
high as 600,000 ug/1 (U.S. EPA, 1978).
     3.  Chronic Toxicity
         An  embryo-larval test has  been  reported with bis(2-chloroethyl)
ether and the fathead  minnow,  Pimeohales promelas.  Adverse effects were not
     *
observed at test concentrations as high as 19,000 ug/1 (U.S. EPA, 1978).
     C.  Plant Effects
         Pertinent data could not be located in the available literature.
     0.  Residues
         A bioconcsntration  factor of  11 was determined  during a 14-day ex-  4
posure of bluegills to bis(2-chloroethyl)ether.  The half-life  was 4-7 days.
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
         Based  on the results  of  an animal  carcinogenesis  bioassay,  and
using a linear, non-threshold model, the  U.S.  EPA (1979a) has  estimated that
an  ambient water  level of 0.42 ug/1 will present an  increased risk of 10" 3
or  less for  BCEE,  assuming  water  and  the injection of  contaminated aquatic
organisms to be the only sources of exposure.

-------
         The  8-hour,  time-weighted average  threshold limit value  (TLV-TWA)
for 8CEE  determined by  the  American Conference  of  Governmental  Industrial
Hygienists (ACGIH, 1978) is 5 ppm for 8CEE.
     3.  Aquatic
         Freshwater or  saltwater  criteria cannot be  derived for  bis(2-chlo-
roethyDether because of insufficient data (U.S.  EPA,  1979a).

-------
                            aiS( 2-CHLQRQETHYDETHER

                                  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.

Fishbein, L.   1977.   Potential  industrial carcinogens  and mutagens.   Publ.
EPA-56075-77-005, Off. Toxic Subst. Environ. Prot. Agency,  Washington, O.C.

Innes,  J.R.M.,  et al.   1969.   Bioassay  of pesticides  and industrial chem-
icals  for  tumorigenicity in mice:   A preliminary note.   Jour.  Natl.  Cancer
Inst.  42: 1101.
                        •
Jorgenson,  T.A.,  et  al.   1977.   Study  of  the  mutagenic  potential  of
bis(2-chloroethyl) and bis(2-chloroisopropyl)  ethers in  mice by  the heri-
table translocation test.  Toxicol. Appl. Pharmacol.  41: 196.

Lingg, R.O.,  et al.   1978.  Fate  of bis  (2-chloroethyl)ether  in rats after
acute oral administration.  Toxicol. Appl. Pharmacol.  45:  248.

Schrenk, H.H.,  et al.   1933.   Acute response  of guinea  pigs to  vapors of
some  new commercial organic  compounds.   VII.   Oichloroethyl  ether.   Pub.
Health Rep.  48: 1389.

Simmon, V.F.,  et al.  1977.   Mutagenic activity of  chemicals  identified in
drinking water.  In:  0.  Scott, et al.  (ed.)  Progress in genetic toxicology.
Elsevier/North HoITand Biomedical Press, New York.

U.S. EPA.   1975.   Preliminary  assessment of suspected carcinogens  in  drink-
ing water.  Rep. Cong. U.S. Environ. Prot. Agency, Washington, D.C.

U.S.  EPA.   1977a.   National  organic monitoring survey.  General  review of
results  and methodology:   Phases  I-III.   U.S.  Environ. Prot.  Agency,  Off.
Water  Supply,  Tech.   Support  Div.  Presented before  Water Supply  Res.  Oiv.
Phys. Chem. Removal Branch, Oct. 21.

U.S. EPA.   1977b.  Potential industrial carcinogens  and  mutagens.  Office of
Toxic Substances.  EPA-560/5-77-005.  Washington, O.C.

U.S.  EPA.   1978.  In-depth studies on health  and environmental  impacts of
selected  water  pollutants.   U.S.   Environ.   Prot.   Agency,   Contract  No.
68-1-4646.

U.S.  EPA.    1979a.    Chloroalkyl  Ethers:   Ambient Water   Quality  Criteria.
(Draft)

U.S.  EPA.    1979b.   Environmental  Criteria and  Assessment Office.   Hazard
Profile:  Chloroalkyl Ethers.   (Draft).

Van Ouuren,  3.L.   1969.   Carcinogenic apoxides,  lactones,  and haloethers and
their mode of action.  Ann. N.Y. Acad. Sci.  163: 633.

-------
Van Ouuren, 8.L.. et  al.   1969.  Carcinogenicity of  haloethers.   jour.  Natl.
Cancer Inst.  43: 481.
Van Ouuren, B.L.,  et al.  1972.  Carcinogenicity of haloethers.   II.  Struc-
ture-activity . relationships  of  analogs  of  bis(chloromethyl)ether.   Jour.
Mat-i  ranear Inst.  48: 1431.

-------
                                     Mo. 25
    3ia(2-ChloroisopropyI)ether


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

           APRIL  30, 1980
           3LS-./

-------
                          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.

-------
                          BIS(2-CHLOROISOPROPYL)ETHER
                                    Summary

     Preliminary results  from  an NCI carcinogenesis bioassay  do not show  an
increase in  tumors following oral  administration of bis(2-chloroisopropyl)-
ether (8CIE).
     BCIE has produced mutagenic  effects  in two bacterial test systems  (Sal-
monella and  E^ coli) but  has  failed to  show  mutagenicity  in one mammalian
study.
     No information  is  available on the  teratogenic or adverse reproductive
effects of BCIE.
     Chronic exposure to BCIE has produced liver damage in animals.
     Data on  the toxicity of  bis(2-chloroisopropyl)ether to  aquatic' organ-
isms are not available.
                                      -3

-------
                          BIS(2-CHLOROISOPROPYL)ETHER
I.   INTRODUCTION
     This profile  is based  on the  Ambient  Water Quality  Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
     The Chloroalkyl ethers  are  compounds  in which a hydrogen atom in one or
both of  the aliphatic  ether chains .are substituted with  chlorine.   Bis(2-
chloroisopropyl)ether (BCIE,  molecular weight 171.07)  is a colorless liquid
at  room  temperature with  a boiling point of 187-188°C  at 760  mm Hg.   The
compound is practically insoluble in water but is miscible with organic sol-
vents.
                                                                        •
     The Chloroalkyl ethers  have a  wide variety  of industrial and laboratory
uses in  organic synthesis,  treatment  of textiles, the manufacture of poly-
mers and  insecticides,  as degreasing  agents,  and in the preparation of ion
exchange resins (U.S. EPA, 1979a).
     The beta-chloroalkyl ethers, like BCIE,  are more stable in aqueous sys-
tem than  the  alpha-chloroalkyl ethers,  which decompose  rapidly.   For addi-.
tional information  regarding the Chloroalkyl  ethers as  a  class,  the reader
is referred to the Hazard Profile on Chloroalkyl Ethers (U.S. EPA, 1979b).
II.  EXPOSURE
     The beta-chloroalkyl  ethers have  been  monitored  in water.   Industrial
discharges  from  chemical  plants involved  in the manufacture of  glycol  pro-
ducts, rubber, and  insecticides  may present high  effluent  levels (U.S.  EPA,
1979a).  The  highest concentration  of BCIE monitored  in  drinking water by
the U.S. EPA (1975) was reported as 1.58 jug/1.
     The concentrations of Chloroalkyl ethers in  foods  have not  been moni-
tored.  The beta-chloroalkyl  ethers, however,  due  to their relative stabili-
ty and low  water solubility,  may have  a high  tendency  to be bioaccumulated.

-------
The  U.S.  EPA  (1979a)  has  estimated  the weighted  average bioconcentration
factor for  bis(2-chloroisopropyl)ether to be 106  for  the edible portions  of
fish  and  shellfish  consumed by  Americans.   This  estimate is  based on the
octanol/wate-r partition coefficient.
III. PHARMACOKINETICS
     A.  Absorption
         Experiments  with radio-labeled  BCIE have  indicated that  the com-
pound  is  readily  absorbed  following  oral  administration  (Smith,  et al.
1977).  No  information  on inhalation or dermal absorption of the chloroalkyl
ethers is available (U.S. EPA, 1979a).
     B»  Distribution
         Species differences  in the distribution  of radio-labeled  BCIE have
been reported by  Smith, et al.  (1977).  Monkeys  retained  higher amounts  of
radioactivity in the  liver,  muscle, and  brain  than did rats.  Urine  and ex-
pired  air  from monkeys  also contained  higher  levels  of radioactivity than
those determined in the rat.   Blood levels of BCIE in  monkeys reached a peak
within 2 hours following  oral  administration and then declined in a biphasic
manner (t 1/2 = 5 hours and 2 days, respectively).
     C.  Metabolism
         Urinary metabolites of  labeled BCIE identified in studies  with rats
included l-chloro-2-propanol,  propylene  oxide,  2-(l-methyl-2-chloro-ethoxy)
propionic acid, and carbon dioxide  (Smith, et al. 1977).
     0.  Excretion
         Smith, et  al.  (1977)  found  that  in  the rat,  63.36  percent,  5.37
percent,  and 15.96 percent of  a 30 mg orally-administered  dose  of BCIE were
recovered after 7  days in the  urine,   feces, and  expired air,  respectively.
In the monkey,  the corresponding  figures were 28.61  percent,  1.19 percent,
and Q percent, respectively.

-------
 IV.  EFFECTS
     A.  Carcinogenicity
         Preliminary  results  of  an NCI  carcinogenicity  bioassay  indicate
 that oral administration  of 8CIE does not produce an  increase  in tumor inci-
 dence (U.S. EPA, 1979a).
     B.  Mutagenicity
         Testing  of BCIE  in the Ames  Salmonella assay  and  in E..  coli  have
 indicated  that the compound  shows  mutagenic  activity  (U.S.  EPA,  1979a).
 BCIE  did not  show mutagenic effects in the  murine heritable  translocation
 test (Oorgenson, at al. 1977).
     C.  Teratogenicity and Other Reproductive Effects
         Pertinent data could not be located in  the  available literature.
     0.  Chronic Toxicity
         Chronic oral  exposures of mice to BCIE produced centrilobular liver
 necrosis in mice.   The major - effects in rats were  pulmonary congestion  and
 pneumonia (U.S. EPA, 1979a).
     E.  Other Relevant Information
         Several  chloroalkyl ethers show initiating  activity  and  therefore
 may interact  with other  agents to  produce  skin papillomas  (Van 'Duuren,  et
 al. 1969, 1972); however, data  specific to BCIE  is not  available.
 V.   AQUATIC TOXICITY
         Pertinent data could not be located in  the  available literature,
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither  the  human health  nor  the  aquatic  criteria  derived by U.S.  EPA
 (1979a), which are  summarized below, have gone through the process  of-public
review;  therefore,  there  is   a  possibility  that  these  criteria  will   be
changed.

-------
     A.  Human
         BCIE is an  isomer of a group of  chloroalkyl ethers which have been
shown to have,,carcinogenic potential.   BCIE has been  shown to be mutagenic;
however, definitive proof  of  carcinogenicity  has not been demonstrated.  The
available data  is  presently under  review  and a definitive determination as
to the carcinogenicity of this isomer cannot be made at this time.
     B.  Aquatic
         No draft  criteria to protect  fish and saltwater aquatic organisms
from bis(2-chloroisopropyl)ether toxicity have been derived (U.S. EPA, 1979).

-------
                      BIS(2-CHLOROISOPROPYL)ETHER (8CIE)

                                  REFERENCES
Jorgenson,  T.,  et  al.   1977.   Study  of  the  mutagenic potential  of bis(2-
chloroethyl)  and bis(2-chloroisopropyl)  ethers  in  mice  by  the  heritable
translocation test.  Toxicol. Appl. Pharmacol.  41: 196.

Smith, C.,  et al.  1977.   Comparative metabolism of  haloethers.   Ann. N.Y.
Acad. Sci.  298: 111.

U.S. EPA.   1975.   Preliminary assessment of suspected carcinogens in drink-
ing water: Interim report to Congress, Washington, O.C.

U.S.  EPA.   1979a.  . Ghloroalkyl  Ethers:   Ambient Water   Quality  Criteria.'
(Draft)

U.S. EPA.   1979b.  Environmental  Criteria and Assessment  Office.   Chloro-
alkyl Ethers: Hazard Profile.  (Draft)

Van Duuren,  B.,  et al.   1969.   Carcinogenicity of haloethers.  Jour.  Natl.
Cancer Inst.  43: 481.

Van Duuren,  8.,  et  al.   1972.  Carcinogenicity  of haloethers.   II. Struc-
ture-activity  relationships  of  analogs  of  bis(chloroethyl)ether.   Jour.
Natl. Cancer Inst.  48: 1431.

-------
V
                                              No.  26
                Bis(Chloronethyl)ether


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

                     APRIL 30, 1980
                            -I

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

-------
                       SPECIAL NOTATION


U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
bis(chlorotnethyl)ether and has found sufficient evidence  to
indicate that this compound is carcinogenic.

-------
                            BIS(CHLOROMETHYL)ETHER
                                    Summary
     9is(chloromethyl)ether  (BCME)  has been  shown  to produce tumors in  ani-
mals following  administration  by subcutaneous injection, inhalation, or  der-
mal  application.   Epidemiological  studies of workers  in the United States,
Germany,  and Japan who were  exposed to  BCME and  chloromethyl methyl ether
(CMME) indicate that these compounds are  human respiratory  carcinogens.
     BCME  has  produced mutagenic effects in the Ames1  Salmonella assay  and
in ,§.,  coli.  Increased cytogenetic abnormalities  have  been observed in  the
lymphocytes  of  workers  exposed to BCME and CMME;  this effect appeared to  be
reversible.
     There  is  no  available evidence to  indicate that the  chloroalkyl ethers
produce adverse reproductive effects or teratogenic effects.
     Information  has not  been  found  on the toxicity  of  bis(chloromethyl)
ether  to  aquatic  organisms.   The hazard  profiles  on  the hafloethers and  the
chloroalkyl  ethers should be consulted for the toxicity  of  related  compounds.

-------
                            BIS(CHLOROMETHYL)ETHER
I.   INTRODUCTION
     This  profile  is based  on the  Ambient Water Quality  Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
     The Chloroalkyl  ethers  are compounds  in which  hydrogen atoms in one or
both  of the  aliphatic  ether  chains  are  substituted  with  chlorine.   Bis-
(chloromethyl)ether,  (BCME;  molecular weight  115.0),  is  a colorless liquid
at room  temperature with a boiling  point of 104°C at 760  mm Hg,  and a den-
sity of  1.328.  The compound immediately nydrolyies in  water,  but is misci-
ble with ethanol, ether, and many organic solvents (U.S. EPA, 1979a).
     The Chloroalkyl  ethers  have  a  wide  variety of industrial and laboratory
uses  in organic  synthesis,  textile  treatment,  the manufacture  of polymers
and insecticides,  the preparation of ion exchange  resins,  and as degreasing
agents (U.S. EPA, 1979a).
     While BCME is very unstable in  water,  it  appears to be relatively sta-
ble in the atmosphere (Tou and Kallos,  1974).   Spontaneous formation of 3CN€
occurs in  the  presence of both hydrogen  chloride and formaldehyde (Frankel,
et al.  1974).   For additional information regarding the  Chloroalkyl ethers
in general, the reader  is  referred  to the BWECAO Hazard  Profile on Chloro-
alkyl Ethers (U.S. EPA,  1979D).
II.  EXPOSURE
     As  might  be expected from  the reactivity of  BCME  in water, monitoring
studies  have not  detected  its  presence in  water.   Human exposure by inhala-
tion appears to be confined to occupational settings (U.S. EPA, 1979a).
     Data  for  human exposure to  ctrloroalkyl ethers by  ingestion  of  food is
                                                                      »
not available, nor  is data relevant  to  human dermal exposure  to chloralkyl
ethers (U.S. EPA, I979a).

-------
     The U.S.  EPA (1979a)  has  estimated the-  weighted average bioconcentra-
tion factor for BCME  to  be  31 for the edible  portions of fish and  shellfish
consumed by Americans.   This estimate  is based on  the octanol/water parti-
tion coefficient.
III. PHARMACOKINETICS
     There is  no specific  information  relating  to the absorption,  distribu-
tion, metabolism,  or excretion of  BCME  (U.S.  EPA,  1979a).   Because of  the
high reactivity  and  instability of BCME  in  aqueous  systems,  it  is  difficult
to generate pharmacokinetic parameters.
IV.  EFFECTS
     A.  Carcinogenicity
         BCME  has been  shown to produce  tumors in  several animal  systems.
Inhalation exposure   of  male  rats  to' BCME  produced  malignant  respiratory
tract tumors (Kuschner,  et  al.  1975), while dermal application to mouse  skin
led to the appearance of skin tumors  (Van Duuren,  et  al. 1963).   Administra-
tion of  BCME  to  newborn mice  by ingestion has been  shown to increase  the
incidence of hepatocellular 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
that these compounds are human  respiratory carcinogens (U.S. EPA,  1979a).
         BCME  has been shown  to accelerate the  rate  of lung tumor  formation
in  strain  A  mice following  inhalation  exposure (Leong,  et al. 1971).   BCME
has also shown activity  as a tumor initiating agent  for mouse skin  (Slaga,
et al.  1973).
     B.  Mutagenicity
                                                                        »
         Testing of  the  chloroalkyl ethers in the Ames Salmonella assay  and
in §_._ coli have  indicated that SCME  produced  direct  mutagenic effects (U.S.
EPA, 1979a).

-------
         The results of  a study on the  incidence of cytogenetic aberrations
in the lymphocytes of workers  exposed to 8CME and  CCME indicate higher  fre-
quencies in  this cohort.  Follow-up  indicates that removal  of workers  from
exposure  led" to  a decrease  in  the  frequency  of  aberrations  (Zudova and
Landa, 1977).
     C.  Teratogenicity and Other Reproductive Effects
         Pertinent data  could  not  be  located  in  the  available  literature
regarding teratogenicity and other reproductive effects.
     0.  Chronic Toxicity
         Chronic  occupational  exposure  to CMME  contaminated  with BCME has
produced  bronchitis  in  workers (U.S.  EPA,  1979a).   Cigarette  smoking has
been  found  to  act synergistically  with  this type  of exposure  to produce
bronchitis (Weiss, 1976, 1977).
     E.  Other Relevant Information
         The  initiating  activity  of  several  chloroalkyl  ethers   indicates
that these compounds will interact with other agents  to produce skin papil-
lomas (Van Ouuren, et al. 1969, 1972).
V.   AQUATIC TOXICITY
     Pertinent  information could  not be  found  in  the available  literature
regarding aquatic toxicity for freshwater or  marine  species.
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
         Based  on  animal  carcinogenesis   data,  and  using  a  linear,   non-
threshold model,  the  U.S. EPA  (1979a) has  recommended a maximum permissible

-------
concentration of BCME  for  ingested water at .02 ng/1.  Assuming  water  is  the
only source of exposure, compliance to  this level should limit the  risk car-
cinogenesis to not more than 10" .
         Based on  animal studies,  the  8-hour,  time-weighted threshold limit
value  (TLV-TVIA)  has been  recommended for  BCME as  one ppb by  the  American
Conference of Governmental and Industrial Hygienists  (1978).
     8.  Aquatic
         Criterion for  the protection of freshwater or marine aquatic  organ-
isms were not drafted due to lack of toxicological'-evidence.

-------
                    BIS(CHLOROMETHYL)ETHER

                          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. Techno!. 8: 356.

Innes, J.R.M., et al.  1969.  Bioassay of pesticides and
industrial chemicals for tumorigenicity in'-mice:  A prelimi-
nary note.  Jour. Natl. Cancer Inst. 42: 1101.

Kuschner, M.-f et al.  1975.  Inhalation carcinogenicity
of alpha halo ethers.  III.  Lifetime and limited period
inhalation 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.

Slaga, T.J., et al.  1973.  Macromolecular synthesis fol-
lowing a single application of alkylating agents  used as
initiators of mouse skin tumorigenesis.  Cancer Res. 33:
769.

Tou, J.C., and G.J. Kallos.  1974.  Kinetic study of the
stabilities of chloromethyl methyl ether and bis(chloromethyl)
ether in humid air.  Anal. Chem. 46: 1866.

U.S. EPA.  1979a.  Chloroalkyl Ethers:  Ambient Water Quality
Criteria  (Draft).

U.S. EPA.  1979b.  Environmental Criteria and Assessment
Office.  Hazard Profile:  Chloroalkyl Ethers  (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.V and K. Landa.  1977.  Genetic risk of occupa-
tional exposures to haloethers.  Mutat. Res. 46: 242.

-------
                                      No. 27
     Bis ( 2-ethylexyDphthalate


  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.

-------
                 BIS-(2-ETHYLHEXYL)PHTHALATE
                           SUMMARY
     Bis-'(-2-ethylhexyl)phthalate has been shown to produce
rautagenic effects in the Ames Salmonella assay and in  the
dominant lethal assay.
     Teratogenic effects in rats were reported following
interperitoneal (i.p.) administration and oral administra-
tion of bis-(2-ethylhexyl)phthalate.  Additional reproductive
effects produced by bis-(2-ethylhexyl)phthalate include
impaired implantation and parturition, and decreased fertility
in rats.  Testicular damage and decreased spermatogenesis
have been reported in rats, following i.p. or oral adminis-
tration, and in mice, given bis-(2-ethylhexyl)phthalate
by oral intubation.
     Evidence has not been found indicating that bis-(2-
ethylhexyDphthalate has carcinogenic effects.  Chronic
animal feeding studies of bis-(2-ethylhexyl)phthalate  have
shown effects on the liver and kidneys.
     Bis-(2-ethylhexyl)phthalate is acutely, toxic to fresh-
water invertebrates at a concentration of 11,000 ^ag/1.
The same species has been shown to- display severe reproduc-
tive impairment when exposed to concentrations less than
3 ug/1.

-------
              .   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 _in_ vitro studies indicates that certain
bacterial flora may be capable of metabolizing phthalates
to the monoester form (Englehardt, et al. 1975).

-------
II.  EXPOSURE
     Phthalate esters appear in all areas of the environ-
ment.  Environmental release of the phthalates may occur
through leaching of plasticizers from ?VC 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 ug/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
                            3.7-S

-------
estimate is based on the measured steady-state  bioconcentra-
tion studies in fathead minnow.
III. PHASMACOKINETICS
     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.  Bilary 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 DEHP 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-

-------
tine.  Seven days after i.v. administration  of  labelled
DEHP 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
                            a 9-

-------
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
o
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.p.  administration  (Singh,  et al.  1972).

-------
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
iri 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
                                                          •
pce-treatment of rats with DEHP produced an increase in
hexobarbital sleeping times (Daniel and Bratt,  1974; Rubin
and Jaeger, 1973; Swinyard, et al. L976).
                            317-7

-------
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          Only one acute  study  on  the  freshwater  cladoceran
(Daphnia magna) has produced a  96-hour  static  LC^Q  value
of 11,000 ug/1 (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  ug/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  gene
                                                            »
through the process of public review; therefore,  there is
a possibility that these criteria will  be changed.

-------
     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 DEEP of 42 mg/day.
          The recommended water quality criteria level for
protection of human health is 10 mg/1 for DEEP (U.S. EPA,
1979).
     B.   Aquatic
          Criterion was not drafted for either freshwater
                       •
or marine environments due to insufficient data.
                            SL7-//

-------
                 BIS-(2-ETHYLHEXYL)  PHTHALATE
                          REFERENCES

Albro, P.VI., 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 H3 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.G., et al.  1977.  The in vitro hydrolysis of some
phthalate diesters by hepatic ami 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 phtha'l-
ate:  Residue dynamics and biological effects in rainbow
trout and fathead minnows.  Pages 519-524.  ^n Trace sub-
stances in environmental health.  University of Missouri
Press, Columbia.

-------
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 13: 553.

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 ui Enviorn-
raental biology.  Interprint Publications, New Dehli, 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.  Teratogenicity 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  I4c-
    v                           i /l
di-2-ethylhexyl phthalate  ai
Jour. Pharm. Sci.  64:  1347.
                              i «
di-2-ethylhexyl phthalate and   C-diethyl phthalate in rats.
                          3.7-13

-------
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.
Pharmacol. 39: 339.

Wallin, R.F., et al.  1974. Di(2-ethylhexyl)  phthalate •
(DEHF) 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.Y. p. 59.

Yamada, A.,  et al.  1975.   Subacute toxicity of di-2-ethyl-
hexyl phthalate.  Trans. Food  Hyg. Soc.  Japan, 29th Meeting
p. 36.
                        *7i#'

-------
                                      No. 28
             Bromoform


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

           APRIL 30, 1980

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

-------
                                                          If9
                            BROMOFORM





SUMMARY


     Bromoform 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.


Broraoform 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; CHB^) is a colorless,  heavy
                                                             »

liquid similar in odor and taste to chloroform.  Bromoform has


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

-------
               Molecular Weight:   252.75

               Melting Point:       8.3'C

               Boiling Point:      149.5'C  (at 760 ram 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 Ho. 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 Pate

     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).

-------
half-life for hydrolysis of bromoform  is  estimated  at  636  years.
Bromoforra 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).
     3.   Bioconcentration
     The bioconcentration factor  for bromoform in aquatic  organ-
isms that contain about 8% lip id  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 (Syraons _et_ aA., 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 haloforra reaction,  results in the produc-
tion of trihalomethanes (including bromoforn) from  the organic
precursors present in raw water.

-------
      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
                                                             (COC\J
 carbonyl bromide (COBr2)f the brorainated analog of phosgene  pPuirt

 mi., f  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 mg/kg  (total dose of 72 mg/kg) or 100 mg/kg (total

 dose  of  2400 mg/kg)  (Theiss ^t_ _al_. , 1977.

-------
     B. Mutagenicity

     Bromoforn was mutagenic in S. typhimurium strain TA  100

(without metabolic activation) (Simmon, 1977).

     C. Other Toxicity

     Rats inhaling 250 rag/m3 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 LCgg (static) in bluegill sunfish is 29.3 mg/1.

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

hr ECegS for chlorophyll A production and cell number in S.

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

-------
     B.   Marine Organisms
     The 96-hr LC^Q (static) in sheepshead minnow  is  17.9  mg/1.
The 96-hr LC'50 (static) in mysid 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 bromoform) in drinking water  has been  set  by the
D.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,11974).  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).

-------
                            REFERENCES

Ahmed, A.E.f ^t_ _al_.   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.  Haloforras in the
essential  oil of the  alga  Asparagopsis taxiformis (Rhodophyta).
Tetrahedron  Letters, _7_:473-476.   (as cited in NAS, 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 Mostrand 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, ?ox. Appl.
Pharm., _4_:354.  (as cited  in U.S.  EPA, 1979b) .

Lucas, G.H.W.   1929.   A  study of  the fate and toxieity of bromine
and chlorine containing  anesthetics, J. Pharm. Exp. Therap.,
_3_4:223-237.  (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
^Jt_al_. eds.  (as cited in  U.S.  EPA,  1979b).

Symons, J.M  et  al.  1975.  National organics reconnaissance  '
survey for halogenated organics (NORS).  J.  Amer. Water Works
Assoc. j57_:634-647.   (as  cited in  MAS, 1978).

Theiss, J.C. _et_ _al_.   1977.   Test  for carcinogenicity of organic
contaminants of United States drinking waters by pulmonary tumor
response in  strain A  mice,  Can.  Res., ^7_:2717.  (as cited in U.S.
EPA, 1979b).

-------
U.S. EPA  1975.  Formation of Halogenated Organics  by Chlorina-
tion of Water Supplies.  EPA-600/1-75-002,  PB  241-511.   (as  cited
in WAS, 197-8).

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 halogenated  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, 9th  ed.,  Merck and Co.,
Inc., Ranway, N.J.

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

           APRIL 30, 1980
            a,*-/

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

-------
                            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 SU_ typhimurium test system.




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



11,000 }ig/l for a marine and freshwater fish,  respectively.

-------
                            BROMOMETHANE




I.   INTRODUCTION




     This profile is based on the Ambient Water  Quality  Criteria




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




     Bromomethane (CH^Br, methyl bromide, monobromomethane,  and




embafume; molecular weight 9^-9^) 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 apace 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

-------
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/m3 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, 1964).



     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.

-------
     C.   Metabolism



          Evidently the toxicity of bromomethane  is mediated  by the



bromomethane molecule itself.  Its reaction with  tissue  (methylation



of sulfhydfyl 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 brqmomethane



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.  1940;

Gorbachev, et al. 1962; von Qettingen,  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 maerochirus) 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.

71.  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/m^; the American Conference of  Governmental

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

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

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

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

-------
     B.   Aquatic Toxicity



          The draft criterion for protecting freshwater  life  is  a



24-hour average concentration of 140 ^g/1, not to exceed 320  ug/1.



The marine criterion is 170 ug/1 as a 24-hour average, not  to exceed



380 jig/1.

-------
                               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-oass 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, 7.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, S?5,
•NjO and other atmospheric constituents. Atinos.  Environ.  11:  819.

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

 U.S.  EPA.  I979a.   Halomethanes:  Ambient Water Quality Criteria.  (Draft).

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

-------
von Qettingen, W.F.  1964.  The halogenated hydrocarbons of industrial and
toxicological importance.  Slsevier Publ. Co., Amsterdam.

-------
                                      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 accuracy.

-------
                        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 (BrC,H,OC,H_; molecular weight 249.11) is a
liquid at room temperature; it has the following physical/chemical properties
(Weast 1972):
               Melting point:  18.72°C
               Boiling point:  310.14°C (760 mm Hg)
                               163°C (10 mm Hg)
               Density:        1.420820         ,
               Solubility:     Insoluble in water; soluble in ether

     No  information could be found on the uses of this substance.

     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 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).

-------
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.  PHAEMACOKINETICS

     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 3 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 nononcogenieity of 4-
bromophenyl phenyl ether as several known oncogens tested negative in this assay.

-------
7.  AQUATIC TOXICXTY

     A.  Acute

     An unadjusted 96 hour LC-Q 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 43 hour LC_Q 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
Organism
Bluegill,
Lepomis macrochirus

Bioassay Test
Method* Cone
S U
Chemical
.** Description
4-Bromophenyl-
phenyl ether
Time
(hrs)
96
LC50
(ug/L.)
4,940
Adjusted
LC50
(ug/L)
2,700
-M
*  S => static


** U » unmeasured
                                          •

   Geometric mean of adjusted values:  4-Bromophenylphenyl ether * 2,700 ug/L



   2,700
    3.9
           690 ug/L
                Table 2.   Freshwater  invertebrate acute values
Organism
Cladoceran,
Daphnia aagna
Bioassay Test
Method* Cone.**
S U
Chemical
Description
4-3romophenyl-
phenyl ether
Time
(hrs)
48
LC50
(ug/L)
360
.Adjusted
LC50
(ug/L)
300
*  S - static


** U =» unmeasured


   Geometric mean of  adjusted values:



   300   .,    /T
     - - U  ug/L
                                      4-Bromophenyl phenyl ether » 300 ug/L
    Table 3.   Freshwater fish  chronic values, 4-Bromophenyl phenyl ether


Organism
Fathead minnow,
P 1m ep hales promelas

Limits
Test* (ug/L)
E-L 89-167

Chronic
Value
(ug/L)
61

                                                61
*  E-L » embryo-larva


   Geometric mean of  chronic values =• 61 ug/L    7—,  =9.1 ug/L
                                                o. /

   Lowest chronic value =  61 ug/L
                                30-6

-------
                               BIBLIOGRAPHY
Friloux J. L971.  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, Shlmkin MB, Weisfaurger EK.  1977.  Test for carcinogenicity
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, I975b).

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.

-------
                                      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.

-------
                       SPECIAL NOTATION


U.S. EPA1 s Carcinogen Assessment Group (GAG) has evaluated
cadmium and has found sufficient evidence to indicate that
this compound is carcinogenic.

-------
                                    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,  in  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
tig/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.
                                 J/-V

-------
                                   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,  1978b)
     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
                                    t
                                    *4
                            31-S

-------
Table 1.  Sutnu rrO|>crtleu of  Cadmium and Its Important Compounds
Solubility
Primary Molecular Physical j Melting Boiling In watur
iiiie or uclBlit llcnulty ututc. • point point 20*C
Ciiiu|-muiJ occurrence For an In (£/iaolo) (B/U!) 20*C (*C) (*C) (g/llter)
llii.liuliin Cuilultiu nickel C.d 112.4 tt.6 Sllvur metal 321 765 Inuolublc
i
r
Cii.lniliin Swelling plant CdO 12B.4 7.0 Drown powder i Dttcoupouea 0.01)015
iml.le in coal toii.hu:,- «' ut 900
1 Inn en I a a I on '•
Ca.lmlinu I'lijiiiciit (or CdS 144.5 4.8 Yellow crystal 1750 Decomposes 0.0013
I'uiiiinila; jilioa-
C luii a .
i:,i,liuliim fruit tree CdSO, 20B.5 4.7 Uhlte 1000 755
bull. iiu luwlclJe cryatalllne
Ca.lmluia Turf treat- CdCO-j 172.4 4.3 IHilte powder Uuconpoaea 0.001
L'iiili>M>iii u wen i " or crystalline below 500
Solubility
In oilier
sol vent a
Soluble lit
acid and"
Soluble In
acid and
Nil-, milta
Soluble In
acid, very
ullulitly
soluble In
HII^OIl
Insoluble
In acid
and alocliol
Soluble In
acid and
KCN, Kit.
suits
Acute I.etluil
9 wu/w lu Hie
appro«liuiite
Iblliul cuncen-
t rut Ion lu wan,
lulialuil an fuuiu
50 IIIB/W IK tlie
lullial concen-
tration In wun,
Inbalud; 72
|.II5U (oral)

27 uiB/kg dog.
II) (lillb-
ciitdneoiiu)


-------
                                         Table  1.   Soiuu I'tupui I leu  of Catlialuu onj Itu  Important  CunipounJs  (Cont'd)
1'iluuiy llalccular
in. u oi weight Dcilulty
i:i.»i|>uim5|) (oral)
Inuoliiblo In
alcohol
Soluble In
uclJ and KCII


(III.,-i J.n.i U.M.,|.| U.I  fiuia Uuuat,  19)1

-------
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

-------
the respirable  range,  up to 25% of  the inhaled amount may be absorbed  (EPA,
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; Elinder-, 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  al.  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;
wahlberg (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

-------
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
                                                                         »
general population  (Imbus,  et al.  1963;  Szadkowski,  et al.  1969).  Occupa-
tionally  exposed  individuals  may  show  markedly  higher  urinary  excretion
                                     3HO

-------
levels (Friberg, at  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  factor/
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
                              31-11

-------
injection  site sarcomas  and testicular  tumors  (Leydigiomas)  (see  Table 2;
U.S. EPA,  1978a).   A large  number  of metals and  irritants produced compar-
able injection site  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; Oeknudt 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 DNA  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 Orosophila  have also produced negative  findings  (Shabalina,
1968; 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


-------
                                                          TABLE 2



                               STUDIES OH CADMIUM CARCINOGENESIS IN EXPERIMENTAL ANIMALS*
Authors
                                             Animals
Compounds and routes
                                                                                                Tumora
lleath £t al. , 1962; Heath and Daniel, 1964   Kats



Kazantzls, 1063; Kazantzla and Hanbury, 1966 Rats



tladdow £t aJL. , 1964; Roe ejt al. , 1964        Rats



fiutlirle, 1964




-------
                                              TABLE  3

                 SUMMARY OF RESULTS  OF HUMAN  EPIDEMIOLOGY STUDIES OF CANCER EFFECTS
                          ASSOCIATED UITH OCCUPATIONAL EXPOSURES TO CADMIUM

Population
(U'oup Studied
Mattery factory
uoikei's
Mattery factory
xvidkei a
Cadmium smelter
workers
Itubber industry
Cadmium Compound
Exposed To
Cadmium oxide
Cadmium oxide
Cadmium oxide,
others
Cadmium oxide
Incidences of
All Cancers
High
Normal
High
High
Incidences of
Lung Cancer
Normal
Normal
High
Normal
Incidences of
Prostrate Cancer
High
High
High
High
Reference
Potts (1965)
i
Kipling and
Uaterhouse
(1967)
Lemon et al .
(1976)
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 (Perm and Carpenter,
1968;  Mulvihill,  et  al.  1970;  Ferm,  1971;  Gale and  Ferm,  1973)  and  rats
(Chernoff, 1973;  8arr,  1973).  Oral  administration of cadmium  (10 ppm)  has
                                                                     »
demonstrated  texatogenic  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  ernbryotoxic  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, 197Sa).
     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).

-------
                                                    TABLE 4

                                     SUMMARY OF MUTAGENICITY TEST RESULTS
     iiystcu
Genetic Effect
                                                            Reported
                                                            Mutageuicity
               References
                         Systems la vitro
Iliiuuin cells
     se Hamster Cells
                         Chromosomal damage
                         Point mutation
	            Point mutation
Jh. subtil is recoiublnant  Gene mutation
     assay
Polyuucleotides          Base mispairing
                                                        Shlralshl zt_ al.'t 1972
                                                        Costa e£ al., 1976
                                                        Takahoshl, 1972
                                                        Nlshloka, 1975

                                                        Slrover and Loeb, 1976
Ihuiiau leukocytes
Iliiiiiau luiikocytuu
Human leukocytes
Iliiiiiau leukocytes
    .'O oocytes
Mitiiuiia 1 a
   »'c
Systems in vivo

CUromosomal damage
Ctu'omosomal damage
Chromosomal damage
Chromosomal damage
Altered spermatogenesls
Cytogenetic damage
Dominant lethal mutations
Dominant lethal mutations
Dominant lethal mutations
Chromosomal abnormalities
Sex-linked recessive lethal
+

+
                                                                                 Shirashi and Yoshlda, 1972
                                                                                 Bui  et._al.,  1975
                                                                                 Deknudt and  Leonard, 1975
                                                                                 liauchinger  et al., 1976
                                                                                 Lee  and Dixon, 1973
                                                                                 Shimada et_ al., 1976
                                                                                 Epstein et^ al. , 1972
                                                                                 Gllliavod and Leonard, 1975
                                                                                 Suter,  1975
                                                                                 Shimada e£ al., 1976
                                                                                 Soraa and Pfeifer, 1973

-------
rats,  rabbits,  guinea  pigs,  hamsters,  and mice  (Parizek and  Zahor,  1956;
Parizek, 1957;  Meek,  1959).  This  susceptibility appears  to tie 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,
1968;  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).

-------
                                                    TABLE 4

                                     SUMMARY OF MUTACENICITY TEST  RESULTS
Tcul System
               Genetic Effect
                                                            Reported
                                                            Mutageulclty
References
lluiiiaii eel la
Chinese llama ter Cella
j^. cercvlijiae
   diilit:
               Systems In vitro

               Chromosomal damage
               Point mutation
               Point mutation
     assay
I'olynucleotldcs
u recombInant  Gene mutation

               Base mispalrlng
                                                                                 Shiraishi £t ai.'. 1972
                                                                                 Coata e£ al.. 1976
                                                                                 Takahoshi, 1972
                                                                                 NishioUa, 1975

                                                                                 Slrover and Loeb, 1976
Human leukocytes
Human luukocytes
Human leukocytes
Human leukocytes
Uiit s|>efiiiatogonia
tloii:;e OOCytes
Ihniue breeding
tluu:,e breeding
l-kiuue breeding
H.iuuiial a
I),  ii.elai
                         Systems in vivo

                         Chromosomal damage
                         Chromosomal damage
                         Chromosomal damage
                         Chromosomal damage
                         Altered spermatogenesls
                         Cytogenetic damage
                         Dominant lethal mutations
                         Dominant lethal mutations
                         Dominant lethal mutations
                         Chromosomal abnormalities
                         Sex-linked recessive lethal
                                                                       Shirashi and Yoshlda, 1972
                                                                       Bui ££ al., 1975
                                                                       Deknudt and Leonard, 1975
                                                                       Bauchinger et al., 1976
                                                                       Lee and Dixon, 1973
                                                                       Shlmada ££ al., 1976
                                                                       Epstein et^ al. , 1972
                                                                       Gilllavod and Leonard, 1975
                                                                       Suter, 1975
                                                                       Shlmada ££ al., 1976
                                                                       Soraa and Pfelfer, 1973

-------
         Chronic  cadmium  exposure  produces  renal  tabular  damage  that  is
characterized  by  the  appearance  of   a  characteristic  protein  9B2-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 ostao-
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; Xoller, 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.   LC5Q  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  Up-
values  for   freshwater  invertebrates   ranged   from  3.5   for  Cladoceran
                                                                      »
(Simoeohalus serrulatus)  to  28,000  pg/1  for the  mayfly (Eohemerella  grandis
qrandis).  Acute LC-0  values  for  marine fish  ranged  from  1,600  ug/1  for
                              31-17

-------
larval  Atlantic silversides  (Menidia menida)  (Middaugh  and  Dean,  1977)  to
114,000 yg/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--.
values  ranged  from  15.5 ug/1  for  the mysid shrimp (Nimmo,  et al. 1977a)- te-
46,600  for the  fiddler crab (Uca puqilator) (O'Hara,  1973).
     B.  Chronic Toxicity
         Chronic values  for freshwater fish ranged  from  0.9 ;jg/l  in a brook
trout  (Salvelinus  fontinalis)  embryo  larval  assay (Sauter,  et al.  1976)  to
50 jug/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,  Mvsidoosis 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
4.8 jug/1.
     C.  Plant Effects
         Effective  concentrations  for freshwater  plants  ranged from  2 jug/1,
which  causes  a  1C   fold growth rate  decrease  in the diatom, Asterionella
formosa  (Conway, 1973),  to  7,400 jug/1, which  causes  a 5C& root weight,inhi-
bition  in Eurasian  water-milfoil (Myrioohvllum  soicatum).   In marine  algae,

-------
96-hour  EC5Q growth  rate  assays  yielded  values  of  160  and 175  ug/1  for
Cvclotslla nana  and  Skeletonema costatum respectively  (Gentile and Johnson,
1974).
     0.  Residues
         Bioconcentration  factors  ranged from  151 for brook  trout to  1,988
for the  flagfish (Jordanella floridae).  One characteristic  of cadmium  tox-
icity in aquatic organisms was  the passible 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,  Pseudopleuronectes  americanus,  and  the
stripped bass, Morone saxatilis, at concentrations  as low as 0.5 ug/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 ug/1.   This level was  also  adopted  as the draft ambient  water
                                                                         *
quality criterion (U.S. EPA, 1979).
                           3M9

-------
         The OSHA  time-weightad average  exposure  criterion  for  cadmium is
100 ;jg/m .
     B.  Aquatic
         The draft  criterion proposed  for  freshwater organisms  to cadmium
has been prepared following  the Guidelines,  and is  listed  according to the
following equation:
                         Q(0.867 In-(hardness) - '4.38)
for a 24-hour average and not to exceed the level described by the following
equation:
                          (1.30  In-(hardness) - 3.92)
                         e
The proposed marine criterion derived following the Guidelines  is  1.0 jjg as
a 24-hour average not  to  excaed  16 ^ig/1 at any time (U.S. EPA, 1979).
                                 3/-3J

-------
                             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.

Bui,  T-H.,   et  al.   1975.   Chromosome  analysis  of lymphocytes
from  cadmium workers  and  Itai-itai  patients.    Environ. Res.
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
and placenta.  Arch. Environ. Health.  26: 237.

Chen,  R.W-.,  et  al.   1975.    Selenium-induced  redistribution of
cadmium  binding  to tissue  proteins:   A  possible  mechanism of
protection against cadmium toxicity.  Bioinorg. Chem.  4:  125.
                                                              »
Chernoff,  N.   1973.    Teratogenic  effects  of  cadmium  in   rats.
Teratology.  3:  29.

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

Conway,  H.L.   1978.   Sorption  of  Arsenic and  cadmium and  their
effects on  growth,  micronutrient utilization,  and  photosynthetic
pigment composition  of Asterionella formosa.   Jour.  Fish. Res.
Board Can.  35: 286.

Cook, J.A.,  et al.    1975.   Factors  modifying  susceptibility  to
bacteria  endotoxins:    The  effect  of  lead  and  cadmium.    Crit.
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.   .1. 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
smokers and nonsmokers.  Science  205: 325.

Epstein,  S,,  et  al.    1972.    Detection of chemical  mutagens  by
che dominant lethal assav in  the mouse.  Toxicol.  Appl.  Pharmacol.
23: 288.

Eto, K., et al.  1976.  Developmental effects of teratogens  influ-
encing the incidence of cleft lip.  Jour. Dent. Res.  55(B):  203.

Exon, et  al.   1975.   Cited  in Health Assessment  Document  for
Cadmium, U.S. EPA, p.  2-91.

Perm, V.   1971.    Developmental malformations  induced  by calcium
— A study at timed injections during embryogenesis.  Biol.  Nenon.
19: 101.

Fern, V.  and S.  Carpenter.    1963.   The  relationship  of cadmium
and  zinc  in experimental mammalian  teratogenesis.   Lab.  Invest.
13: 429.

Pox,  M.R.S.   and  3.E.  Fry.    1970.    Cadmium  toxicity decreased
by dietary ascorbic acid supplements.  Science  169: 989.

-------
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
accumulators with special reference to chronic cadmium poisoning  -
 a  clinical  and  experimental  study.    Acta. Med.  Scand.  138.
Supplement CCXL.

Friberg, L.,  et  al.    1974.    Cadmium in  the environment.    2nd
ed. CRC Press, Cleveland, Ohio.

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-
gansett, Rhode Island.

Gilliavod,   N.  and  A.  Leonard.   1975.   Mutagenicity tests with
cadmium in the mouse.  Toxicology  5: 43.

Gross,  S.B.,  et  al.   1976.   Cadmium  in  liver,   kidney  and hair
of humans,   fetal  through  old  age.   Jour.  Toxicol.  Environ. Health
2: 153.

Hammer,  D.I., et  al.  1971.   Hair  trace metal levels  and  environ-
mental exposure.  Am. Jour. Epidem.  93: 84.

Hem,  J.    1972.   Chemistry  and  occurrence  of  cadmium  and izinc
in surface water and groundwater.  Water Resour. Res.  8:  661.

Hughes,  J.S.  1973.  Acute toxicity of thirty chemicals to striped
bass  (Morone  saxatilis).   Pres.  Western  Assoc.   State  Game Fish
Comm., 3 alt Lake City, Utah.  July, 1973.

Imbus, H.R.,  et al.  1963.   Boron, cadmium,  chromium and nickel
•in blood and urine.  Arch. Environ. Health.  6: 286.

Katagiri,   Y.,  et al.   1971.    Concentration of cadmium  in  urine
by age.   Med. Biol.  82: 239.

Kjellstrom,  T.,  et  al.    1979.    Mortality  and cancer  morbidity
among cadmium-exposed workers.  Environ. Health Perspect.  28: 199.

Roller,  L.D.   1973.   Immunosuppression produced by lead, cadmium,
and mercury.  Am. Jour.  Vet. Res.  34: 1457.

Lauwerys,   R., et  al.  1978.   Placenta! 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 teleosts,  Fundulus heteroclitus
and menidia  menidia to cadmium.   Bull.  Environ.ContamTToxicol.
17: 645.

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
cadmium-treated  golden  hamsters.    Jour.   Embryol.  Exp. Morph.
24: 393.

Nimmo, D.R.,  et  al.   1977a.  Mysidopis  bahia:   An estuarine spe-
cies  suitable for   life-cycle  toxicity  tests  to  determine   the
effects  of   a  pollutant.   Aquatic  Toxicol.  Hazard  Eval.   ASTM
STP634.

Nordberg, G.F.    1974.    Health  hazards of  environmental cadmium
pollution.  Ambio.  3: 55.

Nordberg, G.F.,  et al.   1975.   Comparative toxicity of  cadraium-
metallothionein  and  cadmium chloride  on  mouse  kidney.   Arch.
Path.  99: 192.

O'Hara,  J.    1973.   The  influence  of  temperature  and  salinity
on  the  toxicity  of  cadmium to  the  fiddler  crab,  Uca pugilator.
U.S. Dept. Commer. Fish.  Bull.  71: 149.

Parizek,  J.    1957.    The destructive  effect of  cadmium  ion  on
tesricular  tissue  and its  orevention  by  zinc.    Jour.  Endoctin.
15: 56.

Parizek,  J.  and  A.  Zahor.   1956.   Effect  of  cadmium  salts  on
testicular tissue.  I. Nature.  177:  1036.
                              31-

-------
Paterson, J.C.   1947.   Studies on  the toxicity of  inhaled cad-
mium.   III.  The pathology of  cadmium smoke poisoning  in  man and
in experimental animals.  Jour. Ind. Hyg. Toxicol.  29: 294.

Pickering, Q.H.  and  C. Henderson.    1966.    The  acute  toxicity
of  some heavy  metals to different  species of  warmwater  fishes.
Air Water Pollut. Int. Jour.  10: 453.

Pond, W. and E. Walker.  1975.   Effect of dietary Ca and Cd level
of pregnant rats on reproduction and on dam progeny tissue mineral
concentrations.  Proc. Soc.  Exp. Biol. Med.  148: 665.

Potts,  C.L.   1965.    Cadmium proteinuria - The  health  of  battery
workers exposed to cadmium oxide dust.  Ann. Oc'cup.  Hyg.  8: 55.
Rahola, T.,  et al.   1973.   Retention and  elimination  of
in man.   In  health physics  problems  of  internal contamination.
pp. 213-218.  Budapest: Akademiai Kiado.

Sarauelson,  0. .   1963.    Ion  exchange  separations  in  analytical
chemistry.  John Wiley and Sons, New York.

Sauter, S.,  et  al.   1976.   Effects  of exposure  to  heavy metals
on selected freshwater  fish  —  Toxicity of copper, cadmium, chro-
mium and  lead to  eggs and fry of seven  fish species.  EPA-600/3-
76-105, Contract No. 68-01-0740.  U.S. Environ. Prot. Agency.

Schroeder, H.A. and  M.  Mitchener.   1971.  Toxic  effects  of trace
elements  on  the reproduction of mice  and rats.    Arch.  Environ.
Health.  23: 102.

Schroeder, H.A.,  et al.   1964.   Chromium,  lead,  cadmium, nickel
and  titanium  in  mice:  effect   on  mortality,  tumors and  tissue
levels.  Jour. Nutr .  83: 239.

Schuster, C.N.  and  3.H.  Pringle.   1969.   Trace metal accumulation
by the American oyster,  Crassostrea virginica.   1963 Proc. Natl.
Shellfish Assoc.  59: 91.

Shabalina,  P.P.   1968.   Industrial  hygiene  in  the  production
and use of cadmium stearate.   Hyg.  San.  33: 187.

Shiraishi, Y. and  T.A.  Yoshida.   1972.  Chromosomal  abnormalities
in  cultured  leucocyte   cells from  Itai-Itai  diseae patients.
Proc. Jap. Acad.  48: 248.

Shiraishi, Y.,  et  al.   1972.  Chromosomal aberrations in cultured
human  leucocytes  induced  by  cadmium  sulfide.   Proc. Jap. Acad.
48: 133.
                                                             *
Sorsa, M. and  S.  Pf eif er .   1973.   Effect of  cadmium on develop-
ment  time  and  pcepupal  putting patterns  in  D.   melanogaster .
Hereditas,  75: 273.
                            31* if

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

Sunderman,  F.W.,  Jr.    1977.    Cadmium. Chapter  9  In;  Advances
in modern  toxicology, Vol. 2,  ed.  by  R.A.  Goyer and M.A. Mehlman.
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,
mercuric  chloride  and cadmium chloride in male and female mice.
Mut. Res.  30:  365.

Suzuki, S., st al.   1969.  Dietary factors influencing upon reten-
tion  rate of orally  administered      CdCl2 in mice with special
reference  to calcium  and  protein concentrations  in diet.   Ind.
Health.   7: 155.

Szadkowski,  D.,  et  al.    1969.    Relation  between  renal cadmium
excretion, age- and  arterial  blood pressure.   2. Klin.  Chem.  Bio-
chem.  7: 551.

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
No.  1,  Environmental  Protection Agency,  Washington,  D.C.,  May,
1978.

U.S. EPAj  1978b.  Reviews of the Environmental Effects of Pollut-
ants:  IV. Cadmium.  SPA 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
cats 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.

-------
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.
Safety.

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.
                             - *a fr 
-------
                                         LB-.44-1
                                         No.  32
          Carbon Bisulfide

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

          OCTOBER 30, 1980
                32-1

-------
                       CARBON BISULFIDE




I.    PHYSICAL-AND CHEMICAL PROPERTIES
    *

      CS2 (FW 76.14) is soluble in water at 0.294%  (20°C), and


chelates trace metals, especially Cu and Zn.  It is a colorless,


volatile, and extremely flammable liquid at RT.  CS£ has no


odor wh'en pure.


II.   PRODUCTION AND USE


      C$2 is produced in petroleum and coal tar refining.  Its


principal uses are as a solvent in the manufacture  of rayon,


rubber, chemicals, solvents, and pesticides.^  In 1974, 782

                                                         2
million pounds of CSo 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


      CS2 was detected in 5 of 10 water supplies surveyed by


the EPA.3  NIOSH25 estimates that in the U.S. 20,000 employees


are potentially exposed to CS2«


III.  PHARMACOKINETICS


      A.  Absorption;  Absorption differs with species  and


route of administration^; inhalation and skin absorption are


the most important routes for humans (31).


      B.  Distribution;  Large concentrations of both free


and bound C$2 are found in brain (guinea pig) and peripheral


nerves (rats) of exposed animals.  The ratio of bound to
                             32-2

-------
 free  C$2  is  brain  3:1.   Blood  and fatty tissues contain mainly




 bound  CS2> while liver  contains  €82  mainly in the free (unbound)




      •C.  Metabolism;   C$2  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  proteins  to  form hydro-sulfide-6




      D.  Excretion;  small amounts  of  CS2 metabolites such as thiourea,




 5-mercaptothioazolidone,  and inorganic  constituents  are excreted




 in urine.^ Inhalation studies  have shown that 18% of the




 C&2 inhaled  is  exhaled  unchanged.  Of the remaining  inhaled




 dose, 70% is excreted as  free  or  bound  €82 and  urinary




 sulfates, and 30%  is stored in the body and slowly excreted




 as CS2 and its  metabolites.




 V.  EFFECTS ON  MAMMALS




      A.  Carcinogenicity:  .No available data.^




      B.  Mutagenicity;    No available data.^




      C.  Teratogenicity;  Bariliah  et  al.8 showed  that




 inhalation of 10 mg/m^  is lethal  to  embryos before  and after  implan-




 tation.  CS2 at 2.2  mg/m3 inhaled  for 4  hours/day was  toxic to dams,




and embryotoxic if administered . during  gestation,  and  had  no  effect




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




210 days)  caused disturbances of  estrus.^-^   Topical  application of




CS2 induced  teratogenic  effects in rats.    In a  dominant lethal




test,  inhalation of 10  mg/m^ by male rats  before  copulation




proved lethal to embryos.8
                             32-3

-------
      D.  'Toxicity


          1.  Humans
      %

              C$2 causes damage  to  the central  and peripheral


nervous systems and may accelerate  the development of, or


worsen, coronary heart disease.31


      The lowest lethal concentration has been  reported as


4,000 ppm in 30 minutes.H  In the  same study,  a person sub-


jected to a concentration of 50  mg/m^ for 7 years had CMS


effects.  Moderate chronic exposure of humans at less than


65 mg/m^ for several years has been reported by Cooper^ to


cause polyneuropathy.  In a study by Baranowska et al.^3


humans have been shown to absorb 8.8-37.2 mg from an aqueous


solution containing 0.33-1.67 gm/1.  This was over a period of


1 hour of hand-soaking.


      In poisoning due to continued exposure at fairly low


levels (0.9-378 ppm)31 neuritis  and visual disturbances are


the most common symptoms.31>32   Sensory changes, sensations


of heaviness and coldness, "veiling" of objects, pain in


affected limbs, are often followed by gradually increasing


loss of strength.  Mental symptoms varying in severity


(excitation, irritability, personality changes, insomnia,


and even insanity) may occur.32


      There are several studies  on cardiovascular effects


of CS2 exposure.26"29  Heinberg  et al.26'27 report signifi-


cantly elevated rates of coronary heart disease mortality,


angina, and high blood pressure  in viscose rayon workers.


A five year follow-up again reported increased


                             32-4

-------
 coronary heart disease mortality and higher than expected




 incidences  of  total infarctions, nonfatal infarctions and angina.
      t



 In  a-n 8-year  followup  in 1976,  Heinberg-^O found no excess




 coronary heart disease mortality during the last 3 years of the




 study.




         1 2.   Other species.




                IP  injection of  400 mg/kg was the lowest lethal




 dose in  guinea pigs.14  An  IV LD50 of  694 mg/kg in mice was




 reported by Hylen  and  Chin.^-5




 Toxic effects  have been observed at doses as low as 1.7 mg/kg




 in rabbits.^  Rats showed  toxic SC effects at  1 mg/kg.17-19




 Vinxsgr adov^O showed that 1  ppm  in drinking water was nontoxic




 to rabbits; 70  ppm was fatal.




      In a chronic study, Paterni et al.^1 found that 6




 mg/kg/day produced toxic effects in rabbits.   The lowest




 lethal chronic  dose  for  rabbits was shown to be 0.1 ml  3




 times a  week for 7  months.  ^ Applied topically,  €82 produced




 higher incidence of




 anemia in female than  in male rats,  and  teratogenic•effects (see  above)


               r\ <5                '                   o

 were observed.     When  rats inhaled C$2  at 10  mg/m ,  abnormalities




 of genitourinary and skeletal systems  were noted.   In addition,




 disturbances of ossification and blood  formation and  dystrophic




 changes  in liver and kidney were noted.8






VI.    EXISTING GUIDELINES AND STANDARDS




      The NAS^ did not recommend limits  for drinking  water
                             32-5

-------
because estimates of effects of chronic oral exposure cannot be



made with any confidence.



      The current OSHA PEL is 20 ppm (62 mg/m3), with a



ceiling concentration of 30 ppm (93 mg/m3) for an 8-hour



day, 5 day work week.25 -jhe NIOSH2^ recommended standard




is 3 mg/m3.24
                             32-6

-------
                            REFERENCES (CS2)
  1.   U.S.  EPA,   Identification of organic compounds in effluents
      from  industr-ial-- sour ces ,  1975.

  2.   U.S.  International Trade  Commission, Syn. Org. Chem., 1974.

  3.   U.S.  EPA,'Preliminary Assessment of suspected carcinogens
      in  drinking water.  Report to Congress.  EPA 560/14-75-005;
      ?B  260961,  1975.

  4.'   NAS,   Drinking  Water  and  Health, 1977.

  5.   Dalve  et  ai., Chem.  Biol. Inter. 10_:347-361, 1975.

  6. .  CatigusMxi  and Neal,   BBRC j65_(2): 629-636,  1975.

  7.   Theisinger,  Am.  Ind.  Hyg. Assoc.  3^(2):55-61,  1974.

  8.   Bariliah  et al. ,  Anat.  Gistol. Embriol. £8_(5 ): 77-81, 1975.

  9,   Sal'nikova  and "Chirkova,   Gig. Tr.  Prof.  Zabol L2:34-37,
      1974.

10.   Rbzewiski  et al.,  Med.  Pr . ^(2)1133-139, 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 j^:169-174, 1966.
      (cited  in  Chem. Abs.  7£:31443W, February 24, 1969).

14-.  Davidson and Feinlab,   Am. Heart J.  8_3( 1): 100-114, 1972.

15.   Hylin  and  Chen,   Bull.  Environ. Contam. Toxicol.
     _3(6):322332, 1968.

16."  Merck  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. ^2:233-240,  1974.

20.  Vinogradov,  Gig.  Sanit.  .31(1):13-18, 1966.

21.  Paterm et al., Folia Med.  41:705-722, 1958.
                               32-7

-------
                              32-7
22.  Michalova et al., Arch.  Gewerbepath.  Gewerbehyg.
     _16_:653-665,. 1959.
     «
23.  Gut. Prac. Lek. 2l(10):453-458,  1969.

24.  NIOSH.  .-Criteria for  a Recommended  Standard  CS2>
     May, 1977.

25.  29 CFR 1910.1000.

26.  Hernberg,  Br. J. Ind. Med. 21_7_: 313-325,  1970.

27.  Hernberg et al., Work Env. Health J5_:ll-16,  1971.

28.  Hernberg et al., Work Env. Health ^0_: 93-99 ,  1973.

29.  Tolonen et al., Br . J..Ind. Med . .^2:1-10 ,  1975.

30.  Heinberg et al. , Work Env. Health _2:27-30,  1976.

31.  Proctor, N.H.  and J. P.  Hughes,  Chemical Hazards of
     the Workplace.  Lippincott, N.Y., 1978.

32.  Sax, V. I.  Dangerous Properties of  Industrial
     Materials.  Van Nostrand Reinhold, N.Y., 5th edition,
     1979.
                             32-8

-------
                                         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.

-------
                      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.
                          •33-3

-------
                             CARBON TETRACHLORIDE
                                    Summary

     Carbon  tetrachloride  (CC1J  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.   LC5Q  (96-hour) values
for bluegill range from 27,300 to 125,000 pg/1  in static tests.  For Daphnia
magna.   the  reported  48-hour  EC5Q  is  35,200  jug/1.    The  96-hour  LC5Q  fqr
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.

-------
                             CARBON TETRACHLORIDE
I.   INTRODUCTION
     Carbon  tetrachloride (CC14)  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  fluorocarbons 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, 153.82; 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 miscir
ble with alcohol, acetone and most organic solvents.
     Carbon  tetrachloride may  be quite  stable under  certain environmental
conditions.   The  hydrolytic  breakdown of  CC14 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, et 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).

-------
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  al.
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 CC14 is a  chlorinated  hydrocarbon,  it  is  not produced  in
finished drinking water  as  a result of the chlorination  process (Natl.  Res.
Coun., 1977,1978).
     B.  Food
         Carbon  tetrachloride has been  detected in a  variety of  foodstuffs
other than  fish  and  shellfish in  levels  ranging from 1  to  20 pg/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  CCl^  in  the  atmosphere  is  due  largely  to  the
                                                                       »
volatile  nature  of  the  compound.  Concentrations  of CC1,   in continental
and  marine  air  masses  range  from  .00078 - .00091  mg/m .    Although  some

-------
higher  quantities  (.0091 mg/m3)  have  been measured  in  urban areas, concen-
trations  of CC14  are universally  widespread with  little  geographic varia-
tion  (U.S. EPA, 1979a).
III.  PHARMACOKINETICS
      A.  Absorption
         CCl^  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.                          .
      8.  Distribution
         The organ distribution  of CC1.   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  CCl^ in the  bone marrow.  The  liver,  pancreas and spleen
had one-fifth  the  amount found in  the  bone marrow.  The highest concentra-
tions of  CC1.  after inhalation,  however,  were found in  the  brain  (Von  Qet-
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
.ng/1.
         On  the  cellular  level,  McClean,   et  al.   (1965)  found  CC1. in  all
cell fractions  with higher concentrations  in ribosomes.
                                  3J-7

-------
     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-
bolites  play an  important  role in  the  overall toxicity  of  CCl^ (U.S. EPA,
1979a).   Some of the  CC14  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).
     0.  Excretion
         The  largest  portion  of  absorbed  CC1.   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 feces.  No
CCl^ was detected in the blood or  in  the expired  air, 48  hours  and 6 days,
respectively,  after  CCl^  inhalation  (Beamer,  et  al.  1950).   CCl^  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
         CCl^  has been  shown to  be  carcinogenic  in   rats,  mice,   and  ham-
sters via subcutaneous injection,  intubation,  and   rectal  instillation (U.S.

-------
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 CC14  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  CC14,   methylcholanthrene  (a potent  enzyme inducer)
was  found  to  increase  the incidence  of  nyperplastic  hepatic  nodules and
early carcinomas  in  rats (Rueber, 1970).  Females were  found to  be more sus-
ceptible to the development of nyperplastic nodules  and  carcinomas.
         The National Cancer  Institute (1976)  studied  the carcinogenic ef-
fect  of  CC14  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 CCl^.   Andervant and Ounn  (1955)
transplanted 30  CCl^-induced tumors into  mice.   They observed  growth  in 28
of the hepatomas, through  4 to  6  transplant generations.
     B.  Mutagenicity
         Conclusive evidence on  the mutageniciity  of CC1.  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.
                                      t
                                      •3
                                    33-

-------
     C.  Teratogenicity
         Very  little  data are  available concerning  the teratogenic effects
of  CC14.   Schwetz,  et  al.  (1974)  found CC14  to be  slightly embryotoxic,
and  to a  certain degree  retarded fetal  development,   when  administered to
rats at  300 or  1,000  mg/1 for 7  hr/day on days  6  through 15 of gestation.
Bhattacharyya  (1965)   found  that  subcutaneous  injection  occasionally   gave
rise to changes  in fetal liver.
     D.  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
complain of  fatigue,  lassitude, giddiness,  anxiety,  and headache.   They  suf-
fer 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

-------
 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, 1564).
      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  Oavis (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^  (Von 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 jjg/1 to  125,000  pg/1   (Dawson,  at al. 1977;  U.S.
                                                                      »
EPA,   1978).   With  Daonnia  maona. the reported  48-hr.  EC5Q is  35,200 jjg/1
 (U.S.  EPA,  1978).    The  96-hr. LC50 for the tidewater  silversides (Menidia
 bervilina)  is 150,000 jjg/1 (Dawson, et al. 1977).

-------
     B.  Chronic Toxicity
         An  embryo-larval  test with the fathead minnow (Pimeohales promelas)
showed  no adverse  effect  from  carbon  tetrachloride  concentrations  up  to
3,400 ug/L (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.
     D.  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/m3  for  CC14,
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 CC14  (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
                                  33-t

-------
ug/1, and 0.025 jjg/1,  respectively.   Refer to the Halomethane Hazard  Profile
for discussion of criteria derivation (U.S.. EPA, 1979b).
     B.  Aquatic
         For  carbon tetrachloride,  the drafted  criteria to  protect  fresh-
water aquatic  life is 620  ug/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).

-------
                                      No. 34
              Chloral


  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.

-------
                                    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  jug/1.   Chloral  hydrate is  formed
through the chlofination  of  natural humic  substances in the raw water.   At-
mospheric chloral  concentrations up to  273.5  mg/nv3 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 4
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

-------
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.

-------
                                    CHLORAL

                              ENVIRONMENTAL FATE

     Chloral  (trichloroacetaldehyde)  is  freely  soluble in  water,  forming
chloral hydrate  (Windholz,  et al.  1576).   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 ana1 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,  1575).   Rook  (1574)  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,
1576).  Dilling, et  al. (1576) 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.

-------
                                    CHLORAL
 I.    INTRODUCTION
      This  profile is  based on literature searches  in Biological Abstracts,
 Chemical Abstracts, MEDLINE,  and TOXLINE.
      Chloral [Cl^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  zetaldehyde or paraldehyde in the  presence of  antimony chloride.
 Prior to 1572,  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,  ODVP,  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-
                                                 r
duction of barbituates.  Production of U.S.P.  (pharmaceutical) grade chloral
hydrate  was  estimated  to  be 300,000  pounds  per  year in  1975  (Stanford
Research Institute,  1976).

-------
II.  EXPOSURE
     Boitsov,  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/nr  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 ;jg/l to 5.0 jjg/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-
hol 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 Oilman,  1970).
III.  PHARMACOKINETICS
     A.   Absorption
          Specific information on the absorption of chloral was not found in
                                                                     »
the available  literature.   Goodman arid Gilman  (1970)  reported that chloral
hydrate readily penetrates  diffusion barriers  in the body.
     B.   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 administration, noted its presence
in cerebrospinal fluid, milk,  amniotic  fluid,  and fetal blood.  The auth'ors

-------
 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,  1577).
 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
 trichloroethanol 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.
     0.   Excretion
          Both  chloral  aid  chloral hydrate  are metabolized  to  trichloro-
ethanol  or  trichloroacetic  acid  (Goodman  and Oilman,   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.            ;'

-------
 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.
      B.   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/nr)  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/m3.
          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

-------
 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 LD,.n
 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 LD5Q 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)  rariked
the 96-hour Tl_m aquatic toxicity  of  chloral in the  range  from 1 to 10 ppm.

-------
      B.   Chronic Toxicity
          Information  on the  chronic  aquatic  toxicity  of chloral was  not
 found in the  available  literature.
      C.   Plant Effects
          Shimizu,  et  al.  (1574)  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.
      D.   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 pg/1;  Seattle,
 WA, 3.5 jjg/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
      Boitsov, et  al. (1970) reported  a maximum recommended chloral concen-
tration in  workroom  air of 0.22  mg/1  (220  mg/m-5)  (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.

-------
                                   References


 Boitsov,  A.N., et  al.    1570.  lexicological  evaluation of chloral in the
 process  of  its  liberation  during  spraying  and  pouring  of  polyurethane
 foams.  Gig. Tr. Prof. Zabol.   14: 26.   (Chemical Abstracts CA 73:96934P).

 Oilling,  W.L., et  al.   1576.   Organic  photochemistry-simulated atmopsheric
 photcdecomposition  rates of methylene chloride,  1,1,1-trichloroethane,  tri-
 chloroethylene,  tetrschloroethylene,  and  other  compounds.   Environ.  Sci.
 Technol.   ID: 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.

 Hawley,  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).

 Luknitskii, 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. D: 142.   (Chemical Abstracts CA  82:165838K).

 Pavlova,   L.P.    1975.   Toxicological characteristics  of  trichloroacetal-
 dehyde.  Tr.  Azerb.  Nauchno-Issled.  Inst.  Gig.  Tr.   Pro.  Zabol.   JO: 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 CKem-
 icals.  Von Nostrand Reinhold  Co.,  New York.   p.  170.

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

Windholz, M., et  al.   1976.  The Merck  Index.   Merck and Co., Inc., Rahway,
N.J.  p. 1,236.

-------
                                       No.  35
             Chlordane


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION


U.S. BPA's Carcinogen Assessment Group (GAG) has evaluated
chlordane and has found sufficient evidence to indicate
that this compound is carcinogenic.

-------
                                   CHLORDANE '
                                    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 LC5Q  values  rang-
ing  from 8  to 1160 pg/1.   Freshwater invertebrates  appear  to  be  more resis-
tant  to chlordane,  with  observed  96-hr  LC-Q  values ranging  from  4  to  40
jjg/1.   Five  species of saltwater  fish  have LC5Q 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  Oaphnia  maqna gave  an LC50 of  1.6
wg/i.

-------
                                   CHLOROANE
     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 organochlori-
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  (l,2,4,5,6,7,a,8-octachloro-2,3,3a,4,7,7a-hexahydro-<4,7-
methanoindene)  is  a  pale  yellow  liquid  having  the empirical  formula C,Q-
H-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 jjg/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

-------
uses of chlordane.  However, use  of  chlordane for termite control and limit-
ed usage  (through 1980) as  an  agricultural insecticide  are  still permitted
(A3 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 ;jg/l (Schafer, et al.  1969) and in rainwater (Bevenue, 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

-------
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 ;jg  (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 pg/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 Durban  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.

-------
      D.   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).
'ill. 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).
      B.   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,
                                               f
 1978; Street  and Blau, 1972).  Oxychlordane  cart degrade  to form l-hydroxy-2-
                                                                       *
 cyclochlordenes,   and  l-hydroxy-2-chloro-2,3-epoxy-chlordenes  (Tashiro  and
 Matsumura,  1978).  In general, the metabolism of chlordane takes olace  via a

-------
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-
cretion  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
days  (Barnett  and  Oorough, 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).
                                    3r-

-------
       B.  Mutagenicity
           Pure  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).
       0.  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-
  cluded  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

-------
ug/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 mg/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 LD-Q 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  LC5Q  values
ranging  from 8  to   1160 jjg/1  resulting  from technical  and  pure chlordane
exposure  with a geometric  mean of  16 ug/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 LC5_  value rang-
ing from  4.0  for freshwater shrimp Palaemonetes kadiakensis  (Sanders, 1972)
to 40  jjg/1  (Gammarus  fasciatus),  with a geometric mean  of 0.36 ug/1.   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  (Fercz
and Khan, 1979).

-------
         The LCcg's  for four  species  of saltwater  fish,  sheepshead minnows
(Cyprinodon  veriegatus),  striped bass  (Morone saxatilis),  pinfish (Lagodon
rhomboides), and white  mullet  (Mugil curema),  ranged  from 5.5 to 24.5 jug/1.
The  three-spine  stickleback  (Gasterosteus aculeatus)   yielded  96-hr  LC5Q
values which ranged  from 90-160 pg/1  (Katz,   1961).   Invertebrate  LC5Q val-
ues ranged  from 0.4  for the pink  shrimp,  Penaeus duorarum  (Parrish,  et al.
1976) to  480 jug/1.  The geometric  mean of the adjusted  LC5Q values for in-
vertebrates was 0.18jug/l (U.S. EPA, 1979).
     B.  Chronic Toxicity
         In  a  life cycle bioassay  involving freshwater organisms, the chron-
ic values  for. the  bluegill Lepomis  macrochirus  (Cardwell,  et  al.  1977) was
1.6jug/l.  In  two  tests involving  the  sheepshead minnow,  Cyprinodon variega-
tus, the chronic values were 0.63  ug/1 for the life cycle test (Parrish,  et
al. 1978) and 5.49 jug/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 pg/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  jjg/1 (Butler,
1963).
     D.  Residues
         In  Daphnia  magna,  chlordane   was  bioconcentrated  6,000-fold  after
seven days' exposure and 7,400-fold  by  scuds (Hyallela azteca) after 85 days
of exposure  (Cardwell,  et  al.  1977).   After  33 days' exposure,  the fresh-
                                    ^^fa*

-------
water  alga  (Oedegonium 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-*          10-5
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 ug/1  for  chlordane  in  drinking  water  is  suggested
under the  proposed Interim  Primary  Drinking Water  Standards (40 FR  11990,
March 14, 1975).
                                              ^
         Canadian  Drinking  Water Standards --(.Dept.  Natl.  Health  Welfare,
                                                                      »
1968) limit chlordane to 3 ug/1 in raw water supplies.

-------
     8.   Aquatic
         For chlordane, the proposed  criterion  to protect freshwater aquatic
life is  0.024  /jg/1 for a  24-hour average,  not to exceed  0.36 pg/1  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 pg/1 at  any time
(U.S. EPA, 1979).
                                    -HJ3-

-------
                          CHLORDANE
                          REFERENCES

Ahmed,  F.E.,  et  al.    1977.    Pesticide  induced  DNA damage
and  its repair  in cultured  human cells.   Mutat.  Res.  42:
161.

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
substances  in  workroom air adopted by  the  American Confer-
ence of Governmental Industrial Hygienists for 1977.  Cincin-
nati, Ohio.                               v

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.
Contain. Toxicol. 22: 666.

Barnett, J.R., and H.W. Dorough.  1974.  Metabolism of chlor-
dane in rats.  Jour. Agric. Food Chera.  22: 612.

Benson, W.R.,  et al.   1971.   Chlordane photoalteration pro-
ducts:  Their  preparation and identification.   Jour. Agric.
Food Chem. 19:  857.

Bevenue,  A.,  et  al.    1972.    Organochlorine  pesticides in-
rainwater  Oahu,   Hawaii,  1971-72.    Bull. Environ.  Contam.
Toxicol. 8: 238.                                        «

Butler, P.A.,  et  al.   1953.    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.    Acute chlordane
poisoning.  Arch. Environ. Health 18: 211.

Department of National Health and Welfa're.   1963.  Canadian
drinking water standards and objectives.  Ottawa,  Canada.
Ducat, D.A. and M.A.Q.  Khan.   1979...  Absorption and elimina-
tion  of    C-cis-chlordane  and    C-photo-cis-chlordane  by
goldfish, Carassius auratus.  Arch. Enviorn. Contam. 8: 409.
                             -1.

-------
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.  Contam.
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.  '

Kazan 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. Contain. 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 B14: 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.  In 1970 evalua-
tion of some  pesticide residues in food.   Foo"3~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.
                                       f
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:
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 ac-tivity 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 tetrachlor ide..    Exp.
Mol.  Pathol. 23: 144.

Strassman,  S.C.,  and  F.W. Kutz.    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.

-------
                                         LB:42-1
                                         No. 36
        Chlorinated Benzenes
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY




      WASHINGTON, D.C.  20460






         OCTOBER 30, 1980
                36-1

-------
                            DISCLAIMER
     This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical.  This document has undergone scrutiny to
ensure its technical accuracy.
                               36-2

-------
                       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

persistence of the compound in the environment increases.  On

chronic exposure liver and kidney changes are noted, and the

degree of toxicity increases with the degree of chlorination.

The chlorinated benzenes have not been shown to be teratogens or

mutagens.  Only hexachlorobenzene has been demonstrated to be

carcinogenic in laboratory animals.

     Aquatic toxicity data indicate a trend to increasing toxicity

with  increasing chlorination for all species tested.  For the

bluegill, for example, the following 96-hour LC5Q values; have

been noted:  chlorobenzene, 15,900 ug/1; 1,2,4-trichlorobenzene,

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

and plants are generally less sensitive to chlorobenzenes than

the bluegill.  The sheephead minnow yielded a chronic value of

14.5 ug/1 for 1,2,4,Stetrachlorobenzene in an embryo-level

test.  After 28 days of exposure, the bioconcentration factors

for the bluegill for pentachlorobenzene and 1,2,4,5-tetrachloro-
benzene were 3,400 and 1,800,  respectively.
                               36-3

-------
                       CHLORINATED BENZENES

I.   INTRODUCTION
    «
     This profile  is based  inpart on  the Ambient Water Quality

Criteria Document  for Chlorinated Benzenes (U.S. EPA, 1980).

This document summarizes  the general  properties of  the chlori-

nated benzenes.  For further information on monochlorobenzene,

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, 1980).

     The chlorinated benzenes, excluding dichlorobenzenes*, are

monochlorobenzene  (CgH3Cl), 1, 2,4-trichlorobenzene  (0^3013),

1,3,5-trichlorobenzene (CgH3Cl3), 1,2,3,4-tetrachlorobenzene

(CgH2Cl4), 1,2,3,5-tetrachlorobenzene (C6H2C14), 1,2,4,5-

tetrachlorobenzene (CgH2Cl4), pentachlorobenzene (€5015) and

hexachlorobenzene  (0^015).  All chlorinated benzenes 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 chemical  reactivity.  Viscosity

and nonflammability tend  to increase with degree of chlorination.

Vapor pressures and water solubility decrease progressively with

the degree of chlorination  (U.S.  EPA, 1980).
*the health and environmental effects of dichlorobenzenes are
discussed in HEBD's Nos. 64-67.
                               36-4

-------
      The current production, based on  annual production in the



U.S.,  was 139,105 kkg of monochlorobenzene in 1975, 12,849 kkg of



1, 2,4,-trichlorobenzene, 8,182 kkg of 1, 2, 4, 5-tetrachlorobenzene



and  318  kkg of hexachlorobenzene in 1973 (West and Ware, 1977;



EPA,  1975a).  The remaining chlorinated benzenes are produced



mainly as by-products from the production processes for the above



four chemicals.   Chlorinated benzenes  have many and diverse uses



in industry depending upon the individual properties of the



specific compound.  Some uses are as solvents, chemical inter-



mediates,  flame  retardants, and plasticizers.



11.   EXPOSURE



      A.    Water



           Mono-,  tri-, and hexachlorobenzene have been detected



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.



Monochlorobenzene has been detected in "uncontaminated" water at



levels of 4.7 ug/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,  1980).  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 chlorinated



benzenes  in food.  All the chlorinated benzenes appear to
                               36-5

-------
concentrate  in  fat, and can be absorbed by plants from contaminated

soil.  Both  pentachlorobenzene and hexachlorobenzene have been

detected  in  meat  fat  (e.g. Stijve, 1971; Ushio and Doguchi,

1977).  Hexachlorobenzene, the most extensively studied compound,

has been  found  in a wide variety of foods from cereals to milk

(including- human  breasjt milk), eggs, and meat.  The U.S. EPA

(1980) has estimated  the weighted bioconcentration factors for

freshwater species:

                                        '  Weighted
          Chemical                 bioconcentration factor

     monochlorobenzene                         13
     1,2,4-trichlorobenzene                   182
     1,2,3,5-tetrachlorobenzene             1,800
     pentachlorobenzene                     3,400
     hexachlorobenzene                     22,000

     These estimates were based on the octanol/water parti-

tion coefficients of the chlorinated benzenes.

     C.   Inhalation

          There is no available data on the concentration of

chlorinated benzenes in ambient air with the exception 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/ra2/day (U.S. EPA, 1980).  The primary site of inhalation

exposure to chlorinated benzenes is the workplace 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 the

                               36-6

-------
toxicity of orally administered compounds that absorption 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).  Hexachlorobenzene 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 selectively partition into the lipid portion and are


absorbed far better than those in the aqueous portion (U.S. EPA,


1980).


     B.   Distribution


          The chlorinated benzenes are lipophilic compounds, with


greater lipophilic tendencies in the more highly chlorinated


compounds.  The predominant uptake site is either suspected or


known to be the lipid tissues of the body (Lee and Metcalf,


1975; U.S. EPA, 1980).


     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.  Conjugates  of the more highly


chlorinated compounds, such as hexachlorobenzene,  are only formed


to a limited extent,  and their metabolism is relatively slow.



                               36-7

-------
     D.   Excretion

          The less-chlorinated benzenes are excreted as polar

metabolites or conjugates in the urine.  An exception occurs with

monochlorobenzene is an exception:  in the rabbit, 27 percent of

an administered dose appeared as unchanged compounds in expired

air  (Williams, 1959).  The two highly chlorinated compounds,

pentachlorobenzene and hexachlorobenzene, are predominately
                                 •
eliminated in unchanged form by fecal excretion (Koss and Koransky,

1975; Rozman, et al. 1979).  The biological half-lives of these

two  compounds are extremely long in comparison to those of the

less-chlorinated compounds (U.S. EPA, 1980).

IV.  EFFECTS

     A.   Carcinogencity

          The carcinogenic potential of mono- and tetrachlorobenzene

have not been investigated (U.S. EPA, 1980).  In one study,

trichlorobenzene was not shown to produce any significant increase

in liver tumors (Gotto, et al. 1972).  There is one report, not

critically evaluated by EPA (1980), which alludes to the carcino-

gencity 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-

chlorobenezene.   However,  shorter term studies failed to demonstrate

an increased tumor incidence in strain A mice or ICR mice (Theiss,

et al.  1977;  Shirai,  et al. 1978).   Chlorobenzene has been tentative-

ly selected for long-term bioassay testing by NCI (U.S.  EPA, 1978b).
                               36-8

-------
     B.    Mutagenicity



           There  are no  reports of studies conducted to evaluate




the mutagenic potential of tri-,tetra- and pentachlorobenzene*



Chlorobenzene causes mutations in S.antibioticus, and chromosomal



damage and mitotic inhibition in root tips of higher plants, and



is not mutagenic  in the fungus A.nidulans (U.S. EPA, 1978b).




Hexachlorobenzene was assayed for mutagenic activity in the



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



     C.    Teratogenicity



           There  are no available reports on the teratogenic



potential  of mono-, tri-, and tetra-, Chlorobenzene (U.S. EPA,



1980).  Khera (1974) concluded that hexachlorobenzene is not a




teratogen  when given to CD-I mice at 50 mg/kg/day on gestation



days from  7 to 11.  Pentachlorobenzene, however, induces a dose-



related incidence of sternebral defects in rats (Khera, 1975).



     D.    Other Reproductive Effects



           Both penta- and hexachlorobenzene 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 as in the adult,, with the highest concentration



in fatty tissue.



     E.    Chronic Toxicity



          There are no available data on the chronic effects of



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




product histological changes in the liver and kidney (Irish,



1963; Coate,  et al. 1977).   Chlorobenzene (orally administered at



250 mg/kg  for 3 days)  caused liver dysfunction and porphyria






                               36-9

-------
 (U.S. EPA,  1978b).  There  is  also  evidence  for  liver damage



 occurring with prolonged exposure  of rats and dogs to tetrachloro-



 benzene  (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.



V.   ACUATIC TOXICITY (U.S. EPA, 1980)



     A.   Acute Toxicity



          The dichlorobenzenes are covered in a separate EPA/ECAO



hazard profile and will not be covered in this disucssion on



chlorobenzenes.



          All data reported for freshwater fish are from 96-hour



 static toxicity tests.   Pickering  and Henderson (1966)  reported



96-hour LCso values for goldfish,  guppies and bluegills to be



51,620,  45,530, and 24,000 ug/1, respectively, for chlorobenzene.



Two 96 hour LCso values for chlorobenzene and fathead minnows ar«



33,930 ug/1 in saltwater and 29,120 ug/1 in hard water.  Reported



96-hour values for the bluegill exposed to chlorobenzene, 1,2,4-



trichlorobenzene, 1,2,3,5- and 1,2,4,5-tetrachlorobenzenes and



pentachlorobenzene are 15,900, 3,360,  6,420, 1,550,  and 250



ug/1,  respectively (U.S. EPA,  1978).   These data indicate increasing



toxicity with chlorination, except for monochlorobenzene.  ECsg



 (48 hour) values reported for Daphnia magna are:  chlorcb'enzene






                               36-10

-------
86,000 ug/1,  1,2,4-trichlorobenzene 50,200 ug/1, 1,2,3,5-tetra-



chlorobenzene 9,710 ug/1, and pentachlorobenzene 5,280 ug/1.



          Toxicity tests with the  sheepshead minnow, Cyprinodon



variegatus, performed with five chlorinated benzenes under static



conditions and yielded  the following 96-hour LCso values:



chlorobenzene 10,500 ug/1, 1,2,4-trichlorobenzene 21,400 ug/1,



1,2,3,5-tetrachlorobenzene 3,670 ug/1, 1,2,4,5 tetrachlorobenzene



840 ug/1, and pentrachlorobenzene  835 ug/1.  As with sheepshea^



minnows, sensitivity of the mysid  shrimp, Mysidopsis bahia, to



chlorinated benzenes generally increases with increasing chlori-



nation.  The  reported 96-hour LCso values are as follows:



chlorobenzene 16,400 ug/1, 1,2,4-trichlorobenzene 450 ug/1,



1, 2,3,5-tetrachlorobenzene 340 ug/1, 1,2,4,5-tetrachlorobenzene



1,480 ug/1, and 160 ug/1 for pentachlorobenzene.



     B.   Chronic Toxicity



          Chronic toxicity data are not available for freshwater



fish or invertebrate species.  Only one saltwater species*



Cyprinodon variegatus, 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 ug/1, with a final



chronic value of 64.5 ug/1.



     C.   Plant Effects



          The green freshwater algae Selenastrum capricornutum



has been exposed to five chlorinated benzenes.   Based on cell



number, the 96-hour ECso values are as follows:   chlorobenzene



220,000 ug/1, 1,2,4-trichlorobenzene 36,700 ug/1,  1,2,3,5-



tetrachlorobenzene 17,700 ug/1,  1,2,4,5-tetrachlorobenzene 46,800





                              36-11

-------
ug/l,  and pentachlorobenzene 6,780 ug/1.


     D.   Residues
     »

          No measured bioconcentration factor (BCF) is available


for chlorobenzen.es.  However, the average weighted BCF of 13 was


calculated  from octanol-water partition coefficient and other


factors. .(See above)  (U.S. EPA, 1980).


VI.  EXISTING GUIDELINES AND STANDARDS


     A.   Hunan


          Monochlorobenzene:  The American Conference of Governmental


Industrial Hygienists (ACGIH, 1971) threshold limit value for


monochlorobenzene is 75 ppm.  The U.S. EPA ambient water quality


criterion for monochlorobenzene is 20 ug/1 based on the threshold


concentration for odor and taste, and 488 ug/1 based on its toxic


effects (U.S. EPA, 1980).


          Trichlorobenzene:  The American Conference of Governmental


Industrial Hygienists (ACGIH, 1977) threshold limit value for


1,2,4-trichlorobenzene is (5 ppm).  Because of the insufficiency


of available information for trichlorobenzene U.S. EPA (1980)


determined that a criterion could not be derived using the


guidelines in effect in 1980.


          Tetrachlorobenzene:  The U.S. EPA (1980) ambient water


quality criterion for 1,2,4,5-tetrachlorobenzene based on its


toxic  effects,  is 38 ug/1.


          Pentachlorobenzene:  The U.S. EPA (1979) ambient water


quality criterion for pentachlorobenzene based on its toxic


effects is 74 ug/1.
                              36-12

-------
          Hexachlorobenzene:  The value of 0.6 ug/kg/day



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 at 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).  For maximum protection of human health



from the potential carcinogenic effects of hexachlorobenzene



through ingestion of contaminated water and contaminated aquatic



organisms,  the ambient water criterion is 0.72 ug/1 (10-7 incremental



lifetime risk)(U.S.  EPA, 1980).
                             36-13

-------
                       CHLORINATED BENZENES

                            REFERENCES

Albro, PiW., and R. Thomas. 1974.   Intestinal absorption of
hexachlorobenzene and hexchlorocyclohexane isomers in rats.
Bull.  Environ. Contain. Toxicol. 12: 289.

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

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

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

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

Cabral, J.R.P., et al. 1978.  Carcinogenesis study in mice with
hexachlorobenzene.  Toxicol Appl. Pharmacol.  45:323.

Cam, C., and G. Nigogosyan.  1963.  Acquired toxic porphyria cutanea
tarda due to hexchlorobenzene.  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
pesticide residues in food.  FAO/AGP/1973/M/9/1;  WHO Pestic.  Residue
Ser. 3. World Health Org., Rome,  Italy, p. 291.

Gott, M.,  et al. 1972.   Hepatoma formation in mice after admini
stration of high doses of hexchlorocyclohexane isomers.  Chemosphere
1L279.
                              36-14

-------
Grant, D.L., et al.   1977.   Effect of hexachlorobenzene on re-
production  in the rat.  Arch. Environ. Contain. Toxicol  5:207.

Irish, D.D.  1963. . Halogenated hydrocarbons:  II. Cyclic. In
Industrial  Hygiene 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 hexachlorobenzene  in rats.  Food Cosmet. Toxicol. 12:471.

Khera, K.S. and D.C. Villeneuve.  1975. Teratogenicity studies on
halogenated benzenes  (pentachloro-, pentanitro-, and hexabromo-)
in rats. Toxicology.  5:117.

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

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

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

Koss, G., et al.  1978.  Studies  on the toxicology of hexachloro-
benzene.  III.   Observations  in a  long-term experiment.   Arch.
Toxicol.  40:285.

Lu, P.Y., and R.L. Metcalf.  1975.  Environmental fate and biode-
gradability of benzene derivatives as studied in a model aquatic
ecosystem.  Environ. Health Perspect.  10:269.

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

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

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

                              36-15

-------
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 environ-
ment.  Hand. Allg. Pathol.   6:421.

Rozman,  K., et  al. 1979 Metabolism and pharmacokinetics of penta-
chlorobenzene in rhesus monkeys.  Bull. Environ.  Contarn. Toxicol.
22:190.

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

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

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

U.S. EPA.  1975.  Survey of  Industrial Processing Data:  Task I,
hexachlorobenzene and nexachlorobutadiene pollution from chlorocarbon
processes.  Mid. Res. Inst.  EPA, Off. Toxic  Subs. Contract, Washington,
D.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.  1978b.   Initial Report of the TSCA Interagency Testing
Committee to the Administrator, EPA.   EPA 560-10-78/001.
t
U.S. EPA.  1979.  Ambient Water Quality Criteria  for EPA 440/5-80-028.

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

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

Williams, R.T.   1959.   The metabolism of halogenated aromatic hydro-
carbons.  Page 237 In;  Detoxication mechanisms.  2nd ed.  John Wiley
and Sons, New York.
                            36-16

-------
                                   No. 37
       Chlorinated Ethanes
  Health and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
      WASHINGTON, D.C.   20460

          APRIL  30, 1980
          37-1

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

-------
                       SPECIAL  NOTATION









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



chlorinated ethanes and has  found sufficient evidence to



indicate that this compound  is  carcinogenic.
                              37-3

-------
                     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 chlocoethanes

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.

-------
                     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 103 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  toater

(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
                           3-7-5

-------
     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  ;ag/l  (U.S.  EPA,
     1979).  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).
                                               s
                                  TABLE 1
                         Chloroethanes and  Synonyms
                    Synonyms
Compound Name
Monochloroethane
1,1,-Dichloroethane
1,2-Dichloroethane
1,1,1-Trichloroethane
1,1,2-Tr ichloroethane
1,1,1,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
Pentachloroethane
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-Yetrachloroethane
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 I,1,1-trichloro-
                               37-6

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


levels of  1,2-dichloroethane  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  bioconcentration.  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 Smyth,


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.
                          37-7

-------
     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
                                          V
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.

-------
     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,
                            37-?

-------
and  hexachloroe thane.    Increased  tumor  production  was  also


noted  in  animals  treated  with   1,1,1-trichloroe thane,  but


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


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


tion of  rat  embryo cells and subsequent  fibrosarcoma produc-


tion  by these  cells  when  injected  ir\  vivo,  indicate  that


1,1,1-trichloroe thane does have carcinogenic potential (Price,


et al. 1978)  .


     B.   Mutagenicity
                                          v

          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


strain 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


(Nylander,  et  al.  1978).   Several  metabolites  of  dichloro-


ethane  (chloroacetaldehyde,  chloroethanol,  and S-chloroethyl


cysteine have  also  been shown to  produce mutations  in  the


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


          Testing of hexachioroethane  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-tr ichloroethane  was   shown  to  produce  some  soft
                            37-1-0

-------
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
                              7t


                            37-11

-------
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-dichloroe thane >
1,1,2, 2- tetr achloroethane ^"1,1,2-tr ichloroe thane >hexachloro-
ethane 1 , 1-dichloroe thane ;> 1 , 1 , 1-tr ichloroe thane > 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
                                                           9
     A.   Acute Toxicity
          Acute  toxicity  studies  were   conducted  on  three
species  of  freshwater  organisms  and  two  marine  species.
                            37-

-------
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 LC5Q  values  for  the  freshwater  inverte-
brate Daphnia  magna was  8,070  ug/1 to 218,000 ug/1 for hexa-
chloroethane  and  1,2-dichloroethane  respectively.    Among
marine  organisms,  the sheepshead minnow  (Cyprinodon vagie-
gatus)  produced  LC^Q  values  ranging  from  2,400  pg/I  for
hexachloroethane   to   116,000   ug/1  for   pentachloroethane.
The  marine  mysid  shrimp  (Mysidopsis  bahia)   produced  LCrg
values  ranging  from 940  ug/1 for  hexachloroethane to 113,000
ug/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  pentachloroethane1 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^g  concentrations, based on chlorophyll
a  and  cell numbers   for  the  freshwater  algae  Selenastrum
capriconutum  ranges from  87,000   ug/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 costatum,    a  greater  sensi-
                            37-13

-------
tivity was  indicated  by effective EC50_ 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, 3, and 9 were obtained
for  1,2-dichloro,  1,1,2,2-tetrachloro,  and 1,1,1-trichloro-
                                          \
ethane  for  bluegills.    1,1-,2-Trichloroe thane  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  10~3: 1,2-
dichloroe thane,  7.0   ug/1;  1,1,2-trichloroethane,  2.7  ug/1;
1,1,2,2-tetrachloroethane,  1.3  pg/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.
                            J7-/Y

-------
          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  drafted  for  five  of  the chlorinated  hydrocarbons:  62
pg/1  (average concentation)  not  to exceed 140  pg/1 for hexa-
chloroethane; 170  pg/1 not  to exceed  380 pg/1  for 1,1,2,2-
tetrachloroethane;  440  pq/l  not  to  exceed  1,000 ,ug/l  for
pentachloroethane;  3,900  ug/1  not to  exceed 8,800 pg/1  for
1,2-dichloroethane;  and  5,300  pg/1  not to  exceed  12,000
pg/1  for  1,1,1-trichloroethane.   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  ug/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 rautagenicity  and  DNA-Modifying
effect of haloalkanes.  Cancer Res.   34: 2576.

Dickson, A.O., and J.P. Riley.  1976.  The distribution  of
short-chain halogenated aliphatic hydrocarbons  in  some narine
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.

Holmberg, 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.
Phamacol. 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-trici^loro-
ethane and tetrachlbroethylene.  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 for 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. No. (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
Drosophilia irielanoaaster.  I. Effects of benzene of and 1,2-
dichloroethane.  Mutat. Res.  57: 163.

Page, B.D., and P.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.  I_n
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. Pharmacol.  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.

-------
Smyth, H.F., Jr., et al.  1969.  Range-finding  toxicity data:
list VII.  Am. Ind. Hyg. Assoc. Jour. 30: 470.

Stahl, C.J., et al.  1969.  Trichloroethane 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 animals (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 J^n
vitro.  Biochem. Pharmacol. 20: 463.

Vozovaya, M.A.  1974.  Development o^ 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.  Natl.  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. Pharraacol. Toxicol. 30: 257.

Yllner, S.  1971b.  Metabolism of 1,1,2-trichloroethane-l,2-
^•4C in the mouse.  Acta. Pharnacol. 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-
^4C in the mouse.  Acta. Pharmacol. Toxicol.  29: 499.

Yllner, S.  1971e.  Metabolism of pentachloroethane  in the
mouse.  Acta. Pharmacol. Toxicol. 2^: 481.
                               37- It

-------
                                      No. 38
      Chlorinated Naphthalenes


  Health and Environmental Effects
O.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.

-------
                            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  of  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^Q  values  of octachloro-
naphthalene over 500,000 /ug/1 have been  reported for Daphnia magna and the
bluegill, respectively.  A freshwater  alga  also  resulted in  a  96-hour LC5Q
value for octachloronaphthalene of over 500,000 jLig/1.
     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  LC5Q values of be-
tween 320 and 2,270  jjg/1.   Exposure of sheepshead minnow to 1-chloronaphtha-
                                                                  *
lene in an embryo-larval study resulted in a chronic value of 328 ug/1.

-------
                            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°C-  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.
     B.   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).

-------
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 biocon-
centration  factor  for Halowax 1014  (a  mixture of  chlorinated  naphthalenes)
to  be 4,800  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  pg/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.
     B.  Distribution
         In the rat  fed 1,2-dichloronaphthalene,  the chemical and its metab-
olites were found primarily  in  the  intestine,  kidney,  and  adipose tissue
                                                                  »
(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

-------
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 carcinogenic!ty,
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).  Polychlorinated  naphthalenes containing

-------
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-Xhexachloronaphthalene  mixture in air  for  six weeks.   In a similar
study trichloronaphthalene was inactive.
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         The  96-hour   LC^  value   reported  for   the   bluegill,  Lepomis
macrochirus, exposed to 1-chloronaphthalene  is 2,270 jug/1  (U.S.  EPA,  1978).
With  saltwater  species,  exposure  of  the  sheepshead  minnow,  Cyprinodon
variqatus, and  mysid  shrimp, Mysidopsis  bahia_, to  1-chloronaphthalene pro-
vided  96-hour  LC50  values of  1,290  and 370  Jjg/l,  respectively.   Daphnia
maqna and  the bluegill,  Lepomis  macrochirus,  have  a slight  sensitivity  to
octachloronaphthalene, ' with  respective  48-hour  and  96-hour  I_C50  values
greater than 530,000pg/l (U.S.  EPA, 1978).
     B.  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 jjg/1 (U.S. EPA, 1978).

-------
     C.  Plant Effects
         A freshwater alga,  Selenastrum  capricomutum,  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  caprlcornutum  re-
sulted in  a  96-hour EC^g  value of over  500,000  jug/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
Tetrachloronaphthalene
Pentachloronaphthalene
Hexachloronaphthalene
Octachloronaphthalene
5
2
0.5
0.2
0.1
mg/m3
mg/m3
mg/m3
mg/m3 •
mg/m3
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  ug/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.

-------
     B.  Aquatic
         For 1-chloronaphthalene,  the  draft criterion to  protect freshwater
aquatic life is  29  pg/1 as a 24-hour  average,  not  to exceed 67 pg/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/jg/l at any time  (U.S.  EPA, 1979).

-------
                   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,—J-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 prefer-
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'chlcronaphthalenes.
A.M.A. Arch. Derm.  75: 689.
                           33--; a

-------
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.

-------
                                         LB:46


                                         No.  39
        Chlorinated Phenols


  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
      WASHINGTON, D. C.  20460
          October 30, 1980


                39-1

-------
                          DISCLAIMER


     This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical.  The
information contained in the report is drawn chiefly from secondary
sources and available reference documents.  Because of the limita-
tions of such sources, this short profile may not reflect all
available information including all the adverse health and environ-
mental impacts presented by the subject chemical.  This document
has undergone scrutiny to ensure its technical accuracy.
                               39-2

-------
                         SPECIAL NOTATION



     This document discusses the health and environmental effects



of some of the di, tri, and tetra-substituted chlorinated phenols.



The health effects of p-chloro-m-cresol, 2-chlorophenol, 2,4- and



2,6-dichlorophenol, 2,4,6-trichlorophenol, and pentachlorophenol are



discussed in HEBD's nos.  43, 50, 75, 76, 143, and 168, respectively.



The National Cancer Institute (1979) recently published the results



of a bioassay indicating that 2,4,6-trichlorophenol induces cancer



in rats and mice.
                               39-3

-------
                       CHLORINATED PHENOLS
                             SUMMARY

     Mammalian data supporting chronic effects for most of these
compounds  is limited.  Except for trichlorophenol, there are not
sufficient data to indicate whether any of the other chlorinated
phenols are carcinogens.  In skin painting studies, 3-chlorophenol
and 2,4,5-trichlorophenol promoted papillomas.  Tetrachlorophenol
was not teratogenic or embryolethal in animals, but showed question-
able fetotoxic effects.  Chronic exposure to 4-chlorophenol produced
myoneural disorders in humans and animals.  Adverse health effects
have been noted in workers exposed to 2,4,5-trichlorophenol.
Workers chronically exposed to tetrachlorophenol and pentachloro-
phenol, perhaps contaminated with small amounts of chlorodibenzo-
dioxins, developed severe skin irritations, respiratory difficulties,
and headaches.
     Chlorophenols are uncouplers of oxidative phosphorylation,
and- affect carbohydrate metabolism.   Several affect the nervous
system, causing convulsions.
     The tainting of rainbow trout flesh has been demonstrated at
exposures of 15 to 84 ug/1 for several of the chlorinated phenols.
                               39-4

-------
 I.    INTRODUCTION



      This  profile is  based in part on the Ambient Water Quality



 Criteria Document for Chlorinated  Phenols (U.S.  EPA,  1980).



      The chlorinated  phenols  represent a group of commercially



 produced substituted  phenols  and cresols also referred  to as  chloro-



 phenols or chlorocresols.   The compounds p-chloro-m-cresol,



 2,4-  and 2,6-dichlorophenols,  2,4,6-trichlorophenol,  and penta-



 chlorophenol  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 decreases and the  melting



 and boiling points increase as the  number of  substituted chlorine



 atoms increases.   Although the solubility of  chlorinated phenols



 in aqueous solutions  is relatively  low,  it increases  markedly



when  the pH of the solution exceeds  their specific pKa.   The  solu-



bilities of chlorinated 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,  1980).



     The chlorinated phenols that are most important  commercially



are 4-chlbrophenol, 2,4,-dichlorophenol,  2,4,5-trichlorophenol,



2,3,4-tetrachlorophenol, pentachlorophenol, and 4-chloro-o-cresol.



Many of the chlorophenols  have no commercial  application but  are
                               39-5

-------
 produced  to  some  extent as  byproducts  of  the  commercially  important


 compounds.   The highly  toxic polychlorinated  dibenzo-p-dioxins
       «
 may be formed  during  the chemical  synthesis of  some  chlorophenols.


 During the chlorination of  drinking waters and  wastewater  effluents,


 chlorophenols  may be  inadvertently produced (U.S.  EPA,  1980).

     Chlorinated  phenols are used  as intermediates in the  synthesis


 of dyes,  pigments, phenolic resins, pesticides,  and  herbicides.


 Certain chlorophenols are used directly as flea  repellants,  fungi-

 cides, wood  preservatives,  mold  inhibitors, antiseptics, disinfect-


 ants, and antigumming agents for gasoline.


     Chlorinated  phenols undergo photolysis in  aqueous  solutions

 as a result  of ultraviolet  irradiation; photodegration  leads to


 the substitution  of hydroxyl groups in place  of  the  chlorine atoms


 with subsequent polymerization (U.S..EPA, 1980).  Microbial degra-


 dation of chlorophenols has been reported by  numerous investigators


 (U.S. EPA, 1980).



                3-CHLOROPHENOL and 4-CHLOROPHENOL


 II.  EXPOSURE

     Monochlorophenols  have been found in surface waters in the


Netherlands  at concentrations of 2 to 20 ug/1 (Piet  and DeGrunt,

 1975).  Ingestion of chlorobenzene can give rise to  internal


exposure to  2-, 3-, and  4-chlorophenols, as chlorobenzene  is

metabolized  to monochlorophenols (Lindsay-Smith, et  al. 1972).

No data were found demonstrating the presence of monochlorophenol


 in food.



                               39-6

-------
      For 4-chlorophenol the U.S.  EPA has estimated the weighted



 average  bioconcentration factor for the edible portions of all



 aquatic  organisms consumed by Americans to be 12.   This estimate



 is  base  don the  octanol/water partition coefficient.



      Data were not found in the available literature  regarding



 inhalation exposure.



 III.  PHARMACOKINETICS



      Systematic  studies of the pharmacokinetics  of 3- or 4-chloro-



 phenol are not available.   Dogs excreted 87  percent of administered



 4-chlorophenol in the  urine as sulfuric and  glucuronic conjugates



 (Karpow,  1893, as cited in U.S.  EPAf  1980).



 IV.   EFFECTS



      A.    Carcinogenicity



           Information  is not adequate to determine whether 3-  or



 4-chlorophenol posses  carcinogenic  properties.   A  20  percent solu-



 tion  of  3-chlorophenol 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 litera-



 ture regarding mutagenicity,  teratogenicity  and  other reproductive



effects.



     C.    Chronic Toxicity



          Rats exposed  6 hrs/day for  four months to 2 mg  4-chloro-



phenol/n\3  showed a temporary weight loss and  increased myoneural
                               39-7

-------
 excitability.   Body  temperature  and  hematological  parameters  were



 not  altered  (Gurova,  1964).  Workers exposed  to 4-chlorophenol
       *                                                              ,*


 had  a  significantly  higher  incidence of  neurological  disorders



 when compared with 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  also increased  (Gurova, 1964).



     D.   Other Relevant Information



          3- and 4-Chlorophenol  are  weak uncouplers of oxidative



 phosphorylation (U.S. EPA, 1980).





             2,5-DICHLOROPHENOL,  3,4-DICHLOROPHENOL,



                      and 3,5-DICHLOROPHENOL



 II.  EXPOSURE



     Unspecified dichlorophenol  (DCP) isomers have been detected



 in concentrations of  0.01 to 1.5  ug/1 in Dutch  surface waters



 (Piet  and DeGrunt, 1975).  Dichlorophenols have  been found in flue



gas condensates from municipal incinerators (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)  (Kohle,  et al.f   1976; Foster and Saha, 1978).



III.  PHARMACOKINETICS



     Pharmacokinetic data specific to these dichlorophenol isomers
                               39-8

-------
 could  not  be  located  in  the  available  literature.   It  is  reasonable


 to  assume  that  the  dichlorophenol  isomers  are  absorbed through
       •
 the skin and  from the  gut, and  rapidly eliminated  as are  other


 chlorophenols (U.S. EPA,  1980).


 IV   EFFECTS


     A.   .Carcinogenicity


           Pertinent data  cannot be  located  in  the  available


 literature; 2,4-DCP has been selected  for bioassay.


     B.    Mutagenicity


           None  of the  dichlorophenols  were  found to be mutagenic


 in  the Ames test with  or  without microsomal activation (Rasanen


 and  Hattula,  1977).  Mutagenicity  in mammalian test systems has


 not  been studied (U.S. EPA, 1980).


     C.    Teratogenicity, Other Reproductive Effects and  Chronic


           Toxicity


           Pertinent data  cannot be  located  in the  available litera-


 ture regarding teratogenicity, other reproductive  effects and


 chronic toxicity.
  •

     D.    Other Relevant  Information


           Phenol, and  the lower chlorinated phenols, including


 2,6-dichlorophenol are convulsants  (Farquharson, et al, 1958);


the latter readily penetrates the bovine lens capsule  (Ismail


et al., 1976), and inhibits oxidative phosphorylation  in  that


tissue (Korte et al.,  1976).   The significance of  these results


is as yet unknown.
                               39-9

-------
                         TRICHLOROPHENOLS*





 I.    EXPOSURE



      Trichlorophenols  have  been detected in surface waters  in



 Holland  at  concentrations ranging  from 0.003 to 0.1 ug/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 metabolism  by



 grazing animals of ingested chlorophenoxy acid herbicides 2,4,5-T



 (2,4,5-trichlorophenoxyacetic acid)  and Silvex (2-(2,4,5-trichloro-



 phenoxy)-propionic acid).   Residues  of these 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 (U.S. EPA, 1980).







*The health and environmental effects  of  2,4,6-trichlorophenol



are more extensively discussed  in HEBD No. 168.





                              39-10

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



 bioconcentration  factors  for  the  edible portions  of  all  aquatic



 organisms consumed  by  Americans to  be 130  to 2,4,5-trichlorophenol



 and  110 for  2,4,6-trichlorophenol.   These estimates  are  based  on



 the  octanol/water partition coefficients for these chemicals.



      Trichlorophenols  are found in  flue gas condensates  from



 municipal incinerators (Olie  et al., 1977).



      Most commercial trichlorophenols and their derivatives  contain



 appreciable  amounts of the contaminant  2,3,7,8-tetrachlorodibenzo-



 p-dioxin  (TCDD) and/or its homologues (U.S.  EPA,  1980).  The



 presence  of  this  highly toxic contaminant caused  the U.S.  EPA  to



 publish a Rebuttable Presumption  Against Registration  (RPAR) and



 Continued Registration of  Pesticide  Products  Containing  2,4,5-T



 (43  PR 17116).  The published RPAR  indicated  that 2,4,5-trichloro-



 phenol is  also the  subject of a separate potential RPAR.



 III.  PHARMACOKINETICS



      A.    Absorption and  Distribution



      The  oral LDsg  in  the  rat has been  variously reported  as 820



 and  2960 mg/kg (U.S. EPA  1980).   Information  dealing with  tissue



 distribution after  administration of trichlorophenols could  not



be located in the available literature.  Feeding of  2,4,5-T  and



Silvex to  sheep and cattle produced high levels of 2,4,5-trichloro-



phenol in  liver and kidney and low levels in muscle  and  fat  (Clark



et al., 1976).
                              39-11

-------
      B.    Metabolism

          .Pertinent data could  not  be  located  in the available
       *
 literature.

      C.    Excretion

           In  ratsf  82  percent of  an administered dose (1  ppm  in

 the diet for"  3 days) of  2,4,6-trichlorophenol  was eliminated  in

 the urine  and 22 percent in  the feces.   Radiolabeled feces was

 not detected  in liver, lung  or  fat  obtained  5  days after  the  last

 dose  (Rorte,  et al., 1976).  The  approximate blood half-life  for

 2,4,5-trichlorophenol  is  20  hours,  after dosing  of sheep  with

 Erbon  (an herbicide which  is metabolized to  2,4,5-trichlorophenol)

 (Wright et al., 1970).

          2,4,5-Trichlorophenol was  detected in  1.7  percent of

 urine samples collected  from the  general population  (Kutz et al.,

 1978).

 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 dimethylbenzanthrene (Boutwell and Bosch, 1959).

2,3,5-, 2,3,6-, 2,4,5-, and 2,4,6-Trichlorophenol were not found

to be mutagenic in the Ames test with and without microsomal

activation (Rasanen and Hattula, 1977).  2,4,6-Trichlorophenol

induces cancer in rats and mice (NCI, 1979).

     C.   Teratogenicity and Other Reproductive Effects

          Pertinent data could, not be located  in  the available

literature regarding teratogenicity and  other reproductive effects.


                              39-12

-------
      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 rag/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 pathology.  At  10,000 mg/kg

diet  (1000  mg/kg body weight),  growth was slowed in females.  Histo-

pathologic  changes were noted in liver  and kidney.  There were no

hematologic changes.  At  3000 mg/kg  feed  (300 mg/kg body weight),

milder histopathologic changes  in  liver and  kidney were observed.

The histopathologic  changes were considered  to  be reversible.

     Adverse health  effects including chloracne, porphyria cutanea-

tarda  with  hyperpigmentation, hirsutism and  urinary excretion of

porphyrins  were  described in workers  involved in the  manufacture of

2,4,5-D and 2,4,5-T  (Bleiberg,  et  al.,  1964).   It is  possible that

some of these symptoms represent 2,3,7,8-tetrachlorodibenzo-p-dioxin

toxicosis  (U.S.  EPA, 1980).
  •
     E.   Other  Relevant  Information

          Studies  on the  subcellular  effects of trichlorophenols

shows  them  to be powerful uncouplers  of oxidative phosphorylation.

2,4,5-Trichlorophenol readily penetrates the bovine eye lens (Ismael,

1975), and affects the carbohydrate metabolizing system of that

tissue (Korte et al., 1976).
                               39-13

-------
                         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.  Commer-
cial pentachlorophenol contains 3 to 10 percent tetrachlorophenol
(Goldstein et al., 1977; Schwetz et al., 1974).  Commercial tetra-
chlorophenol contains pentachlorophenol (27 percent) and toxic non-
phenolic impurities such as chlorodibenzofurans and chlorpdioxin
isomers (Schwetz et al., 1974).  The presence of tetrachlorophenol
in drinking water has not been documented (U.S. EPA, 1980).  Exposure
to other chemicals such as tetrachlorobenzenes can result in exposure
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 (1980) has estimated a weighted
average bioconcentration 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 municipal 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.
                               39-14

-------
     B.    Metabolism  and  Excretion


           In  rats,  over 98  percent  of  an  intraperitoneally  administere^

       %
dose of  2,3,4,6-tetrachlorophenol was  recovered  in  the  urine  in  24


hours.   About 66 percent  was  excreted  as  the  unchanged  compound  and


35 percent as tetrachloro-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 7 percent 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).


     Fungi methylate  pentachlorophenols to  the corresponding anisoles,


(U.S. EPA, 1980).  The chronic health  effects consequences  of


these compounds are not known, and the possibility of methylation


in mammalian  liver or intestine has not been documented.


     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).
                               39-15

-------
      C.   -Teratogenicity

          Tetrachlorophenol did  not  induce  teratogenic  effects  in
       *
rats  at doses of  10 or  30 mgAg  administered  on  days  six  through 15

of gestation  (Schwetz et al.,  1974).

      D.   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

          Sawmill workers exposed to  wood dust containing 100-800

ppm 2,3,4,6-tetrachlorophenol, 30-40  ppm pentachlorophenol, 10-50

ppm chlorophenoxyphenols, 1-10 ppm chlorodibenzofurans  and less

than 0.5 ppm chlorodibenzo-p-dioxins  developed severe skin irrita-

tions, respiratory difficulties  and headaches (Levin et al., 1976).

          No toxicity studies of 90 days or longer were found in

the available literature.

     F.   Other Relevant Information

          2,3,4,6-Tetrachlorophenol is a strong  uncoupler of

oxidative phosphorylation, and affects mixed function oxidases

(U.S.   EPA, 1980).

                        CHLORINATED PHENOLS

I.   AQUATIC TOXICITY

     A.   Acute Toxicity (U.S.  EPA, 1980)

          The acute toxicity of eight chlorophenols was determined
                               39-16

-------
 in  nine  bioassays.   Acute  96-hour  LC$Q  values  for  freshwater  fish
 ranged from  30  ug/1  for  the  fathead minnow,  Pimephales promelas,
 for 4-chloro-3-methylphenol  to  9,040  ug/1  for  the  fathead minnow
 for 2,4,6-trichlorophenol.   Among  the freshwater invertebrates,
 toxicity for Daphnia magna was  tested with seven chlorophenols
 in  eight 48-hour static  bioassays.  Acute  LV^Q values ranged  from
 290  ug/1 for 2,3,4,6-tetrachlorophenol  and 4-chloro-2-methylphenol
 to  6,040 ug/1 for 2,4,6-trichlorophenol.   Acute 96-hour static 1>C$Q
 values in the sheepshead minnow ranged  from  1,660  ug/1 for 2,4,5-
 trichlorophenol to 5,350 ug/1 for  4-chlorophenol.  The only marine
 invertebrate species acutely tested has been the mysid shrimp,
 Hysidopsis bahia, with acute 96-hour  static  LCso values reported
 as:  3,830 ug/1 for  2,4,5-trichlorophenol; 21,900  ug/1 for 2,3,5,6-
 tetrachlorophenol, and 29,700 ug/1 for  4-chlorophenol.
     B.   Chronic Toxicity (U.S. EPA, 1980)
          No data other  than that presented  in the specific hazard
 profile  for  2-chlorophenol, 2,4-dichlorophenol, and pentachlorophenol
were available for freshwater organisms.   An embryo-larval study
provided a chronic value of 180 ug/1  for sheepshead minnows,
Cyprinodon variegatus, exposed to 2,4-dichloro-6-methylphenol.

     C.   Effects on Plants (U.S.  EPA, 1980)
          Effective concentrations for 15  tests on four species of
                               39-17

-------
freshwater  plants  ranged  from  chlorosis  LCso  of  603  ug/1  for 2,3,4,6-



tetrachlorophenol  to  598,584 ug/1  for  2-chloro-6-raethylphenol in
      «                                                             /


the duckweed,  Lemna minor.  The marine algae,  Skeletonema costaturn,



has been used  to assess the relative toxicities  of three  chlorinated



phenols.  Effective concentrations, based  on  chlorophyll  a content



and cell-growth, of 440 and 500 ug/1 were  obtained for  2,3,5,6-tetra-



chlorophenol.   2,4,5-Trichlorophenol and 4-chlorophenol were roughly



two and seven  times as potent, respectively,  as  2,3,5,6-tetrachloro-



phenol.



     D.   Residues



          Steady-state bioconcentration  factors  have not  been



calculated  for the chlorinated phenols.  However, based upon octanol/



water partition coefficients, the  following bioconcentration factors



have been estimated for aquatic organisms  with a lipid  content of



eight percent:  41 for 4-chlorophenol; 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 (U.S.  EPA, 1980).



     E.   Miscellaneous



          The  tainting of fish flesh by  exposure of rainbow  trout,



Salmo gairdneri, to various chlorinated  phenols has derived  a range



of estimated concentrations not impairing  the flavor of cooked fish



from 15 ug/1 for 2-chlorophenol to 84 ug/1 for 2,3-dichlorophenol



(U.S.  EPA,  1980).



II.  EXISTING GUIDELINES AND STANDARDS



     Water quality criteria recommended  for chlorinated phenols by



the U.S. EPA (1980) are given in the following table:
                               38-18

-------
                 Recommended Water Quality Criteria
Compound
                                  Human Health
Criterion from
 Organoleptic
   Effects
    (ug/1)
Criterion from
Toxicological
    Data
   (ug/1)
Aquatic Life
   (ug/1.)
Monochlorophenols

  3-chlorophenol              0.1
  4-chlorophenol              0.1

Dichlorophenols

  2,3-dichlorophenol          0.4
  2,4-dichlorophenol          0.3
  2,5-dichlorophenol          0.5
  2,6-dichlorophenol          0.2
  3,4-dichlorophenol          0.3

Trichlorophenols

  2,4,5-trichlorophenol       1.0
  2,4,6-trichlorophenol       2.0

Tetrachlorophenols

  2,3,4,6-tetrachlorophenol   1
  2,3,5,6-tetrachlorophenol
                      none
                      none
                      none
                      3.09
                      none
                      none
                      none
                      1600
                        12(c)
                      none
                 29,700(b)
                    970(a)
(a) Chronic toxicity value, freshwater

(b) Acute toxicity value, saltwater

(°) Based on NCI carcinogenesis bioassay
                               39-19

-------
                         CHLORINATED PHENOLS

                             REFERENCES

       *
Ahlborg, U.G., and K. Larsson.  1978.  Metabolism of tetrachloro-
phenols in the rat.  Arch. Toxicol.  40: 63.

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

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

Clark, D.E., et al.  1976.  Residues of chlorophenoxy acid herbicides
and their phenolic metabolites in tissues of sheep and cattle.
Jour. Agric. Food Chem.  23: 573.

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.

Goldstein, J.A., et al.  1977.  Effects of pentachlorophenol on
hepatic drug-metabolizing enzymes and porphyria related to contamina-
tion with chlorinated dibenzo-p-dioxins and dibenzofurans.  Biochem.
Pharmacol.  26: 1549.

Gurova, A.I.  1964.  Hygienic characteristics of p-chlorophenol in
the aniline dye industry.  Hyg. Sanita.  29: 46.

Ismail, R., et al.  1975. Permeability of the isolated bovine lens
capsule for environmental chemicals.  Exp. Eye Res.  20: 179.

Karpow, G.  1893.  On the antiseptic action of three isomer chloro-
phenols 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 isomers.  Can Jour. Biochem.  54: 203.

Korte, I., et al.  1976.  Studies on the influences of some environ-
mental 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
metabolites in urine from the general population.  Pages 363-369 In;
K. Rango Rao, ed.  Pentachlorophenol:   Chemistry, pharmacology and
environmental toxicology, Plenum Press, New York.


                               39-20

-------
                         CHLORINATED PHENOLS

                              REFERENCES  (Continued)


 Levin,  J.O.,  et al.   1976.   Use  of  chlorophenols  as  fungicides in
 sawmills.   Scan.  Jour.  Work Environ.  Health.   2:  7l.

 Lindsay-Smith,  Jr.,  et  al.   1972.   Mechanisms  of  mammalian hydroxyla-
 tion:   Some novel metabolites of chlorobenzenes.   Xenobiotica 2:  215.

 McCollis'ter,  D.D.,  et al.   1961. Toxicolpgic  information on 2,4,5-
 trichlorophenol.   Toxicol.  Appl. Pharmacol.   3: 63.

 National Cancer Institute.   1979.   Bioassay of 2,4,6-trichlorophenol
 for possible  carcinogencity NCI-CG-TR-155.

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

 Piet, G.J., and  F.  DeGrunt.   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,  Luxembourg.

 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.

 Schwetz, B.A.,  et al.   1974-.   Effect  of purified  and  commercial
 grade tetrachlorophenol  on  rat embryonal and fetal development.
 Toxicol. Appl.  Pharmacol.   28: 146.

 U.S. EPA.   1980.  Chlorinated  Phenols:  Ambient Water Quality
 Criteria.   EPA  440/5-80-032.

Wright, F.C., et  al.  1970.   Metabolic and residue studies with 2-
 (2,4,5-trichlorophenoxy)-ethyl 2,2-dichloropropionate.  Jour.  Agric.
 Food Chem.  18: 845,
                               39-21

-------
                                       No.  40
         Chloroacetaldehyde


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

           APRIL 30, 1980
                 ~_L7
                 -/

-------
                          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.

-------
                               CHLOROACETALDEHYDE

                                     Summary

     No carcinogenic effects were 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.
                                    1)0-3

-------
                               CHLOROACETALDEHYDE



I.   INTRODUCTION



     Chloroacetaldehyde (C,H,C10) is a clear, colorless liquid with a pungent
                          ^ O


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-chloroacetaldehyde 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 al., 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 inhalation



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,
LTcQ, 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.  Metabolism
         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 in 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 j_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, ONA and RNA, eliciting proportionally greater
toxicity.  This is in agreement with other studies  conducted on vinyl chjoride
metabolism (Hefner et al., 1975; Bolt et al., 1977).
                               /_  —

-------
     Chloroacetaldehyde was shown to cause the destruction of lung hemoprotein,
cytochrome P450, as well as liver microsomal cytochrome P450, with no requirement
for NAOPH (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.  Carcinogenicity
          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).  Lopn'eno 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 mutagem'cally

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-Oawley and Black Bethesda

rats.  Groups of rats received .001879 and .003758 ml/kg of chloroacetaldehyde

(representing 0.3 and 0.6 of the acute LD50 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-Oawley and Black Bethesda rats, New Zealand albino rabbits



and Hartlez strain guinea pigs.   The results were reported as follows:  the



LD5Qs (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 LD50 (ml/kg) in rabbits was



reported as .2243; and the inhalation LT5Q 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).

-------
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).

-------
                               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.  2:179.

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.

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.
                                                                     i
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.

-------
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
                                             14
17.   Watanabe, P. G. et al.  1976a.  Fate of   C vinyl  chloride after single
     oral administration in rats.  Toxicol. Appl.  Pharmacol.   36:339.

     Watanabe, P. G. et al. 1976b.  Fate of 14C  vinyl  chloride folli
     inhalation exposure in rats.  Toxicol. App.  Pharmacol.   37:49.

     Yllner, S.  1970.  Metaboli:
     Pharmacol. Toxicol.  30:69.

     Yllner, S.  1971.  Metaboli:
     Pharmacol. Toxicol.  30:257.
18.   Watanabe, P. G. et al. 1976b.  Fate of    C  vinyl  chloride following
                                                       icol
                                                        14
19.   Yllner, S.  1970.  Metabolism of chloroacetate  -1- C  in  the mouse.   Acta

                                                         14
20.   Yllner, S.  1971.  Metabolism of 1,2-dichloroethane-   C in the mouse.   Acta
                                     it

-------
                                       No.  41
         Chloroalkyl Ethers


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION










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



chloroalkyl ethers and has found sufficient evidence to



indicate that this compound is carcinogenic.

-------
                      CHLOROALKYL  ETHERS
                            SUMMARY
     Bis(chlororaethyl)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 Jj.  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  reported
96-hour LC50 value for bis(2-chloroethyl)ether  in the.
bluegill is greater than  600,000  ug/1.  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 LC50 value for the  bluegill  and  2-chloro-
ethyl vinyl ether is  194,000 ug/1.

-------
                     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
nanograra 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 Chloroalkyl 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 bioconcentration 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 Chloroalkyl ethers has
not been determined (U.S. EPA, 1979).

-------
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  (t]y2'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*



BCIE 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).

-------
     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
            -'X
     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 & 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).

-------
          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 jE. 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).

-------
     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 LC50 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 obs'erved 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 bioconcentratioh
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.

-------
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 chlorpalkyl

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-
                                                        i
cient data (U.S. EPA, 1979).

-------
                     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.

Iones, 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. N.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.

-------
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.
                              Sf

-------
                                      No. 42
           Chlorobenzene
  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.

-------
                                 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 LC-n  values  ranging from
 24,000  to  51,620 jug/1.  Hardness  does not significantly  affect  the values.
 In saltwater,  a fish and shrimp had reported 96-hour LC-Q  values of 10,500
;jg/l and 6,400 pg/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.

-------
 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  monochlorobenzene  (MCB;
 CgH5Cl;  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  jug/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.

-------
      B.   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  hydrophobic,  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-
                                                                      i
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   (Lu, 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-

-------
lanthrene  to  induce microsomal enzymes provided protection  for  rats (Oesch,
et  al.  1973).  The  metabolism  of chlorobenzene may also  lead to the forma-
tion of carcinogenic active intermediates (Kohli, et al. 1976).
     D.  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 chlorobenzene.
     A.  Chronic Toxicity
         Data  on  the chronic toxicity of  chlorobenzene  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
         Chlorobenzene appears to  increase the activity of  microsomal NADPH-
cytochrome  P-A50 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
         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 pg/1,.  re-
spectively,  for chlorobenzene.   Two  96-hour LC^g  values for  chlorobenzene
and  fathead minnows, Pimephales promelas,  are  33,930 ug/1 in soft water  (20
mg/1)  and  29,120 jug/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 EC-Q  value of 86,000 pg/1
was  reported.'  In saltwater studies,  sheepshead  minnow  had  a reported  un-
adjusted  LC^Q  (96-hour)   value  of 10,500  ;ug/l,   with   a  96-hour  EC5Q of
16,400 ug/1 for mysid shrimp (U.S.  EPA, 1978).
     B.  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  capricomutum is considerably  less
sensitive  than  fish  and  Daphnia magna.  Based on cell  numbers, the species
has  a reported  96-hour  EC5g  value of  224,000  ;ug/l.   The  saltwater alga,
Skeletonema costatum,  had  a 96-hour EC5Q)  based on cell numbers of 341,000
/jg/1.
     D.  Residues
         A bioconcentration factor  of  44  was obtained assuming an 8 percent
lipid content of fish.
                                     y-7

-------
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 jug/1 as  a 24-hour average;  the concentration  should
not  exceed  3,500 jug/1  at any  time.   To  protect  saltwater aquatic life,  a
draft  criterion  of 120 jug/1 as  a  24-hour  average with a  concentration not
exceeding 280 pg/1 at any time has been recommended  (U.S.  EPA, 1979).

-------
                         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.
 ^n?Industrial 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.  Pharraa-
 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  p5-450 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 InfA.D.
Mclntyre and C.F. Mills, eds.  Ecological and toxicological
research.  Plenum Press, New York.

-------
                                      No. A3
         p-Chloro-m-cresol


  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.

-------
                               p-CHLORO-m-CRESOL

SUMMARY

     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 LO^g of 400 mg/kg and an  oral LDL  of  500 mg/kg have been
reported.

I.  INTRODUCTION

    p-Chloro-m-cresol (4-chloro-3-raethylphenol; C_H_C10; 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. 59-50-7) as listed in the initial TSCA
Inventory (U.S. EPA 1979) shows that between 10,000 and  90,000  pounds of
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).

-------
               II.  EXPOSURE
                    A.  Environmental Fate
                    Voets et al. (1976) reported that p-chloro-ra-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  LDc0 f°r p-chloro-m-cresol in rats  is  400 rag/kg  (NIOSH  1975).
               The  oral LD    for p-chloro-m-cresol in rats is 500  mg/kg.   In  mice the
                         LiO
               intraperitoneal LD   is  30  mg/kg and the subcutaneous LD    is  200 mg/kg
                                 L»O                                    Lo

-------
(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 LC50 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.

-------
                                              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.

jt   .          U.S. EPA.  1979.   Toxic Substances  Control Act Chemical  Substance Inventory,
•f             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.  Cosraet.  Chem. ,  26:75-81.
                                                                                i

              Windholz M.  ed. 1976.   The  Merck Index,  Merck  & Co.,  Inc., Rahway,  New Jersey.

-------
                                      No.  44
            Chloroethane
  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.

-------
                        CHLOROETHANE


                           SUMMARY


     There is no available evidence which  indicates  that


monochloroethane produces carcinogenic, rnutagenic, 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 toxi-


city may be produced by monochloroethane.
                                         «.

     Data examining the toxic effects of chloroethane  on


aquatic organisms were not available.

-------
                        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 monochloroethane  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.  Snail amounts of  the



chloroethanes may be formed by chlorination of drinking  water

-------
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)

-------
IV.  EFFECTS




     Pertinent data could not  be  located  in  the  available



literature on monochloroethane for  carcinoqenicity,  mutageni-



city, teratogenicity and other reproductive  effects.



     A.   Chronic Toxicity



          Hunan symptons of monochloroethane poisoning  indi-



cate central nervous system depression, respiratory  failure,



and cardivascular 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 AND STANDARDS



     A.   Human



          The eight-hour TWA standard  prepared by OSHA  for



monochloroethane is 1,000 ppm.



          Sufficient data are  not available  to derive a cri-



terion to protect human health from exposure to  monochloro-



ethane in ambient water.



     B.   Aquatic



          There are not sufficient  toxicological data to cal-



culate exposure criteria.

-------
                                 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.

-------
                                      No. 45
            Chloroethene


  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.

-------
                          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 chloride  has been found to



be carcinogenic in  laboratory animals and has Joeen 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.
                             yr-J

-------
                           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 (Fal.k,

-------
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
;jg/l and  0.6 pg/1)  (Dressman and  McFarren,  1978) .   The  National
                                   -5

-------
Science Foundation (NSF) has adopted a voluntary standard of 10 ppmj
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 /jg/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. SPA,  1979). "  •

-------
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



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.



     C.   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 _iri 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

-------
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  DMA by  chloroacetaldehyde identical
to  that  observed  in hepatocyte  DNA  following  the administration
of vinyl chloride to rats in 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  14-,-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-

-------
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  CO-;  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  C02;  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
                                  - 9

-------
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 vinyl
chloride  workers  nor  significant   increases  in  standard mortality

-------
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

                                t

                                 -11

-------
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-Cravioto, 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-

-------
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



          Pretreatment 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 chloride.



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.

-------
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 prop'ellant was issued
(39 FR  14753  (April 26, 1974)).   Other aerosol  products,  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 /jg/1,  51.7 pg/1 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).

-------
                                 CHLOROETHENE
                               (VINYL CHLORIDE)

                                  REFERENCES
Anderson, D., et al.   1976.   Vinyl  chloride:  dominant lethal studies in male
CD-I mice.  Mutat.  Red.  40: 359.

Caputo, A.,  et  al.   1974.   Oncogenicity of vinyl  chloride at low concentra-
tions in rats and rabbits.   IRCS  2: 1582.

Dressman,  R.C.  and  E.F.  McFarren.   1978.   Determination of  vinyl chloride
migration  from  polyvinyl  chloride pipe  into  water.  Am.  Water  Works Assoc.
Jour.  70: 29.

Ducatman,  A.,  et al.   1975.   Vinyl  chloride  exposure and  human chromosome
aberrations.  Mutat.  Rec.   31: 163.

Duprat,  P.,  et al.    1977.   Metabolic  approach  to  industrial poisoning:
blood  kinetics  and  distribution   of  l^C-vinyl  chloride  monomer  (VCM).
Toxicol Pharmacol.  Suppl.   142.

Falk, H.,  et al.  1974.   Hepatic disease among workers  at  a vinyl chloride
polymerication plant.  Jour. Am. Med. Assoc.  230: 59.

Fox, C.R.   1978.  Plant uses  prove  phenol  recovery with resins.   Hydrocarbon
processing.  November, 269.

Funes-Cravioto, F.,  et  al.   1975.   Chromosome  aberrations in workers exposed
to vinyl chloride.   Lancet  1: 459.

Green,  T.  and  D.E.  Hathway.   1975.   The  biological  fate in rats  of vinyl
chloride  in  relation  to  its   oncogenicity.    Chem.   Biol.  Interactions.
11: 545.

Hathway, D.E.   1977.   Comparative mammalian metabolism of vinyl  chloride and
vinylidene  chloride  in  relation to  oncogenic  potential.  Environ.  Health
Perspect.  21: 55.

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.

International Agency for Research on  Cancer.   1974.   Monograph on the evalu-
ation of carcinogenic risk of chemicals to man.  Vol. 7.  Lyon, France.

Jaeger, R.J.   1975.   Vinyl chloride monomer:  comments  on its hepatotoxicity
and interaction with 1,1-dichloroethylene.  Ann. N.Y. Acad. Sci.   246: 150.

John, J.A.,  et  al.   1977.   The effects  of  maternally inhaled vinyl chloride
on  embryonal and  fetal development  in  mice,   rats  and  rabbits.   Toxicol.
Appl. Pharmacol.  39: 497.

-------
Kappus, H., et  al.   1975.   Rat liver microsomes catalyse covalent binding  of
          chloride to macromolecules .  Nature  257: 134.
Kappus,  H.,  et al.   1976.   Liver microsomal  uptake  of (l^C) vinyl chloride
and  transformation  to  protein  alkylating metabolites  in  vitro.   Toxicol.
Appl. Pharmacol.  37: 461.

Laib, R.J.  and H.M. Bolt.  1977.  Alkylation  of RNA by vinyl chloride meta-
bolites  in vitro  and in  vivo:  formation  of  l-N^-ethenoadenosine .   Toxico-
logy  8: 185.

Lange, C.E.,  et al.  1974.  The so-called vinyl chloride sickness-and-occu-
pationally-related  systemic sclerosis?  Int. Arch. Arbeitsmed.   32: 1.

Lee,  C.C.,  et al.   1977.  Inhalation toxicity of vinyl chloride and  vinyli-
dene chloride.  Environ. Health  Perspect.   21: 25.
                                                  *.
Lee,  C.C.,  et al.   1978.   Carcinogenicity of vinyl  chloride and vinylidene
chloride.  Jour. Toxicol. Environ. Health   4:  15.

Makk, L.,  et  al.   1976.   Clinical and morphologic features of hepatic angio-
sarcoma in vinyl chloride workers.  Cancer  37:149.

Maltoni,  C.   1976a.   Carcinogenicity  of  vinyl  chloride:  Current  results.
Experimental  evidence.   Proc.  6th Int.  Symp.  Biological Characterization of
Human Tomours,  Copenhagen  May  13-15,  1975.  Vol. 3  Biological characteriza-
tion  of  human  tumours,  1976.    American  Elsevier Publishing Co.,  Inc.,  New
York.

Maltoni,  C.   1976b.   Predictive  value  of carcinogenesis  bioassays.   Ann.
N.Y. Acad. Sci.  271: 431.

Maltoni,  C.   and  G.  Lefemine.   1974a.    Carcinogenicity bioassays of vinyl
chloride.  I. Research plan and  early results.  Environ. Res.  7:387.

Maltoni,  C. and G.  Lefemine.   1974b.  La  potentiality dei saggi sperimentali
mella predizion; dei  rischi oncogeni  ambiental:   Un esemplo:  11 chlorure di
vinile.  Acad. Natl. Lincei.  56: 1.

Maltoni,  C. and G.  Lefemine.   1975.  Carcinogenicity  assays of vinyl chlor-
ide: Current  results.  Ann. N.Y. Acad. Sci.  246: 195.

Monson, R.R.,  et  al.  1974.   Mortality among vinyl  chloride workers.  Pre-
sented  at  Natl.  Inst.   Environ. Health  Sci.  Conf.,  Pinehurst, N.C.,  July
29-31.

National Cancer Institute Monograph  41.   1975.   Third  national  cancer sur-
vey: incidence data.

Ott, M.G., et al.   1975.   Vinyl  chloride  exposure in a controlled industrial
environment:  a  long-term mortality experience  in  595 employees.   Arch. Envi-
ron. Health   30: 333.

-------
Purchase, I.F.H.,  et  al.   1975.  Chromosomal and  dominant lethal effects of
vinyl chloride.  Lancet  28: 410.

Radike,  M.,  et  al.   1977a.   Transplacental  effects of  vinyl  chloride in
rats.  Annual Report.  Center  for  the  Study of the Human Environment. USPHS-
ES-00159.  Dept. Environ. Health, Med. College, University of Cincinnati.

Radike,  M.J.,  et al.  1977b.   Effect  of ethanol  and vinyl chloride  on the
induction of liver  tumors:  preliminary  report.   Environ.  Health Perspect.
21: 153.

Smirnova, N.A.   and  N-.P.   Granik.   1970.   Long-term. side  effects of acute
occupational poisoning by  certain  hydrocarbons and  their  derivatives.  Gig.
Tr. Prof. Zabol.  14: 50.

Spirtas,  R.  and R.  Kaminski.   1978.   Angiosarcoma 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, O.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, D.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.

-------
                                      No. 46
     2-Chloroethyl Vinyl 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 accuracy.

-------
                        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
LD5Q:  250 mg/kg; dermal LD5Q 3.2 ml/kg; LCLQ:  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 (C1CH_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).

-------
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 B-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 bioconcentration 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
                     HAZARD
SIC
CODE

25
28
30
31
34
35
36
37
38
39
50
73
                             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
 1,683
 1,669
 2,279
 9,149
    35
   432
   553
   299
   240
 6,194
    20
                                               I
TOTAL
                                                           2,059
               23,473
                 23,473

-------
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 (Bannug 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 LD5Q for 2-chloroethyl vinyl ether in rats is 250 mg/kg (U.S. EPA,  1975,
Patty 1963).  Dermal exposure to the shaven skin of rabbits for 24 hours resulted
in an LD5Q 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.

-------
           Table 2.   Freshwater fish acute values  (U.S.  EPA,  1979b)

                                                                        Adjusted
                       Bioassay Test      Chemical      Time    ^so      ^50
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

-------
                                References
Lange NA (ed.).  1967.  Lange's Handbook of Chemistry, rev. 10th ed.,  New York:
McGraw-Hill Book Co.                                       '

McCann 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. DHEW, 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. 16:413-416.

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.

-------
                                       No.  47
Chloroform  (Carbon Trlchlorotnethane)


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION









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



chloroform and has found sufficient evidence to indicate



that this compound is carcinogenic.

-------
                          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 96-hour LCcn 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 LC5Q



of 28,900 pg/1.  The observed 96-hour LC5Q for the saltwater



pink shrimp is 81,500 ug/1.  In a life cycle chronic test,



the chronic value was 2,546 ug/1 for D£Enn-'-a. 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.
                             7-y

-------
                          CHLOROFORM

I.    INTRODUCTION

     This profile is based on the Ambient Water Quality

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

     Chloroform (CHC13; 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° ;jg/l  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, 19795).



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
TUTT
13
23
64
100.
22
69
10
iod.

00

do

00

-------
A similar estimate, not using NOMS 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).
                                   J

-------
    Table 1.  Hepatocellular Carcinoma Incidence in Mice'
               Controls            Low
          Colony    Matched  	Dose
Male      577/~    1718*     138 mg/kg  18750

          (6%)       (6%)           (30%)
                                                     High
                                                     Dose
                                                277 mg/kg  34/45

                                                        (98%)
Female
1/80
(1%)
0/20
(0%)
238
mg/kg
36/45
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     4/50   180/mg/kg   12/50

                                    (8%)                 (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.

-------
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 gairdneri), of  43,800 and
66,800 ^jg/1 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  LC,-n  of 28,900  ug/1
(U.S. EPA 1979a).  The observed 96-hour LC5Q for the  pink
shrimp (Panaeus duorarum) is 81,500 ^ag/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.

-------
     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~Bay)           ~            "        _,             ,
                         0         10  '      10 °          10 3
2 liters of drinking     0    0.021 ug/1  0.21 pg/1     2.1 ug/1
water and consumption
of 18.7 grams fish and
shellfish.
                                                           »
Consumption of fish      0    0.175 /jg/1  1.75 ug/1    17.5
shellfish only.


-------
     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 criterion to protect
freshwater aquatic life, based on chronic invertebrate toxi-
city, is 500 pg/1 as a .24-hour average and the concentration
should not (based on acute effects) exceed 1,200 /ig/1 at
any time (U.S. EPA, 1979a).  To protect saltwater  aquatic
life, the concentration of chloroform should not exceed
620 jag/1 as a 24-hour average and the concentration should
not exceed 1,400 ^ig/1 at anytime (U.S. EPA, 1979a) .  These
were calculated from an experiment on a marine invertebrate.

-------
                                  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  duorarumTT  Contract  No.  WA-6-99-1414-8.   U.S.  Environ.  Prot.
Agency.

Brass, H.J.  and R.F.  Thomas.   1978.  Correspondence  with Region III.  Tech.
Support Div., U.S. Environ. Prot. Agency,  Washington, O.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. Phartnacodyn.  196: 98.

Hardie,  O.W.F.   1964.   Chlorocarbons  and chlorohydrocarbons:  chloroform.
^n:  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,  O.D.    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.

Lenmann,  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. PB-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.  Oept. 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, 8.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, O.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, O.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, O.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.

-------
                                      No. 48
           Chloromethane
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.   20460

           APRIL 30,  1980
                -S7H-

-------
                          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
rautagenic 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 pg/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  pg/1.  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).

-------
     B.    Food
          There is no information on the presence of chloro-
raethane 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
but results in only moderate blood levels with continued
exposure.  Signs and pathology, of intoxications suggest

-------
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_._ typhimurium 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-

-------
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 Toxicity                  <•
          A single 96-hour static renewal test serves as
the only acute study for freshwater providing an adjusted
LC^g 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

-------
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 ^ug/1, not to exceed



8,400 pg/1 as a 24-hour average concentration.
                              i

-------
                        CHLOROMETHANE
                          REFERENCES

Andrews, A.W., et al.  1976.  A comparison of the rautagenic
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 toxlcity 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.

National 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, M 0 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 suspe-..:.ed cac •' '.no-
gens in drinking water, and appendices.   A  report to Co ngr ;_•:.; s,
Washington, D.C.

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

U.S. EPA.  I979b.  2nviror.-p.2r.ta]. Criteria ar-:5 Assessment
Office.  Halomathanas:  Ha:;a.rd 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.  .

Windhoiz, M.,  (ed.)   1976.  The Merck Index.   M.^tck and Co.,
Rahwav, N.J.

-------
                                      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.

-------
                       2-CHLO RONAPHTHALZNE




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,QHyCl; 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 ._V

     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

     A.  Environmental Fate

     Polychlorinated naphthalenes do not occur naturally 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 PCS 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 photodegradation 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.
                               tff-S

-------
     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 _et_ _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 DNA 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
                                                            •

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 al. (1972) noted that workers  at

-------
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. j|t__al/  1975.  Identification of chlorinated  diben-
zofurans in. American polychlorinated biphenyls. Nature  256,  305.
(as cited in U.S. EPA, 1979b).

Canonica, L. ^t_ ^1_. 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-^^fF-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 cited 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 the environment J.  Assoc.  Off.
Anal.  Chem. 61, 1335.  (as cited in U.S. EPA, 1979b).

Erickson, M.D., et al.  1978b.  Development 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. Contain. 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.

-------
Kleinfeld, M., _e_t _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.   DREW Publ.  No.
79-100.

Okey, R. W. and R. H. Bogan.  1965.  Apparent involvement  of
electronic mechanisms in limiting raicrobial 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. 0., _et_ _al_.  1976a.  Metabolism  of chlorinated
naphthalenes. . J. Agric. Food Chem. 24, 581-583.

Ruzo, L.O., _et_ _alL. 1976b.  Uptake and distribution of
chloronaphthalenes and their metabolities in pigs.  Bull.
Environ. Contain. 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. Dermatol. 75, 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,
I979c.

Vos, J.G., ^st_ _al_.  1970.  Identification and toxicological evalu-
ation of chlorinated dibenzofurans and chlorinated  naphthalenes
in two commercial polychlorinated biphenyls.  Food  Cosmet.
Toxicol.  8_, 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.

-------
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-
                             y?-//

-------
                                      No. 50
           2-Chlorophenol


  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.

-------
                       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.

-------
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 CgHgCl (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.

-------
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

-------
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; Farquharso'n, et al.,  1958).   Toxic ity studies


indicate that 2-chlorophenol is absorbed  through the skin.


     B.   Distribution


          Pertinent  data regard.ing  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 chlo.robenzene  to monochlorophenols,


including 2-chlorophenol, has been  shown  J.n  vitro  with rat

-------
liver (Selander, et al. 1975) and in vivo> with rabbits



(Lindsay-Smith, et al. 1972).



     D.   Excretion



          Studies on rate and route of excretion for



2-chlorophenol in humans were not available.  Dogs excreted



87 percent of administered 2-chlorophenol in the urine as



sulfate and glucuronide conjugates (Von Oettingen, 1949).



The same metabolites were found in the urine of rabbits after



administration of chlorobenzene (Lindsay-Smith, et al. 1972);



however, out of the total free and conjugated chlorophenols



only 6 percent were present as 2-chlorophenol.



IV.  EFFECTS



     A.   Carcinogenicity



          Insufficient data exist to indicate that 2-chloro-



phenol is a carcinogen.  In the only study found (Boutwell



and Bosch, 1959), 2-chlorophenol promoted skin cancer in mice



after initiation with dimethylbenzanthracene and when repeat-



edly applied at a concentrations high enough to damage the



skin.  2-Chlorophenol was not carcinogenic when applied re-



peatedly without initiation with dimethylbenzanthracene, but



did induce a high incidence of papillomas and no carcinomas.



     Information regarding mutagenicity,  teratogenicity,



other reproductive effects and chronic toxicity could not be



found in the available literature.



     F.    Other Relevant Information



          2-Chlorophenol is a weak uncoupler of oxidative



phosphorylation (Mitsuda, et al.,  1963)  and  a convulsant



(Farquharson,  et al., 1958;  Angel  and Rogers, 1972).
                          .TO-/

-------
V.   AQUATIC TOXICITY



     A.   Acute Toxicity



          Acute studies on four  species  of  fish  have  produced



96-hour static LC50 values ranging  from  6,590  ug/1  in the



bluegill  (Lepomis macrochirus)  (U.S. EPA, 1978)  to  20,170



ug/1 to the guppy (Poecilia reticulatus).   Juvenile bluegills



were more sensitive in a static  renewal  assay  with  an LC50



value of  8,400 ug/1.  The fathead minnow (Pimephales   prome-



las) was  the only freshwater  fish tested in a  flow  through



system and gave an LC5Q value of 12,380  ug/l»  Daphnia



magna has been found to have  48-hour static LC5Q  values



of 2,580  ug/1 and 7,430 ug/1.  No data concerning the effects



of 2-chlorophenol to marine fish or invertebrates are avail-



able.



     B.   Chronic Toxicity



          Effects were not obtained in a chronic  embryo-



larval test of 2-chlorophenol at concentrations  as  high as



1,950 ug/1 for the freshwater fathead minnow.    Additional



chronic studies are not available.



     C.   Plant Effects



          The only plant assay available provides an  effec-



tive concentration of 500,000 ug/1  in chlorophyll reduction



in the algae, Chlorella pyrenoidosa.



     D.   Residues



        .  A measured bioconcentration factor of  214 has been



obtained  for the bluegill.  The half-life was  less  than one



day, indicating a rapid, depuration rate  for 2-chlorophenol.

-------
     E.   Miscellaneous



          Flavor impairment of the edible portion of fish



exposed to 2-chlorophenol has been reported.  The highest



concentration of 2-chlorophenol in the exposure water which



would not impair the flavor of cooked rainbow trout (Salmo



gairdneri) has been estimated at 60 ug/1 Shumway and



Palensky, 1973).



VI.  EXISTING GUIDLINES AND STANDARDS



     Neither the human health nor the aquatic criteria de-



rived 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 prevention of adverse organoleptic ef-



fects, the U.S. EPA (1979) draft interim criterion recommend-



ed for 2-chlorophenol in ambient water is 0.3 ug/1.  There



are no other standards or guidelines for exposure to 2-chlo-



rophenol.



     B.   Aquatic



          Based on the tainting of fish, the draft criterion



to protect freshwater organisms from 2-chlorophenol is 60



ug/1 as a 24-hour average, not to exceed 180 ug/1 at any



time.  No criterion was derived for marine life (U.S.  EPA,



1979) .
                           SO'f

-------
                       2-CHLOROPHENOL

                         REFERENCES

Aly, O.M.  1968.  Separation of phenols  in waters by  thin
layer chromatography.  Water Res.  2: 587.

Angel, A., and K.J. Rogers.  1972.  An analysis of  the  con-
vulsant activity of substituted benzenes  in the mouse.  Toxi-
col. Appl. Pharmacol.  21: 214.

Barnhart, E.L., and G.R. Campbell.  1972.  The effect of
chlorination on selected organic chemicals.  U.S. Government
Printing Office, Washington, D.C.

Bjerke, E.L., et al.  1972.  Residue study of phenoxy herbi-
cides in milk and cream.  Jour. Agric. Food Chera.   20:  963.

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

Clark, D.E., et al.  1975.  Residues of  chlorophenoxy acid
herbicides and their phenolic metabolites in tissues of sheep
and cattle.  Jour. Agric. Food Chem.  23: 573.

Doedens, J.D.  1963..  Chlorophenols.  Page 325 _in Kirk-Othmer
encyclopedia of chemical technology.  John Wiley and Sons,
Inc., New York.

Ettinger, M.B., and C.C. Ruchhoft.  1950.  Persistence  of
monochlorophenols in polluted river water and sewage dilu-
tion.  U.S. Pub. Health Serv., Environ.  Health Center,  Cin-
cinnati, Ohio.

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

Henshaw, T.B.  1971.  Adsorption/filtration plant cuts
phenols from effluent.  Chem. Eng.  76:  47.

Jolley, R.L.  1973.  Chlorination effects on organic
constituents in effluents from domesti'c  sanitary sewage
treatment plants.  Ph.D. dissertation.   University  of
Tennessee.

Jolley, R.L., et al.  1975.  Chlorination of cooling water: A
source of environmentally significant chlorine-containing
organic compounds.  Proc. 4th Natl. Symp.  Radioecology.
Corvallis, Ore.                                            •

Joschek, H.I., and S.I. Miller.  1966.   Photoclea.vage of
phenoxyphenols and bromophenols.  Jour.  Am. Chem. Soc.  88:
3269.

-------
Judson, C.M., and M. Kilpatrick.  1949.  The effects of  sub-
stituents on the dissociation constants of substituted
phenols.  I.  Experimental measurements in aqueous  solutions.
Jour. Am. Chem. Soc.  74: 3110.

Lindsay-Smith, J.R., et al.  1972.  Mechanisms of mammalian
hydroxylation:  Some novel metabolites of chlorobenzene.
Xenobiotica  2: 215.

Loos, M.A., et al.  1966.  Formation of 2,4-dichlorophenol
and 2,4-dichlorophenoxyacetate by Arthrobacter Sp.  Can.
Jour. Microbiol.  13: 691.

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

Nachtigall, H., and R.G. Butler.  1974.  Metabolism of
phenols and chlorophenols by activated sludge microorganisms.
Abstr. Annu. Meet. Am. Soc. Microbiol.  74: 184.

Omura, K., and T. Matsuura.  1971.  Photoinduced reactions -
L Photolysis of halogenophenols in aqueous alkali and in
aqueous cyanide.  Tetrahedron  27: 3101.

Rodd, E.H.  1954.  Chemistry of carbon compounds.   III-A.
Aromatics.  Elsevier Publishing Co., Amsterdam.

Sax, H.I.  1975.  Dangerous properties of industrial mate-
rials.  4th ed.  Van Nostrand Reinhold Co., New York.

Selander, H.G., et al.  1975.  Metabolism of chlorobenzene
with hepatic microsomes and soluble cytochrome P45Q Sys-
tem.  Arch. Biochem. Biophys.  168: 309

Sherman, J., et al.  1972.  Chronic toxicity and residues
from feeding nemacide 0 (2-,4-dichlorophenol) 0, 0-diethylphos-
phorothioate to laying hens.  Jour. Agric.  Food Chem.  23:
617.

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

Sidwell, A.E.  1971.  Biological treatment of chlorophenolic
wastes - the demonstration of a facility for the biological
treatment of a complex chlorophenolic waste.  Water Pollut.
Control Res. Ser.  12130 EKG.
                                                          »
Stecher, P.G., ed.  1968.  The Merck Index.  8th ed.  Merck
and Co., Rahway, N.J.
                          So-11

-------
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.

U.S. EPA.  1979.  2-Chlorophenol: Ambient Water Quality Cri-
teria (Draft).

Von Oettingen, W.F.  1949.  Phenol and its derivatives: the
relation between their chemical constitution and their effect
on the organism.  Natl. Inst. Health Bull.  190: 193.

-------
                                              SJ-45-01
                                   No.  51
              Chr omium
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
      WASHINGTON, D.C.   20460

          October 30, 1980


                51-1

-------
                          DISCLAIMER
     This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.  The information contained in the report is drawn chiefly
from secondary sources and available reference documents.  Be-
cause 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 sub-
ject material.  This document has undergone scrutiny to ensure
its technical accuracy.
                             51-2

-------
                           CHROMIUM


                           Summary




     Hexavalent chromium (CrVI), at low concentrations in water,


has a deleterious effect on the growth of fish, aquatic inver-


tebrates, and certain species of algae.  For the most sensi-


tive aquatic species, Daphnia magna, a final chronic no-effect


level of less than 10 ug/1 has been derived by the U.S. EPA.


For trivalent Cr(Crlll) toxic effects are more pronounced in soft


than in hard water; chronic no-effect levels are derived as a


function of water hardness.


      Several hexavalent Cr compounds have produced tumors


in animal studies.  Human epidemiology studies indicate a


possible etiology of Cr exposure in the production of lung


tumors in occupationally exposed workers.  Trivalent Cr has
                                          •

not shown carcinogenic effects.


     Mutagenic effects, including cytogenetlc effects in


exposed workers, have been reported for hexavalent chromium


compounds.   Trivalent chromium compounds were not mutagenic


in the Ames bacterial assay.  Teratogenic effects of chromium


have been reported in a single study and have not been


confirmed.


     Impairment of pulmonary function has been reported in


chrome electroplating workers subject to chronic chromium


exposure.  However, exposure to multiple agents complicates


the interpretation of this  finding.
                             51-3

-------
                            CHROMIUM

 I.    INTRODUCTION
       «
      This  profile  is  in  large part based on the Ambient
 Water Quality  Criteria Document  for Chromium  (U.S. EPA, 1980).
      Chromium  (Cr)  is a  steel gray, lustrous, hard metal that
 melts at 1857  + 20°C, boils at 2672°C, and has a specific
 gravity of 7.18 to 7.20  at  20 °C  (Weast, 1974).  Cr compounds
 exist in a variety of oxidation  states; the most commonly
 occurring  are  those of the  trivalent and hexavalent states.
 Physical properties of some Cr compounds are  summarized in
 Table 1.
      Cr compounds  are utilized in the paint and dye industries
 as pigments and mordants, in metallurgy for the production of
 stainless  steel and other alloys, in the chrome tanning of
 leather goods, in  the production of high melting refractory
 materials,  and for chrome plating.
      Hexavalent Cr compounds are relatively water soluble and
 are readily reduced to more stable and insoluble trivalent
 forms by reaction  with organic reducing matter.  Trivalent
 chromium forms stable hexacoordinate complexes with a great
 variety of  ligands  (water,  ammonia, urea, halides, sulfates,
 ethylene diamine,  organic acids).  In neutral and basic
 solutions,  trivalent  Cr may form polynuclear bridge compounds
 that  eventually precipitate.  Hexavalent Cr exists in solution
 as a  component of  an  anion  (hydrochromate, chromate,  or
dichromate) and does  not precipitate from alkaline solution.

                             51-4

-------
The  specific anionic  form of hexavalent Cr  is dependent on  •



pH - in the acid range hydrochromate predominates, while in



the  alkaline range the predominant  form is  chromate  (Trama



and  Benoit, 1960).  Cr VI occurs naturally  in alkaline soft



waters (Robertson, 1975) and in aerated sea water (Fukai,



1967; Cutshall et. al., 1965; Emerson et. al., 1979).  The



oxidation of CR III is expected to  occur on energetic grounds



(Carlin, 1965; U.S. EPA, 1977).  In fact, .however, oxidation



takes place only very slowly in natural waters, except in the



presence of Mn02 (Schroeder and Lee, 1975;  U.S. EPA, 1978).



Under laboratory conditions oxidation does  occur (Schroeder



and Lee, 1975; Stephens, 1977).  In contrast, the reduction



of Cr VI to Cr III occurs rapidly in lake waters (Schroeder



and Lee, 1975).



     It seems probable that in most waters, especially under



neutral or slightly acid conditions-, Cr VI  is reduced to Cr



III, the hydroxy complexes of which precipitate out and/or



are absorbed onto clays and other soil elements (N.A.S.,



1974; U.S. EPA, 1978).



     Since Cr is an element, it persists indefinitely in the



environment in some form.   Trivalent Cr compounds are more



likely to accumulate in sediments,   while hexavalent forms



remain soluble and dissipate with the water flow (U.S. EPA, 1980)





II.  EXPOSURE



     Large amounts of hexavalent Cr are produced and utilized
                             51-5

-------
 in industry,  primarily as chromates and dichromates (U.S.

 EPA,  1980).   Industrial processes consumed 320,000 metric

 tons  of  Cr metal alone in 1972.

      Much of  the detectable chromium in air and water is

 presumably derived  from industrial processes.  Levels of

 total Cr in the air exceeding 0.10 mg/m^ were reported

 from  59  of 186 urban areas examined (U.S. EPA, 1973).   Air

 levels in non-urban areas generally fall below detection

 limits.  Mean concentration of Cr in 1577 samples of surface

 water was determined as 9.7 ug/1 (Kopp, 1969).  Cr is naturally

 distributed in the  continental crust at an average concentration

 of  125 rag/kg  (N.A.S., 1974).

      Based on available monitoring data, the U.S. EPA (1980)

 has estimated the uptake of Cr by adult humans from air,

 water and food:


              Source                Uptake ug/day

              Atmosphere                1
              Water                    20
              Food  Supply               50-100
                                        121


      A different estimate for self-selected diets was 280ug/day

 (NAS, 1974).  It is often stated that the American diet may

be marginally deficient in Cr.  Since a MDR has not yet been

established (Mertz, 1978), and since absorption factors (see

below) are as yet poorly understood, this statement is open

to question.
                             51-6

-------
Table \.  Physical Hropertlea of Typical Chromium Compounds
Compound
On 1 da t ion stale 0
Chromium car bony 1


In benzene
clirouiium(O)
Oxidation slate * 1
i>lu( Llpliunyl )-
chromium (1)
lull Ida
Oxidation slale * 2
Cliroiuuua acclatu


Chroiiious chloride

Clironous ammonium
auH'alu
Oxidation stale » 3
Chromic chloride


Chruwlo acclyl-
Ciirunic |iolasslum
aiill'dlb (chroma
it 1 UOl )
Clirttulu uhlurldu
Cliruin i^^li 1 or 1 du
llull.t^^H'.llU
Formula Appearance

(Cr(CO>6 Colorless
cryatala

(CJI, ),.Cr Droun
b b f. . ,
crystals

(C. II^C,!!, )_CrI Orange plates



Cr,(C II 0 )U-2II,0 Red crystals
223212

CrCl White
cryatala
CrSO|(.(Hlllt)2SO||.6ll20 Blue cryatala

CrCl. Urlght purple
* plates

Cr(CII-.COCIICOCM ) Hed-vlolet
J 3 * cryatala
KCr(SO( )_• )2H_0 Deep purple
crystals

(Cr(ll Ot.Cl )CI-2II20 Urlght eruun
cryatala
(Cr(ll.,0)6)Cl3 V»olot
crystals
Crystal ayatom Density
and space group (g/cm )

Orlhorhoinblo, C:! 1*77. a
£r 10

Cubic, Pa.. . 1.519
3

1-'17.«



Monoollnlo, C2./Q 1.79


Tetragonal, DJ! 2.93
Ml*
S
HonooUnlc, C.
•a __c
•* » rviOrD o n-»
lloxa^oital, D. 2.U7-C


Honoollnlo 1.3M
£
Cubic, A 1.U261(-
(1 ID

Trial Inlcor 1.B3525
uonoclinlo
llhoiabohudral, 0,.

Halting Dolling
point Pglnt

150 151
(decomposed) (decomposed)
(sealed tube)
281-21)5 Sublimes 150
(vacuum)

178 Decomposes
•





815 1120



Sublimes 685


208 315
89
( Inoongruent )

95
90

Solubility

Slightly soluble In
CC1U; Insoluble in
U20, (C2H5)20,
Insoluble In ILO;
soluble in C II,
b o

Soluble In
C2">j0"« c»,"ijM


Slightly soluble In
II 0; soluble In
aolida
Soluble In II-,O to blue
solution, absorbs U
Soluble In U.,0,
absorbs Q

Insoluble In U.,0.
soluble In presence
ol' Cr
Insoluble In II .,0; ...
soluble In C,|l .
0 6
Soluble In IIO


Soluble In II^O, green
solution turning
groen-vlolut
Soluble In H.,0, violet
solution turning
uruun-vlolbl^

-------
Compound 'Formula
throoiic oildu Cr.O-
* J
Oxidation atate » 1
Chromium (IV) oxide CrO,
£
Chroulua(IV) CrCli,
L-tllurldu
Oxidation state * 5
barium chrouate(lV) Ua..(CrOh).
J 1 «


Oxidation slate * 6
Chronlum(Vl) CrO
oxldb

Cliri.uyl chloride CrO.Cl.

Ammonium (HII.KCr 0
dlclirowjlu
rolaaunim *2Cr2°7
dtuhrouule
Sodium dl chroma le ll' Ci-0 • 211-0
1
Potassium chruraute K CrO^

Ziudluo uhromate lla^CrO.

Potassium chloro- KCrO^Cl
chruuate
!illvur uliroualu Ig CrO^
* 1
.
ll.irluiu cliroiiiiile liuCi-O.
'1

Appearance
Green powder
or crystals

Dark Drown or
black powder



Dtack-green
crystals



Huby-red
crystals

Cherry-red
liquid

Red-orange
crystals
Orange-red
crystals
Orauge-rcd
crystals
follow
crystals
Yellow
crystals
Orange
crystals
Iliiroon
crystuls

Main yellow
solid

Crystal aystea Density
and apace group (g/cm )
llhombohcdral, D,. $.22^

IU
Tutragonul, »,!. 4.90
(calculated)
Stable only at
.high temp.

Same aa
Ca.-d'O. )
J H 2
•

Ortliorhomblo, C?' 2'725
3

1.9I1525

Honocllnlo 2.l552c
•
Trlollnlo . 2.676.,.

Honoollnlo ''^''"pS
3
Orlhorhouiblo 2.TW &
17
Ortliorhoiuhlo. D ' 2.723-,^

Monocllnlo 2.*I97^(|
"
Monocllnlc 5.625,,.-
25

Orthorhoinblo 4.'I90.>|.
'•>

Melting Dolling
point point
2135 oa. 3000


Deooopoaea
to Cr20
630


*




197 Decomposes
..'

-96.5 115.0

Deoonpoaea

390 Decomposes

01.6 Decomposes
(tnoongruont)
971

792

Decomposes




Deoonposoa


Solubility
Insoluble


Soluhle In act da to
CrJ* and Cr°*



Slightly decomposes
In ILO; soluble In
dllnCe acids to
Cr1* and Cr

Very aoluble In ll.0|
aoluble In CD
COCII, (Cll C0)^5
Insoluble In ll^Oi
liydrolyxesi Soluble
In CS 001
Soluble In U.,0

Soluble In H.,0

Very soluble In U.,0

Soluble In H.,0

Soluble In U.,0

Soluble In U.,0,
hydrolyxes
Very alightly aoluble
In ILO; soluble In
dilute acids
Very slightly aol'ubla
In II. ,0; soluble In
strung acids

-------
Compound Formula
Strontium chroma te SrCrO^
Lead chroma te PbCrO^
Appearance
Yellow solid
Yellow solid
Orange solid
lied solid
Crystal system Density
and apace group (g/cn )
Honoollnlo. C*^ 3'fl95i5
Ortliorhomblc _
Honoollnlo, CJL 6-l2|5
Tetragonal
He 1 ting boiling
point ' point
(°0 (°C)
Decomposes
U'lM
Solubility

Slightly soluble In
II 0; soluble In
dilute aclda
Practically insoluble
In II 0} soluble in
strong aclda
Source:  Adapted fron U.S. EPA, I97B.

-------
      The U.S. EPA (1980)  has derived a bioconcentration factor


 (BCF) of 11 for chromium.




 III. PHARMACOKINETICS



      A.    Absorption



          • The efficiency of Cr absorption by the  gastroin-


 testinal tract is a function of the oxidation and chemical


 forms of the compound and the presence of other dietary


 constituents, and poorly understood intestinal epithelial


 barriers (U.S. EPA,  1980; Mertz,  1978).   Oral administration


 of trivalent Cr results in little absorption.  In order to be


 assimilated chromium must be present in the  form  of  an  organic


 complex  with nicotinic acid termed glucose tolerance factor  (GTF)


 (Mertz,  1969;  1971;  1978).  Inorganic Cr is  poorly assimilated


 (a few per cent)  (Mertz,  1969;  1971).   Cr from animal sources  is


.much better utilized than that from vegetables, in which it  may


 occur in high concentrations (Mertz,  1978).   Dermal  absorption of


 Cr does  not contribute greatly to total  body load, except in
  •

 situations where  toxic external concentrations have  produced


 ulceration (U.S.  EPA,  1980).   Pulmonary  exposure  to  Cr,  which  can


 be significant in some industrial situations,  leads  to  prolonged


 retention at this site (Baetjer,  et al.  1959).  Under most conditions,


 however,  the contribution of the  inhalation  route to total absorbed


 Cr is small (U.S.  EPA,  1980).


      B.    Distribution


           Analysis of the metabolism and distribution of Cr




                                51-10

-------
is complicated by the fact  that  the methods available  for  the




estimation of Cr at low levels do not adequately distinguish




between its different forms (U.S. EPA 1980; 1978).  In




addition, difficulties of interpretation arise  from the fact




that cellular constituents  reduce Cr to the trivalent  form




(Petrilli and DeFlora 1978; Nakamuro 1978).




     Absorbed Cr is primarily transported bound to siderophilin,




a metal transport protein which  predominantly binds iron.




     The organ distribution of Cr is highly dependent  on the




chemical form administered.  For instance, while trivalent Cr




does not extensively cross  the placental barrier, when admin-




istered to pregnant rats in completed form (GIF), it is




taken up by the fetus.  The highest concentrations of  Cr




accumulate in skin, lung, muscle and fat (Mertz 1969,  Casarett




and Doull, 1979).  Pulmonary Cr  arises from inhalation, and




does not equilibrate with other  body stores.  Cr concentration




in tissues other than lungs decline somewhat with age  (Mertz 1969)




     Hexavalent Cr is reduced to the trivalent  form in skin.




In the blood little hexavalent Cr is detected.  The reticulo-




endothelial system, liver, spleen, testis and bone marrow




have an affinity for trivalent Cr, (Mertz 1969); chromates




are bound largely to red blood cells (Mertz 1969).  Inside




cells,  about half of the Cr is in the nucleus.




     C.    Metabolism




          Analysis of chromium metabolism is complicated by




the extensive binding of chromium to tissue components






                            51-11

-------
 (enzymes, proteins, nucleic acids) and by the inability of
     *
 analytical methods to distinguish between the different forms


 of chromium (U.S. EPA, 1978;  1980).


      Studies of the kinetics  of radiochromium distribution in


 humans .indicated three major  accumulation and clearance


 components (Lim, 1978).   Animal studies with radioactive


 chromium trichloride injected intravenously showed that heart,

 lung,  pancreas, and brain retain only 10 to 31 percent of


 their  initial radioactivity after four days.  Spleen, kidney,


 testis and epididymls concentrate chromium (Hopkins, 1965).

 Average urinary and blood concentrations are 0.4 and 2.8


 ug/lOOg, respectively (Casarett and Ooull, 1979).  Because of


 rapid  clearance, blood concentration is not an indicator of

 Cr intake (Mertz, 1971).

     D.   Elimination


           Chromium turnover in humans appears to be very slow


 (National Academy of Sciences, 1974).  One component of
i
 chromium elimination has  been calculated to have a half-life


 of 616 days  (Taylor, 1975).  In rats, three compartments


 for trlvalent chromium have been estimated to have half-

 lives  of 0.5,  5.9, and 83.4 days, respectively (Mertz, et al. ,


 1965).

     Chromium is excreted in  both urine and feces.  Urinary

 excretion is  the major route  of elimination, accounting


 for recovery  of 80 percent of injected chromium (Mertz, 1969).


 Up to  20 percent of intravenously injected trivalent chromium


 was found in the feces  of rats (Visek, et al.  1953).   Milk


                           51-12

-------
also  contributes  to  excretion  (Casarett, 1979).



IV..   EFFECTS



      A.    Carcinogenicity



           Carcinogenicity of various hexavalent Cr compounds



in humans  has been well documented  (U.S. EPA, 1980).  EPA1s



Carcinogen Assessment Group (CAG) has determined that there



is substantial evidence that hexavalent Cr compounds are



carcinogenic in man.  Six epidemiologic studies, conducted



at five different locations, of 1200 chromate workers provide



strong evidence that inhalation of Cr VI produces lung cancer



(U.S. EPA, 1978;  1980).  One study  (Taylor, 1966) also showed



an increase in digestive cancer.  In rats and hamsters



inhalation studies using calcium chromates have produced



cancer (Laskin, 1973), and Cr VI is carcinogenic when implanted



in intrabronchial pellets, as well as by subcutaneous and



intramuscular injection in mice and rats.  However, the



Carcinogenicity of Cr VI has not been tested by oral admini-



stration (U.S.  EPA,  1980).



     The determination of the Carcinogenicity of Cr VI compounds



rests mainly on epidemiologic studies (see above) of employees



in industries which use or produce chromates.  Cr III compounds



are used principally in the manufacture of ferrochrome,



chromite bricks and steel, in leather tanning and in lithography,



Data on the Carcinogenicity of trivalent Cr are felt to be



inadequate (Heimann, 1976).  Rats showed a weak carcinogenic



response to chromic (Cr III) acetate (Hueper and Payne, 1962;





                            51-13

-------
 Maltoni,  1974).   Cr may be a  co-carcinogen  or  promoter:



 chromium  carbonyl is a mild synergist  for benzo(a)pyrene  in



 the  production of carcinomas  in  tracheal grafts  in rats



 (Lave  and Mass,  1977).  Such  effects could  be  important in



 the  development  of lung cancer following pulmonary exposure



 to chrornates.



     B.    Mutagenicity



           Cytogenetic effects in workers exposed to welding



 fumes  have been  attributed to inhaled  chromium (Hedenstedt, et



 al., 1977).  These effects have  also been reported in chromate



 production workers (Bigalief, et al.,  1977).



     Cr compounds induce  chromosomal aberrations in human and



 animal leukocytes,  and mutations in bacteria and yeasts (U.S.



 EPA, 1980; Petrilli  and DeFlora, 1978a,b; Nakumoro 1978).



 In these  tests Cr VI  compounds have much higher activity



 than Cr III compounds.  Under some assay conditions cellular



 reducing  agents  (ascorbic  acid,  NADH,  NADPH, GSH) prevent Cr



 VI mutagenicity  by reducing it to CR III (Petrilli and



 DeFlora,  1977; 1978a,  b).  Nakamuro, however (1978) found



 that Cr (III) acetate,  nitrate and chloride induce chromosomal



 damage in  cultured human leukocytes, and are bacterial mutagens,



       C.   Teratogenicity



           Embryonic  abnormalities have been produced in the



 developing chicken by direct  injection of trivalent or



hexavalent chromium  into the  yolk sac  or onto  the chorioallan-



 toic membrane  (Ridgway  and Karnofsky,  1952).   This effect





                            51-14

-------
has not been further investigated,  and  is  worrisome because



of the reported  placental  permeability  to  complexed Cr  (Mertz



1969).



      D.    Other  Reproductive  Effects



           Pertinent information could not  be  located  in the



available  literature.



      E.    Chronic  Toxicity



           Except as regards the carcinogenicity of Cr VI,



the concentrations of Cr encountered in the normal environment



do not constitute  a human  health hazard.   However, acute



and chronic  toxicity problems associated with exposure  to Cr



are of concern in  the industrial environment.  These effects



have been  reviewed (NIOSH, 1975; EPA, 1980),  and include



damage to  liver, kidney, skin,  respiratory passages and lungs



(U.S.  EPA, 1978, 1980; NAS 1974, 1977;  NIOSH, 1975).  Allergic



dermatitis is a  pronounced property of  both tri- and hexavalent



Cr compounds  (EPA,  1980; Casarett and Doull,  1979).



      Subtle changes in pulmonary function  have been observed



in workers employed in electroplating (Bovett et. al.f  1977).



Cr VI  causes ulceration and perforation of the nasal systems,



chronic  rhinitis and pharyngitis, but these effects have been



observed only in workers chronically exposed  to relatively



high concentrations of chromates (NIOSH, 1975).



V.    AQUATIC TOXICITY



      A.    Chronic Toxicity



          No data  for chronic toxicity of  trivalent chromium





                            51-15

-------
 for  freshwater  fishes  is available.  The geometric mean of



 chronic  toxicity values for the  freshwater invertebrate



 Daphnia  magna is based on data from a single study, and is



 reported as 445 ug/1.  No chronic data  for trivalent chromium



 for  freshwater  algae are available.



     Chronic embryo-larval tests on six species of fresh



 water  fish exposed to  Cr VI resulted in values ranging from



 37 to  72 ug/1 for rainbow trout  (Salmo gairdneri) and lake



 trout, Salvelinus mamaycush.  White suckers,  Catostomus



 conunersoni, and channel catfish, Ictalurus punctatus, were



 intermediate in sensitivity and  northern pike, Esox lucius,



 and bluegills, Lepomis macrochirus, were least sensitive



 with chronic values of 360 and 368 ug/1 respectively.  In



 life cycle or partial life cycle tests, both the rainbow trout



 and snook trout, Salvelinus fontinalis, were sensitive with



 chronic  values of 265 ug/1.  Chronic testing of hexavalent



 chromium in Daphnia magna found  significant survival and



 fecundity changes at concentrations as low as 10 ug/1.  The



 effects  of hexavalent chromium .on the freshwater algae,



Ch1amydomonas reinhardi, were recorded at levels as low as 10



ug/1.  The Eurasian watermilfoil displayed the greatest



resistance to hexavalent chromium, even at levels as high as



9,900 ug/1.



     There are no chronic toxicity data available for trivalent



chromium compounds in marine fish, invertebrates or algae.



     The only available bioconcentration data for freshwater





                            51-16

-------
 species are  from studies on rainbow trout, and indicate a



 bioconcentration factor of 1  for potassium chromate.  Marine



 bioconcentration factors in three  species of bivalve molluscs,



 Mytilus edulis, (34) , Crassostrea Virginia (166) , and Mya arenaria ,



 (152), give  a 'geometric mean  of 114.  The weighted average BEF



 is 11  (U.S.  EPA, 1980).



     B.   Acute Toxicity



          The acute  toxicity  of trivalent. chromium compounds



 has been examined extensively.  The 96-hour LCso values



 for 14 tests ranged  from 3,330 to 71,900 ug/1 and correlates



 with the hardness of water over a range of 20 to 360 ug/1 (as



 CaC03) in 11 species of freshwater fish.  The guppy Poecilia



 reticulata was most  sensitive and the bluegill the most



 resistant.  Among eight species of freshwater invertebrates,



 acute 96-hour LCso values ranged from 2,000 to 64,000 ug/1.



     For hexavalent chromium  96-hour LCso values ranged from



 17,600 ug/1 in the fathead minnow, Pimephales promelas, in



 soft water to 195, --- ug/1 for large mouth bass, Micropteus



 salmoider, in hard water.   The 96-hour LCso values for
freshwater invertebrates exposed to hexavalent chromium ranged



from 3,100 ug/1 in the rotifer, Philodina acuticornis, to



12,000 ug/1 in the rotifer, Philodina roseola.



     There are no pertinent acute toxicity data available



regarding the toxicity of Cr III compounds to marine species.



     The acute toxicity data for hexavalent chromium to marine



fishes resulted in 96-hour LCso values of 30,000 to 30,000





                            51-17

-------
 ug/1  for the  speckled  sanddab,  Citharichthys  stigmaeus, and



 91,000  ug/1 for .the mummichog,  Fundulus heteroclitus.  In-
      %


 vertebrates appeared more  sensitive to hexavalent chromium



 than  marine fish.  The 96 hour  LCso values for hexavalent



 chromium ranged from 2,000 ug/1 for the polychaete worm,



 Nereis  vinens, to  105,000 ug/1  for the mud snail, Nassarius



 obsoleutus, in static  bioassays.



      The U.S. EPA  (1978) offers an extensive  review of the



 environmental effects  of chromium compounds in freshwater and



 marine  organisms.



 VI.   EXISTING GUIDELINES



      Standards promulgated by various U.S. agencies are



 summarized in Table I.



      Based on animal data indicating carcinogenic effects of



 chromium VI and estimates of lifetime exposures from



 consumption of both drinking water and aquatic life forms,



 the U.S.  EPA (1980) has estimated that the concentrations of



hexavalent chromium in ambient  water should be no greater
 »


than  7.1  ng/1 to keep the lifetime risk of cancer below 1 in



100,000.  This risk calculation  is based on the conservative



assumption that ingestion of Cr VI can cause cancer.   EPA's



Water Quality Criteria Document  (U.S. EPA 1980) discusses



this and' alternative assumptions.



     The  OSHA time-weighted average exposure criterion for



chromium  (carcinogenic compounds) is 1 ug/m3;  for the "non-



carcinogenic"  classification of chromium compounds the



criterion is 25 ug/m3  (OSHA 1979).



                            51-18

-------
                                         TABLE 1

             Recommended or Established Standards for Cr in the United  States
MEDIUM
 CHEMICAL
 SPECIES
REFERENCE
STANDARD
Drinking Water
Domestic Water Supply

Fresh Water (aquatic
  life)

Ambient Water Quality
  Criteria

Livestock Water
Work Place AIR
 Cr VI


 total chromium

 total chromium
 total chromiumc
 Cr VIC

 Cr VI
 care inogenic
 Cr VIa
                         noncarcinogenic
                         Cr VIa
                         soluble chromic
                         and chromous salts

                         metal and insoluble
                         salts
U.S. Public Health
Service (1962)

U.S. EPA (1976)

U.S. EPA (1976)
U.S. EPA (1980)
U.S. EPA (1980)

Nat'l. Acad. Sci.
(1972) and Nat'l.
Acad. Eng. (1972)

Nat'l. Inst. Occup.
Safety and Health
(1975)

Nat'l. Inst. Occup.
Safety and Health
(1975)

29 CFR 1910.1000
                      29 CFR 1910.000
50 ug/1


50 ug/1

100 ug/1
50 ug/1
0.007 ug/1

1 mg/1
1 ug/m3



25 ug/m3 TWAb
50 ug/m3 ceiling


0.5 mg/m3


1.0 mg/ m3
aCarcinogenic compounds
 mono-or dichromates of
  >ime-weighted average
             .      , - ^ ~
are here taken to include all forms of Cr VI other
H, Li, Na, K, Rb, Cs,  and NH4.
                              than CrO3 and

-------
     For the protection of aquatic species, proposed water
     t
criteria for both trivalent and hexavalent chromium in fresh-

water and marine environments have been prepared in accordance

with the Guidelines for Deriving Water Quality Criteria

(Federal Register 43_: 21506, May 18, 1975 and Federal Register

£3_:29028, July 5, 1978).  In freshwater environments the

proposed criterion for hexavalent chromium is 10 ug/1, not to

exceed 110 ug/1, and the proposed criterion for trivalent Cr

is given a Chronic Final Value represented by the following

equation:

        C.F.V. = e (0.83 In (water hardness) = 2.94)

     The proposed criterion for trivalent chromium in marine

environments could not be determined by criteria established

in the  Guidelines.
                            51-20

-------
                          References

Baejter, A., et al.  1959.  The distribution and retention
of chromium in men and animals.  AMA Arch.  Ind. Health 20: 126.

Bigalief, A., et al.  1977.  Evaluation of the mutagenous
activity of chromium compounds.  Gig. Tr. Prof.  abol.  6: 37.

Bovett, P., et al.  1977.  Spirometric alterations in workers
in the chromium electroplating industry.  Int. Arch. Occup.
Environ. Health 40: 25.

Carlin, R. L., ed.  1965.  Transition Metal Chemistry, Marcel
Dekker, N.Y.; Volume I.

Cassarett, L. J• and J. Doull.  1979.  Toxicology, The Basic
Science of Poisons.  MacMillan, N.Y., Second edition, 1979.

Cutshall, N., Johnson, V. and C. Osterberg.  1965.  Chromium
51 in sea water; chemistry.  Science 152: 202-203.

Emerson, S., Cranton, R. E. and P. S. Liss.  1979.  Redox
species in a reducing fjord: equilibrium and kinetic
considerations.  Deep Sea Res. 26A: 859-878.

Fukai, R.  1967.  Valency state of chromium in sea water.
Nature 213: 901.

Hedenstedt, A., et al.  1977.  .Mutagenicity of fume particles
from stainless steel welding.  Scand. J. Work. Environ. Health
3: 203.

Heimann, H.  1976.  Chromates and cancer.  Presented at the
International Conference on Health Hazards in the Painting
Trades.  Geneva, Switzerland, September 23-24.

Hopkins, L.  1965.  Distribution in the rat of physiological
amounts of injected Cr-51 (III) with time.  Am. J. Physiol.
209:  731.

Hueper, W. C. and W. W. Payne.  1962.  Experimental studies
in metal carcinogenesis.  Chromium, nickel, iron, arsenic.
Arch. Environ. Health.  5: 445-562.

Kopp, J.  1969.  The occurrence of trace elements in water
In; Trace Substances in Environmental Health III, University
of Missouri, Columbia, MO. p. 59.
                            51-21

-------
Lane, B. and M. Mass.   1977.  Carcinogenic!ty and co-
car cinogenicity. of chromium carbonyl in heterotropic tracheal
grafts.  Cancer Res. 37:  1476.

Laskin, S., et al.  1970.  Studies in pulmonary carcinogenesis
in; Inhalation Carcinogenesis, M. Hanna, P. Nettlesheim,
J. Gilbert (eds.).  U.S.  Atomic Energy Commission, p. 321.

Lim, T.  1978.  The kinetics  of the trace element chromium
(III) in the human body.  Paper presented at 2nd International
Congress of Nuclear Medicine  and Biology", Washington, D.C.

Maltoni, C., G. Lefemine, P.  Chieco and D. Caretti.  1974.
La cancerogenes;  ambientale e professionale: nuove prospective
.alia luce della cancerogenes; da cloruro de vinile.  Osp. Vita
1: 4-66.  (Quoted in Petrilli and DeFlora, 1978).

Mertz, W., et al.  1965.  Biological activity and fate of
trace quantities  of intravenous chromium (III) in the rat.
Amer. J. Physiol.  209: 484.

Mertz, W., et al.  1969.  Chromium occurrence and function
in biological systems.  Physiol. Rev. 49: 163.

Mertz, W.  1978.  Trace elements.  Contemporary Nutrition.
3(2): 48-49.

Mertz W. and E.E. Roginski, 1971.  Chromium metabolism:  the
glucose tolerance factor, in  Nutrition, Newer Trace Elements,
W. Mertz and W.E. Cornatzer.  Marcel Dekker, Inc., N.Y.

Nakamuro, K., K. Yoshikawa, Y. Sayato and, H. Kirata. 1978.
Comparative Studies of  chromosomal aberration and mutagenicity
of trivalent and hexavalent chromium.  Mutat. Res. 58: 175-181.

National Academy of Sciences.  1974.  Medical and -biological
effects of environmental  pollutants:  Chromium.  Washington, D.C.

National Institute for  Occupational Safety and Health (NIOSH).
1975.  Criteria for a recommended standard occupational
exposure to chromium (VI).  U.S.D.H.E.W.  Publications #76-129.

OSHA.  1979.  29 CFR 1910.1000 (1979).

Petrilli, F. L. and S.  DeFlora.  1978.  Metabolic de-
activation of hexavalent  chromium mutagenicity.  Mutat.
Res.   54: 139-147.
                            51-22

-------
Petrilli, F., and S. DeFlora.  1977.  Toxicity and mutagenicity
of he.xavalent chromium in Salmonella typhimur ium.  Appl.
Environ. Microbiol.  33: 805.

Ridgway, L. and D- Karnofsky.  1952.  Effects of metals in
the chick embryo - toxicity and production of abnormalities
in development.  Ann. N.Y. Acad. Sci.  55: 203.

Robertson, F. N.  1975.  Hexavalent chromium in the groundwater
in Paradise Valley, Arizona.  Groundwater.   516-527.

Schroeder, H., et al.  1962.  Abnormal trace metals in man-
chromium.  J. Chronic Pis.  15: 941.

Stephens, R.D., D.L. Storm and K.C. Ting, 1977.  Environmental
Oxidation of Chromium.  California Department of Health,
Hazardous Materials Section, Berkeley CA  94704.

Taylor, F.  1966.  The relationship of mortality and duration
of employment as reflected by a cohort of chromate workers.
Am. J. Pub. Health.  56: 218.

Trama, F. and R. Benoit.  1960.  Toxicity of hexavalent
chromium to bluegills.  J. Water Pollut.  Control Fed.  37: 868.

U.S. EPA.  1973.  Air quality data for metals - 1968 and 1969.
EPA document #APTD 1467.

U.S. EPA.  1978.  Reviews of the environmental effects of
pollutants:  Chromium.  EPA document #600/1-78-023.

U.S. EPA.  1980.  Ambient Water Quality Criteria for Chromium,
EPA 440/5-80-035. October.

Venitt, S. and L. Levy.  1974.  Mutagenicity of chromates in
bacteria and its relevance to chromate carcinogenesis.  Nature
250: 493.

Visek, W., et al.  Metabolism of Cr-51 by animals as in-
fluenced by chemical state.  Proc. Soc. Exp. Biol. Med.  84: 610

Weast, R.  1974.  Handbook of Chemistry and Physics, 55th ed.,
CRC Press, Cleveland,  Ohio p. 2216.
                            51-23

-------
                                      No. 52
              Chrysene


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION










U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated



chrysene and has found sufficient evidence to indicate that



this compound is carcinogenic.

-------
                                   CHRYSENE
                                   Summary
     Chrysene  is  a  member of  the  polynuclear aromatic  hydrocarbons (PAH)
class.  Numerous compounds  in  the PAH class are well-known  as potent animal
carcinogens.  However, chrysene is generally  regarded as only a weak carcin-
ogen  to animals.   There  are  no  reports available  concerning  the chronic
toxicity of  chrysene.   Although exposure to chrysene  in the environment oc-
curs  in conjunction with  exposure to other PAH,  it  is not  known  how these
compounds may interact in human systems.
     No standard toxicity  data  for chrysene are available for freshwater or
marine organisms.

-------
I.   INTRODUCTION
     This  profile  is based  on the Ambient  Water Quality  Criteria Document
for Polynuclear  Aromatic  Hydrocarbons  (U.S.  EPA, 1979a)  and  the Multi-media
Health Assessment Document for Polycyclic Organic Matter  (U.S. EPA, 1979b).
     Chrysene  (ciaHi2^   *s   one   of   the  fasn^y  of  polynuclear  aromatic
hydrocarbons  (PAH)  formed as  a result of  incomplete combustion  of organic
material.   Its  physical/chemical  properties  have  not  been  well-character-
ized, other  than a  reported  melting  point of  254°C  and a boiling point of
448°C (U.S. EPA,  1979b).
     PAH,  including  chrysene,. are  ubiquitous  in the environment, being found
in ambient air,  food, water,  soils,  and sediment (U.S..  EPA,. 1979b). The PAH
class contains a number of potent  carcinogens (e.g.,  benzo(a)pyrene), moder-
ately  active  carcinogens  (e.g.,   benzo(b)fluoranthene),  weak  carcinogens
(e.g., chrysene),  and cocarcinogens (e.g., fluoranthene),  as well as numer-
ous non-carcinogens  (U.S.  EPA, 1979b).
     PAH  which contain more  than  three  rings  (such as  chrysene)  are rela-
tively stable in the environment.  and  may be  transported in air and water by
adsorption  to  particulate  matter.    However,   biodegradation   and chemical
treatment are effective in eliminating most PAH in the environment.
     The  reader  is  referred to the PAH Hazard  Profile  for more general dis-
cussion of PAH (U.S. EPA,  1979c).
II.  EXPOSURE
     A.   'water
         •Levels  of  chrysene are not routinely  monitored  in water.  However,
the concentration. of six  representative  PAH  (benzo(a)pyrene,  fluoranthene,
                                                                        »
benzo(k)fluoranthene, benzo(j)fluoranthene,  benzo(g,h,i)perylene,  and inde-
no(l,3-cd)pyrene) in U.S.  drinking water averaged  13.5  ng/1  (Basu and Sax-
ena,  1977,1978).

-------
     B.  Food
         Chrysene has been  detected  in a wide variety of foods such as coco-
nut  oil (12  ppb),  and  smoked or  cooked meats  (up to  66 ppb)  (U.S.  EPA,
1979b).  Although  it  is not possible  to  accurately estimate the human diet-
ary  intake of chrysene,  it has  been concluded  (U.S.  EPA, 1979b)  that the
daily  dietary  intake  for all types  of PAH is in the range of 1.6 to 16 ug.
The  U.S.  EPA  (1979a)  has  estimated  the  weighted  average. bioconcentration
factor  for chrysene to  be 3,100 for the edible portion of  fish and shellfish
consumed by  Americans.   This estimate is based  on the octanol/water parti-
tion coefficient for chrysene.
     C.  Inhalation
         Chrysene is commonly  found in ambient air.  Measured concentrations
of chrysene  have reportedly been in the range of  0.6  to 4.8 ng/m  (Gordon,
1976;  Fox  and Staley,   1976).   Thus, the  human  daily intake  of  chrysene by
inhalation of  ambient  air may  be in the range of  11.4 to  91.2 ng, assuming
that a human breathes 19 m  of air per day.
III. PHARMACOKINETICS
     Pertinent data  could  not  be located  in the  available  literature  con-
cerning the  pharmacokinetics  of chrysene or  other  PAH  in humans.  Neverthe-
less,  it  is possible  to make  limited assumptions  based on  the  results of
animal research conducted with several PAH, particularly benzo(a)pyrene.
     A.  Absorption
         The absorption of chrysene  in humans  has not been  studied.   How-
ever, it is  known  (U.S.  EPA,  1979a)  that, as a  class,  PAH  are well-absorbed
across the respiratory  and  gastrointestinal epithelia.   In particular, chry-
                                                                       »
sene  was  reported  to   be  readily  transported  across  the gastrointestinal
mucosa  (Rees,  et al.  1971).   The high lipid solubility  of compounds  in the
PAH class supports this observation.

-------
     8.  Distribution
         The distribution of  chrysene  in mammals has not been studied.   How-
ever,  it  is known  (U.S.  EPA, 1979a)  that  other PAH  are  widely distributed
throughout  the  body  following  their absorption  in  experimental  rodents.
Relative to  other tissues,  PAH tend to  localize in body  fat  and  fatty  tis-
sues (e.g., breast).
     C.  Metabolism
         Limited  work  on the metabolism of chrysene  has  been conducted,  as
part of an  investigation into the mechanism of  its bioactivation to a muta-
gen/carcinogen (Wood, et al.  1977).
         Chrysene,  like  other PAH,  is  apparently metabolized by  the  microso-
mal  mixed-function  oxidase  enzyme  system  in  mammals  (U.S.   EPA,  1979b).
Metabolic  attack, on one  or more of the aromatic double  bonds  leads to  the
formation  of phenols,.and  isomeric  dihydrodiols by  the  intermediate forma-
tion of reactive  epoxides.   Dihydrodiols are further metabolized by  microso-
mal  mixed-function  oxidases  to  yield  dial  epoxides,  compounds  which   are
known, to be  biologically reactive  intermediates for certain PAH.   Removal  of
activated intermediates  by  conjugation with glutathione  or glucuronic acid,
or by  further metabolism to  tetrahydrotetrols,  is  a  key  step in  protecting
the organism from toxic interaction with cell macromolecules.
     0.  Excretion
         The  excretion  of  chrysene  by mammals  has not been  studied.    How-
ever, the  excretion of closely related  PAH  is rapid,  and  occurs mainly  via
the feces (U.S. EPA, 1979a).  Elimination- in the bile .may account  for a  sig-
nificant percentage  of administered  PAH.   However,  the rate of disappearance
                                                                        »
of various PAH from  the  body, and  the  principal routes of excretion, are  in-

-------
fluenced both by the structure of  the parent compound and the route of  admi-
nistration  (U.S.  EPA,  1979b).   It is  unlikely that  PAH  will accumulate  in
the body with chronic low-level exposures.
IV.  EFFECTS
     A.  Carcinogenicity
         Chrysene is regarded as  a weak animal carcinogen (U.S. EPA,  1979b).
LaVoie  and  coworkers  (1979) reported that  chrysene  can act.as  both a  tumor
initiator and as a complete carcinogen on the skin of  mice.
     B.  Mutagenicity
         Chrysene is  positive in  the Ames  Salmonella  assay  in the presence
of  a  metabolizing enzyme  system  (LaVoie,  et al.  1979; Wood, et  al.  1977).
Chrysene is also  positive in the  induction of sister-chromatid exchanges  in
Chinese hamster cells (Roszinsky-Kocher, et al. 1979).
     C.  Teratogenicity
         Pertinent  data  could  not be  located  in the  available  literature
concerning  the  possible teratogenicity of  chrysene.   Other related  PAH are
apparently  not significantly teratogenic in mammals (U.S. EPA, 1979a).
     D.  Other Reproductive Effects and Chronic Toxicity
         Pertinent data could not  be  located in the available literature re-
garding other reproductive effects and chronic toxicity.
V.   AQUATIC TOXICITY
     The only  data  concerning the  effects  of chrysene  to  aquatic organisms
is  a  single bioconcentration  factor  of 8.2 (24-hour)  for  the marine  clam
(Ranqia cuneata) (Neff, et  al. 1976).  No standard aquatic toxicity data for
chrysene either in acute  or chronic studies are available  for freshwater or
                                                                         »
marine species.

-------
 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
          There are no  established exposure criteria  for chrysene.  However,
 PAH as a class  are  regulated by  several  authorities.  The World Health Or-
 ganization has  recommended  that the concentration of PAH  in  drinking water
 (measured as the  total of fluoranthene,  benzo(g,h,i)perylene,  benzo(b)fluor-
 anthene,   benzo(h)fluoranthene,   indeno(l,2,3-cd)pyrene,  and  benzo(a)pyrene)
Tnot exceed 0.2  jug/1.  Occupational exposure  criteria have been  established
 for coke  oven emissions, coal  tar products,, and coal  tar pitch volatiles,
 all of which contain  large  amounts  of  PAH   including  chrysene   (U.S.  EPA,
 1979a).
          The U.S. EPA  (1979a)  draft  recommended  criteria  for PAH  in water
 are based upon  the  extrapolation  of  animal carcinogenicity data for benzo-
 (a)pyrene and dibenz(a,h)anthracene.
      8.  Aquatic
          Data is insufficient for drafting freshwater or marine criterion.

-------
                             CHRYSENE

                            REFERENCES
Basu, D.K.,  and  J.  Saxena.   1977.   Analysis of  raw and drinking
water samples for polynuclear  aromatic  hydrocarbons.  EPA P.O.  No.
CA-7-2999-A,  and  CA-8-2275-B, Expo. Evalu.  Branch,  HERL,  Cincin-
nati.

Basu, O.K.,  and  J.  Saxena.   1978.   Polynuclear aromatic hydrocar-
bons in selected U.S. drinking waters and their raw water sources.
Environ. Sci. Technol.  12: 795.

Fox, M.A.,  and S.W.  Staley.   1976.   Determination  of  polycyclic
aromatic  hydrocarbons in  atmosphere  particulate  matter  by high
pressure  liquid   chromatography  coupled  with  flourescence  tech-
niques.  Anal. Chem.  48: 992.

Gordon, R.J.,  '1976.  Distribution of.airborne polycyclic aromatic
hydrocarbons  throughout  Los   Angeles.    Environ.  Sci.  Technol.
10: 370.

Lasnitzki, A., and  Woodhouse,  D.C.   1944.   The effect of 1:2:5:6-
Dibenzanthracene  on  the  lymph-nodes  of the  rat.    Jour.  Anat.
78: 121.

LaVoie, E., et al.  1979.  A comparison of the mutagenicity  tumor-
initiating  activity and complete carcinogenicity  of polychlorin-
ated aromatic  hydrocarbons  In;  Polynuclear  Aromatic Hydrocarbons,
P.W. Jones and P. Leber (eds.).  Ann Arbor Science Publishers.

Neff, J.M.,  et al.   1976.   Accumulation and release of  petroleum-
derived aromatic  hydrocarbons by four  species  of  marine animals.
Mar. Biol.  38: 279.

Rees, E. 0., et al.   1971.  A study of  the mechanism of  intestinal
absorption of benzo(a)pyrene.   Biochem. Biophys. Act.  225:  96.

Roszinsky - Kocher, et al.  1979.   Mutagenicity of PAH's.    Induc-
tion of cister-chromatied  exchanges in vivo.   Mutation Research.
66: 65.

U.S. EPA.    1979a.    Polynuclear  Aromatic Hydrocarbons:   Ambient
Water Quality Criteria (Draft).

U.S. EPA.   1979b.  Multimedia Health Assessment Document for Poly-
cyclic  Organic Matter.    Environmental  Criteria  and   Assessment
Office, Research Triangle Park,  N.C.  Prepared by Syracuse Research
Corporation.

U.S. EPA.   1979c.  Environmental Criteria  and  Assessment Office.
Hazard Profile:  Chlorinated Ethanes (Draft).

-------
Wood A.W.,  et  al.   1977.   Metabolic Activation of Libenzo(ah)an-
thracene and its Dihydrodiols  to  Bacterial Mutagens.   Cancer  Res.
38: 1967.

World Health Organization.   1970.   European standards for  drink-
ing waters.  2nd edition.  Revised.  Geneva.

-------
                                      No.  53
              Creosote


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION










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



creosote and has found sufficient evidence to indicate that



this compound is carcinogenic.

-------
                          ;         CREOSOTE
I.   INTRODUCTION
     Creosote is  a coal-tar distillate  used  mainly as a  wood preservative.
It is  highly  toxic to  wood-destroying  organisms  and  has a  low  evaporation
rate (Farm Chemicals  Handbook,  1977).   In 1972, an estimated 521,000 tonnes
(575,000  tons)  were  produced  by  six  companies at 25 sites in  the United
States (von Rumker, et  al.  1974).  About  90  percent of the creosote is sold
to the wood-preservation industry; the remainder is burned as fuel (von Rum-
ker,  et al. 1974).
     Creosote's other pesticidal uses are as an  herbicide,  an insecticide,
an acaricide,' an  arachnicide,  a fungicfde, a  tree dressing,  a disinfectant,
and. a horse repellent (Table 1).

                                   TABLE 1.
                         USES  AND SITES  FOR CREOSOTE
                               (Cummings,  1977)
        Use
Preservative
Insecticide
  (screwworm)
Acaricide (mites)
Arachnicide (ticks)
Herbicide

Fungicide
Insecticide
(Certain insects, worms,
  moths and borers)
Horse repellent

Disinfectant
                                                   Site
                                       Wood
                                       Horses and mules

                                       Poultry and horses.
                                       Poultry and horses
                                       Along roads, highways, and fences;
                                         farms; flower beds
                                       Rope, canvas, tarpaulins, tree wounds
                                       Tree dressing
                                       Wood stalls, mangers, gates, fence
                                         rails, posts, trees, trailer sites
                                       Outhouses, water closets, garbage
                                         cans, feeding and watering equipment

-------
      Creosote is produced by  the  distillation of coal tar  obtained  from the
 coking of c'oal.  The composition  of  creosote is highly variable  and depends
 on the composition of  the  coal used to make  the tar,  the design  and operat-
 ing conditions of  the  coke oven  (e.g.,  gas  collection system,  temperature,
 coking time),  and the  design and  operating condition of  the still  (e.g.,
 feed rate, temperature,  and blending of  tar distillation  fractions)  (43 FR
 48154,  1978).
      Continuous tar  distillation  at temperatures  of up  to 400°C  produces
 fractions typically ranging from  crude  benzene bo residue  pitches  (von Rum-
 ker, et al.  1974).  A  common  distillation temperature for  creosote  is about
 200 to 400°C (Hawley,   1977;  von  Rumket, et  al.  1974).   The creosote frac-
 tion is a mixture  of  organic  compounds, mainly  liquid and solid cyclic hy-
 drocarbons,   including  two-ring and  polynuclear aromatic hydrocarbons (PAH)
•(Table 2).  Among  the  PAH,  phenanthrene represents 12 to  14 percent  of the
 composition of creosote  (Considine,  1976).    6enzo(a)pyrene  (BaP) is present
 at a concentration of  about 200 ppm (Guerin,  1977).
 II.  EXPOSURE
      A.    Water
           Each year  an  estimated 60  to 115 million pounds  (27,000-52,000
 tonnes)  of creosote are  discharged in wastewater treatment  sludges  by creo-
 sote producers.   At  large  tar  distillation  plants,  wastewater streams con-
 taining  creosote are treated on-site and/or conveyed  to public  sewage treat-
 ment  facilities.   Wastewater  sludges  treated  on-site  are  transferred  to
 landfill  or burial sites  (von  Rumker,  et al.  1974),.   The estimated  flux of
                                                                2
 creosote   from  these   disposal  sites  ranges from  0.75  kg/m /hr  to  11.0
 kg/m2/yr   (U.S.  EPA,  1980).   In   1972,  about  one  billion  pounds  ("455,000

-------
                                   TABLE  2.

                  PHYSICAL AND CHEMICAL  PROPERTIES OF  CREOSOTE
 Synonyms:   Brick  oil,  coal tar oil,  creosote oil, creosotum, cresylic  creo-
            sote,  dead  oil,  heavy  oil, liquid pitch oil, naphthalene oil,  tar
            oil, wash oil

 Structural  and Empirical Formula:  Consists  principally of liquid and  solid
            cyclic hydrocarbons; contains  substantial  amounts  of  naphthalene
            and anthracene;  12-14  percent  phenanthrene;  200  ppm benz(a)pyrene

 Molecular Weight:   —

 Description:   Dark- brown  green,  yellowish  or  colorless   above  38°C,   naph-
               thenic.  odor;  soluble in alcohol, benzene toluene;  immiscible
               with water

 Specific Gravity  and/or Density:  d25 more than 1.076
                                   25

 Melting and/or Boiling Points:  Common distillation range 200 to 400°C

 Stability:     Overall  degradation rate (0.48/day)  = same as microbial degra-
               dation

 Solubility  (water): approx.  5 g/1; sed .  /Z_
                                    n20 .  1

 Vapor  Pressure:   —

•Bioconcentration  Factor (8CF) and/or
 Octanol/water partition coefficient (Kow):  BCF =0.6
                                            KQW =  i.o
 Source:   Hawley,  G.G.,  1977;  Windholz,  1976;  U.S.  EPA,  1980;  Lopedes,  1978

-------
tonnes) of creosote  were  used to preserve railroad  ties,  marine pilings and
utility poles (NIOSH, 1977a).
          Some of  the organics  present  in creosote are  moderately soluble.
Creosote partitions  between  sediments and water  in a  ratio  of 1:5.   It  is
considered stable  in groundwater,  but decomposes at an estimated  rate of 90
percent in five days  in river water flowing 50-250  miles.  About  99 percent
decomposed in a lake environment in one year (U.S. EPA, 1980).
          Creosote migrates from treated wood  into  the environment,  but the
impact  of  this migration  is  unknown.   Creosote-was  found  to have  a vapor
loss of 27.5 and  15.2 percent  from  the  outer  two inches  of  seasoned and
green  poles,  respectively; high residue  creosote  was estimated  to  have  a
10.3 and 4.4 vapor loss, respectively.   Creosote  losses to the aquatic envi-
ronment  are  the greatest  during  the  first years  after  installation.   One
eight-year study is summarized below (43 FR 48154, 1978).
                                           Creosote Loss
                    Year                pounds/linear foot
                     1                         0.31
                     2                         0.05
                     3                         0.06
                     4                         0.22
                    4-8 •                      0.15 (average)

     B.  . Food
          Naiussat and Auger  (1970) found  that PAHs  in a contaminated lagoon
accumulated  to  the  greatest  extent  in species  near  the top  of  the  food
chain.   One of these  compounds,  BaP,  has been  reported to accumulate in mus-
sels (about  50 pg/kg;  20  times  background) taken  from creosote-treated pil-
ings (43  FR 48154,  1978).   Elevated  levels of  BaP in mussels  growing near
                                                                      #
creosoted timbers  or pilings  suggest that creosote is a  significant source
of BaP  in the' marine  environment.   This  suggestion  was supported by compari-

-------
 sons  of  gas  chromatography  profiles  of polycyclic aromatic hydrocarbons iso-
 lated from mussels and creosoted wood (Dunn and Stich, 1976).
          High levels of PAH have  been  found  in commercial seafoods grown in
 impoundments  constructed  of creosoted wood..  Commercial  samples  of oysters,
clans,  and  mussels  were  found  to contain BsP at concentrations  generally
 less  than  10 ng/g (wet weight).   PAHs were also  found in cockels, abalone,
scallops, lobster,  and  shrimp.  Levels  of BaP  and  other related  PAHs  were
found to be  inversely  related to the  ability  of the species  to metabolize
PAH,  except  in the case of lobster.   Unexpectedly high levels  were found in
 all  edible -meat, of  lobsters  maintained in commercial tidal compounds  con-
structed of  creosoted timber:   up to  281 ng/g  BaP,  303  ng/g  chrysene,  222
ng/g  benzo(a)anthracene,   261  ng/g  benzo(b)fluoranthene,  153  ng/g  dibenz-
 (a,h)anthracene, and B7 ng/g indeno(l,2,3-cd)pyrene (Dunn and Fee,  1979).
III..PHARMACOKINETICS
      A.   Absorption
          Creosote, is. (readily)  absorbed  through the  skin and  mucous  mem-
branes (NIOSH, 1977b).
IV.   EFFECTS
      A.   Carcinogenicity
          Creosote has  been associated  with  several  occupational cases  of
skin cancer over a 50-year  period (Farm Chemicals Handbook,  1977);  its  role
in human cancer is still not-clearly  understood (NIOSH,  1977b).
          Henry (1947),  Lenson (1956), 0'Donovan  (1920), Cookson  (1924),  and
Mackenzie (1898) described  various kinds of workers who  were occupationally
exposed to creosote  and developed skin tumors.   Dermal application  of  creo-
sote  produced skin tumors in mice (Woodhouse,  1950;  Poel and  Kammer,  19*57;
Lijinsky, et al.  1956;. Boutwell and Bosch,  1958; Roe, et  al.  1958).  Roe,  et

-------
al.  (1558)  also  found that dermal  application  of creosote to  mice  produced
lung tumors.  Boutwell  and Bosch (1958) found  that creosote  had the ability
to  initiate tumor  formation when  applied  for a  limited period  prior  to
treatment with croton oil.  Sail and  Shear (1940)  found that  the number  of
skin tumors was  increased  by dermal treatment  with creosote  and benzo(a)py-
rene over the number  of tumors produced by  benzo(a)pyrene  or  creosote alone.
There  is  considerable  evidence  to  show  that  creosote produces tumors  in
mice; that creosote,  when  applied dermally,  is  a tumor-initiating agent when
followed by  dermal treatment  with  croton  oil  (Boutwell  'and Bosch,  1958);
that  creosote accelerates the  tumor  production caused  by  benzo(a)pyrene
(Sail and Shear,  1940);  and that workers  occupationally exposed  to  creosote
developed tumors  (Table 3).  These  studies  have not yet demonstrated  a cor-
relation between  the  carcinogenic  potency of creosote  oils and  the  content
of benzpyrene (Patty,  1963).
          Results from  dose response  studies   are  summarized below  (NIOSH,
1977a).
           Concentration
           and duration                              Effects
           100% 3x/wk                        Skin carcinomas  in 82%,
           28 wk                             tumors in 92%
           20-80% 3x/wk                      Skin carcinomas  in 88%,
           6-44 wk                          tumors in 100%
           100% 2x/wk                        Skin and lung tumors
           21 wk                             in 74%
           1DO% 3x/wk                        Skin tumors  in  50%
           70 wk
                                                      *•
           10-100% 2x/wk*                    Skin tumors  in 38-74%
           70 wk
           2% 2x/wk*                        No tumors
           70 wk
           *Creosote  plus  1  percent 7,12-dimethylbenz(a)anthracene.

-------
                                   TABLE 3.

                   SUMMARY  TABLE ON ONCOGENICITY OF CREOSOTE

                            A.  Human Case Reports
                   Substance
                   and Type
Authors    Year  of Exposure
   Occupation
   of Exposed
  Individual(s)
      Type of Tumor
         Response
Mackenzie  1896  Handling of
                 Creosote
0'Donovan  1920  Handling of
                 Creosote

Cookson    1924  Handling of
                 Creosote
Henry      1947  Handling of
                 Creosote

Lenson     1956  Painting of
                 Creosote
Worker who dipped  Warty elevation on arms;
railway ties in    papillomatous swellings
creosote           on scrotum

Workers who creo-  Skin cancer
soted timbers
Creosote factory
worker
Squamous epitheliomata
on hand; epitheliomatous
deposits in liver, lungs,
kidneys and heart walls
37 men of various  Cutaneous epitheliomata
occupations
Shipyard worker
Malignant cutaneous
tumors of the face
                              B.   Animal Studies
Dermal Exposure

Authors
Sail and
Shear
Woodhouse
Lijinsky,
et al.
Poel and
Kammer
Boutwell
and Bosch
Roe,
et al.

Year
1940
1950
1956
1957
1958
1953

Substance
Tested
Creosote and
benzo(a)pyrene
Creosote oil
#1 creosote
oil
Blended creo-
sote oils;
Light creosote
oil
Creosote
(Carbasota)
Creosote oil
(Carbasota)

Animal and
Strain
Mice (Strain A)
Mice (Albino;
Undefined strain)
Mice - Swiss
Mice (C57L
Strain)
Mice (C57L.
Strain)
Mice (Albino -
random bred)
Mice (Strain
Undefined)

Type of Tumor
Response
Accelerated tumor forma-
tion
Papillomas and carcinomas
Papillomas and carcinomas
Papillomas and carcinomas
metastatic growths in
lungs and lymph nodes
Papillomas
Papillomas and carcinomas
Skin and lung tumors

-------
     B.   Mutagenicity
          Simmon and Poole  (1978)  found  that,  following metabolic activation
by Arochlor  1254-stimulated rat liver homogenate,  both the creosote  PI  and
the coal  tar-creosote  P2 produced a  mutagenic dose-response and  a doubling
above background mutation  rate  with  Salmonella typhimurium  strains TA 1537,
TA 98, and  TA 100.   Mitchell and  Tajiri  (1978)  found  that,  following meta-
bolic activation by  Arochlor 1254-stimulated rat liver homogenate,  creosote
PI and coal  tar creosote P2 increased  the number  of forward mutations at the
thymidine kinase locus of L5178Y mouse lymphoma cells  in a dose-related man-
ner.    There  is considerable  evidence  which proves  that creosote PI  and P2
                                       *
cause mutations in Salmonella typhimurium  strains TA 1537,  TA 98 and TA 100,
and in L5178Y mouse lymphoma cells.
     C.   Teratogenicity and Other Reproductive Effects  .
          Investigations utilizing pregnant swine indicate  that direct con-
tact  with  lumber  freshly treated  with creosote  would  produce  acute toxico-
sis,   resulting in  extensive mortality in newborn swine.   The  direct contact
of the pregnant sow  with lumber freshly  treated with  creosote  provides suf-
ficient  dermal absorption  to cause  fetal  deaths  and  weak pigs  at  birth.
Creosote is  extremely  toxic to young  swine;  the  degree of  toxicity lessens
as the pigs become older (Schipper, 1961).
     D.   Chronic and Acute Toxicity
          Skin contact with  creosote  or  exposure  to  its  vapors may  cuase
burning, itching, papular  and vasicular  eruptions,  or  gangrene.   Eye  injur-
ies  can  include  keratitis,  conjunctivitis,  and "corneal   abrasion  (Patty,
1963).   Exposed  skin  shows  increased  susceptibility  to sunburn, an  effect
                                                                     •
attributed to  photo-toxic  substances usually present in commercial grades of
creosote.   Eventually,  exposed  skin  areas  become  hyperpigmented  (NIOSH,
1977b).
                                        -II

-------
          Serious  systemic effects,  including  cardiovascular collapse  and
death, have  been observed only  after  ingestion (NIOSH,  1977b).   Fatalities
have occurred within  14 to 36 hours after  ingestion  of 7 grams by adults or
1 to 2 grams  by  children.  Symptoms of systemic illness include salivation,
vomiting, respiratory difficulties,  vertigo,  hypothermia, cyanosis,  and mild
convulsion  (Patty,  1963).   Once widely  used  in   medicine,  occasional  in-
stances of  self-medication are  still reported and  sometimes  lead  to chronic
visual  disturbances,   hypertension,  and  gastrointestinal  bleeding  (NIOSH,
1977b).
          The oral  LD5Q  in  rats is estimated  at  725 mg  creosote  per kilo-
gram  body weight  (mg/kg).  The  reported  UX   for dogs, cats, and rabbits
is 600 mg/kg (Fairchild, 1977).
V.   AQUATIC TOXICITY
     Ellis  (1943)  found  fish kills  occurring at creosote concentrations as
low  as  6.0 mg/1  in less  than  10 hours.   Applegate,  et al.  (1957),  using
small numbers of  subjects,  found  that  concentrations  of 5.0 mg/1 produced no
mortalities  in   rainbow  trout  (Salmo   qainneri),   bluegill   (Lepomis  macro-
chirus), or lamprey larvae (Petromyzon marinus).
     The  8-day  LDeg  of a  60:40  mixture of  creosote  and coal tar  in bob-
white quail (Colinus virqinianus) was  reported  to be  about 1,260 ppm;  in the
mallard duck (Anas  platyrhynchos), 10,388 ppm.   The 24-hour 50 percent medi-
um tolerance  limit (Tl-5g) of the creosote/coal tar mixture  was 3.72  ppm in
rainbow trout (Salmo  qainneri)  and  4.42 ppm  in  the bluegill  (Lepomis  macro-
chirus).   The  24-hour  TL5Q concentrations in goldfish  (Carrasius  auratus)
and rainbow trout were 3.51 and 2.6 ppm, respectively (Webb, 1975).

-------
VI.  EXISTING GUIDELINES AND STANDARDS
     The Office of  Toxic Substances of  EPA has issued RPAR on  creosote  and
is continuing preregulatory assessment under Section 6 of  the  Federal Insec-
ticide, Fungicide and Rodenticide Act.
     A  time-weighted  average creosote  concentration of 0.1 mg/m^ has been
recommended for occupational air exposure.
     The aquatic  toxicity rating  for  creosote is  reported  as TLm96 =  IQ_]_
ppm (Fairchild, 1977).
                                      Jfl

-------
                                  REFERENCES


 Applegate,  V.C.,  et al.  1957.  Toxicity  of 4,346 chemicals  to  larval Ian-
 preys  and fishes.  Oept. of Interior, Special Sci. Rept. No. 207.

 Boutwell, R.K.  and O.K. Bosch.  1558.  The  carcinogenicity  of creosote oil:
 its role in the induction of skin tumors in mice.  Cancer Res.  18: 1171.

 Considine,  O.M.   (ed.)   1576.   Van  Nostrand's  Scientific  Encyclopedia,  5th
 ed.  Van Nostrand Reinhold Co., New York.

 Cookson, H.A.   1524.   Epithelioma  of the. skin  after prolonged  exposure  to
 creosote.  Brit. Med. Jour.  68: 368.

 Cummings, W.   1577.   Use of profile for coal tar  derivatives (exclusive  of
 wood preservatives).  Mentioned in 43 FR 48211,  1578.

 Dunn,  B.P.  and J.  Fee.  1579.  Polycyclic  aromatic  hydrocarbon  carcinogens
 in commercial seafoods.  Jour.  Fish Res. Board Can.   36: 1469.

 Dunn,  B.P.  and H.F. Stich.  1976.   Monitoring  procedures  for  chemical car-
 cinogens in coastal waters.  Jour. Fish Res.  Board Can.  33: 2040.

 Ellis,  M.M.   1543.  Stream pollution studies in  the State  of Mississippi.
 U.S. Dept. of Interior, Special Sci. Rept. No. 3.

 Fairchild,  E.J.   1577.   Agricultural chemicals  and pesticides: A  subfile  of
 the NIOSH registry  of  toxic effects  of  chemical substances.  U.S. Oept.  of
 HEW,. July.

 Farm  Chemicals Handbook.   1577.   Meister  Publishing  Company,  Willoughby,
 Ohio.

 Guerin,  M.R.    1577.   Energy  sources of  polycyclic  aromatic  hydrocarbons.
 Oak Ridge National Laboratory.

 Haw ley, G.G.   1977.   The Condensed Chemical Dictionary, 9th ed.  Van  Nos-
 trand Reinhold Co., New York.

 Henry,  S.A.   1947.  Occupational  cutaneous  cancer  attributable  to  certain
chemicals in industry.   Brit. Med.  Bull.   4:  398.

 Lenson,  N.   1556.   Multiple  cutaneous  carcinoma  after  creosote  exposure.
 New Engl. Jour. Med.  254:  520.

 Lijinsky, W.,  et  al.   1556.   A  study of the chemical constitution and  car-
cinogenic action of creosote oil.  Jour.  Natl. Cancer  Inst.   18: 687.

 Lopedes, O.N.  (ed.)  1578.  Dictionary of  Scientific  and  Technical Terms,
 2nd ed.

Mackenzie,  S.   1858.  Yellow pigmentary strains of haemorrhagic origin  and  a
class of tar eruption.   Brit. Jour.  Derm.   10: 417.

-------
 Mitchell,  A.D.  and D.T. Tajiri.  1978.   In  vitro  mammalian mutagenicity as-
 says of creosote PI and P2.  SRI International.  EPA Contract No. 68-01-2458.

 Naiussat,  P.  and C.  Auger.  1570.  Distribution of  benzo(a)pyrene  and pery-
 lene  in  various  organisms  of the  Cliperton Lagon  ecosystem.   C.R.  Acad.
 Siv., Ser. D.  270: 2702.

 National  Institute for Occupational Safety and Health.   1977a.   Criteria for
 a Recommended Standard: Occupational  exposure to coal tar  products.   DHEW
 (NIOSH) Publ. No. 78-107.

 National  Institute for Occupational Safety  and Health.   1977b.   Health Haz-
 ard Evaluation Determination.  DHEW (NIOSH) Publ. No. 75-117-372.

 0'Donovan, W.J.   1920.  epitheliomatous  ulceration among tar workers.  Brit.
 Jour. Derm. Syphilis.  32: 215.

 Patty,  F.A.    1963.    Industrial  Hygiene  and Toxicology,  Vol.   2,  2nd  ed.
 Interscience, New York.

 Poel, W.E. and A.G.  Kammer.   1957.   Experimental carcinogenicity of coal-tar
 fractions.  The  carcinogenicity of  creosote oils.   Jour. Natl.  Cancer Inst.
 18: 41.

 Roe, F.J.C.,  et  al.   1958.   The carcinogenicity  of creosote oil.  The induc-
 tion of lung tumors in mice.  Cancer Res.  18: 1176.

 Sail, R.D.  and M.J.  Shear.   1940.   Studies in carcinogenesis.   XII.  Effect
 of the basic fraction of creosote oil on  the  production  of  tumors in mice by
 chemical carcinogens.  Jour. Natl. Cancer Inst.  1: 45.

 Schipper,  I.S.   1561.   The  toxicity  of  wood  preservatives for  swine.   Am.
 Jour. Vet. Res.  22:  401.

 Simmon, V.F.  and D.C.  Poole.   1978.   In  vitro  microbiological  mutagenicity
 assay of creosote  PI  and. creosote P2.   SRI  International.   EPA  Contract No.
 68-10-2458.

 U.S. EPA.  1980.   Aquatic  fate and transport estimates  for  hazardous  chemi-
 cal exposure  assessments.   Environmental Research  Laboratory, Athens,  Geor-
 gia.

 von Rumker,  R.,  et  al.   1974.  Production,  distribution,  use  and  environ-
mental impact  potential of  selected  pesticides.   Report No.  EPA  540/1-74-
 001.  U.S.  Environ. Prot.  Agency,  Office of Water and  Hazardous Materials,
 Office of Pesticide Programs.

 Webb, D.A.   1975.  Environmental  aspects of  creosote.   Proceedings  American
 Wood-Preservation Association.   7: -176.
                                                                         »
 Windholz,  M.   1976.  The Merck Index,  9th ed.  Merck and Co., Inc.,  Rahway,
New Jersey.

-------
Woodhouse, O.L.   1950.  The  carcinogenic activity  of  some petroleum  frac-
tions and extracts; comparative  results in tests  on mice repeated  after  an
interval of eighteen months.  Jour.  Hygiene.   48:  121.

-------
                                      No. 54
     Cresols and Cresylic Acid


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

           APRIL 30, 1980

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

-------
                                                  SJ-27-12


                   Cresol and Cresylic Acid




I.   INTRODUCTION

     Cjresols are methyl phenols with methyl group at the

o-, p-, m- position.  It has a molecular weight of 108, a

melting point of between 11-35°C and a boiling point of

between 191-203°C.  It is slightly soluble in water, but

soluble in alcohols, glycols, dilute alkalis, ether and

chloroform.  Cresylic acid is the refined product from coal

tar and contains the three isomers of cresol (the crude

product from coal tar is creosote).

     Cresols are quite stable in soil due to their antimicro-

bial properties.  o-cresol is degraded in air to quinones and

dihydroxybenzene by 03 with an estimated half-life of 1 day.

The m- and p- isomers are expected to behave similarly.

     Cresols are used as disinfectants, agricultural chemicals,

solvents, chemical intermediates, metal cleaners, and motor

oil additives.   p-cresol is permitted in U.S. as a food

flavoring and for fragrance in soaps, lotions and perfumes.

Annual production if 150 million pounds.  NIOSH1 estimates

that the annual environmental release of the mixed isomers is

30 million pounds.

II.  PHARMACOKINETICS
                                             «•
     Cresols are rapidly metabolized and thus unlikely to bio-

accumulate in mammals.2

III. EFFECTS ON MAMMALS

     A.   Carcinogenicity:  CAG^ concluded that the data base

-------
for this chemical is weak.  No data exist on which to determine




carcinogenesis in mice.  The literature cites three case




reports of cancer in humans occupational/ exposed.




     B.   Mutagenicity:  CAG^ concluded that cresols cause




chromosome fragmentation in plants.  No other mutagenicity




studies have been done.




     C.   Toxieity;  They are corrosive to the skin and




mucuous membranes and moderately toxic by ingestion and dermal




exposure.  The organs affected are CNS, liver, lung, kidneys,




stomach, eyes, and heart.  No epidemiological studies of




workers have been done.^-




IV.  EXISTING GUIDELINES




     The current occupational standard (TWA) is 5 ppm.  NIOSH^




recommends a lowering to 2.3 ppm.

-------
              DOSSIER

                ON

              CSZSOLS'
                BY
     Clement Associates, Inc.
 1055 Tnomas Jefferson Street, NW
     Washingtonr•D.C.   20007
          December, 1977
  Contract No. NSF-C-ENV77-15417

           Prepared, for

TSCA Interagency Testing Committee
         Washington, O.C.

-------
                            FOREWORD
     This dossier has been prepared by Clement Associates,  Inc.
 (Clement), in partial fulfillment of Contract NSF-C-SNV77-15417,
 sponsored by the National Science Foundation, to provide techni-
 cal support to  the Toxic Substances Control. Act  (TSCA)  Interagency
 Testing Committee.  The Committee is charged with the responsibility
 for making recommendations to the Administrator of. the  Environmental
 Protection. Agency  (EPA) regarding chemical  substances or mixtures
 which should be given priority by SPA for testing to determine ad-
 verse effects on. man or the environment.

     The dossier was designed to provide the Committee  with infor-
 mation on the chemical's physical.and chemical properties,  exposure
 characteristics/ and biological properties  in sufficient detail to
 support an. .informed' judgment on whether the substance should be given
 priority for testing.. The dossier is not intended to represent a com-
 prehensive critical review. 'Such a.review  could not be performed with
 the constraints imposed upon the Committee  (and, therefore, the con-
 tractor) by the statutory deadlines of TSCA.

     Faced with the task of preparing dossiers which could  be quick-
 ly assembled and yet contain sufficient information for the Commit-
 tee's purposes,. Clement proceeded along the following lines.

     Literature searches were conducted using the National  Library
 of Medicine's TOXLINE and the Environmental Mutagen Information
 Center  (EMIC)  automated data banks..  Each reference on  a list of
 sources of general information (see "General References" in biblio-
 graphy)  was reviewed.  Further- references and information were
 obtained from monographs, criteria documents, reviews,  and  reports
 available from government agency files and  trade association li-
braries.  Information received in response  to the Committee's July
 1977 Federal Register notice requesting information on  certain
 substances was reviewed.  Clement scientists relied upon, their own
knowledge of the literature- to augment the  data sources.

     In general, secondary sources were relied upon in  preparing
.the: dossiers.   When an article was judged to con-tain information
of major- significance or to. require a critical.* re view the primary
 source was consulted.  The text makes clear whether a primary or
secondary source of information was used.

-------
                    KEY TO ABBREVIATIONS
 TCLo - Lowest published toxic concentration
        - the concentration of a substance in air which has
          been reported to produce any toxic effect in animals
          or humans over any given exposure time.

 TDLo - Lowest published toxic dose
        - the lowest dose of a substance introduced by any
          route other'than inhalation over any given period
          of time that has been reported to produce any toxic
         . effect in animals or humans.

 LCLo - Lowest published lethal concentration'
        - the lowest concentration of a substance,  other than
          an LC50,  in air that has been reported to have
          caused, death in humans or animals over any given
          exposure  time.

 LDLo - Lowest published lethal dose
        - the lowest dose of a substance other than LD50
          introduced by any route other than inhalation over
          any given period of time that has been reported to
          have caused death in humans or animals.

 LC50 - Median lethal concentration
        - the concentration of a test material that kills 50
          per cent  of an experimental animal population
          within a  given time period.

 LD50 - Median lethal dose
        - the dose  of a test material, introduced by any route
          other than inhalation,  that kills 50'percent of an
          experimental animal population within a. given time
          period.

 LT50 - Median  Lethal  Response Time
      •Statistical  estimate  of the  time from dosage to  the
       death of 50  percent of the organisms  in  the population
       subjected to a  toxicant under specified  conditions.
TLm  - Median tolerance limit
       - the concentration of a test material at which 50 per
         cent of an experimental animal population are able
         to survive for a specified time period.

TLV®- Threshold limit value
       - the airborne concentration of a substance to which
         nearly all workers may be repeatedly exposed day
         after day without adverse effect.

-------
 TLV^TWA - Threshold limit value - tine weighted average
           - the time-weighted average concentration of a .
             substance for an 8-hour workday or 40-hour
             workweek, to which nearly all workers may be
             repeatedly exposed, day after day, without
             adverse effect.

 TLV^STZL- Threshold limit value - short term exposure limit-
           - the .maximal concentration of a substance to which
             workers can be exposed for up to 15 minutes
             without suffering acute or. chronic toxic effects.
            . No more than four excursions per day are per- •
             mitted.  There must be at least 60 minutes
             between•exposure periods.  The daily TLV-TWA
             must not be exceeded.
        «• • .                               •

 BOO      - Biochemical oxygen demand
           -a measure of the presence of organic materials
             which will be oxidized biologically in bodies
             of water.

NOHS Occupational Exposure:

         -  Rank
           - an ordering of the approximately 7000  hazards
             occurring in the workplace  from most common to
             least common .

         -  Estimated number of persons exposed
           -•includes  full- and part—time workers..  For hazards
             ranked 1  through 200,  the figure projected to
             national  statistics by NIOSH is given;  for the re.-
             maining hazards  the number  of people exposed given
             in the survey was multiplied'by a -fixed number to
             give  a rough estimate of  national exposure.   The
             fixed number used,  --30--/  is derived from the sta-
             tistical  sampling technique used in this survey.

i       -  insoluble

ss   .    — slightly soluble

s        -  soluble

vs       -  very soluble

00       -  soluble in  all proportions

bz       -  benzene

chl     -  chloroform

-------
 eth     - ether


 peth    - petroleum ether'


 ace     - acetone


 lig     - ligroin


 ale     - alcphol•


 CC1,    - carbon tetrachloride
    4

dil. aUc.  - dilute alkalis

     /
                                 ..'••••^
 CS2     - carbon disulfide


 os      -— organic  solvents


 oos     - ordinary organic  solvents

-------
                         CRESOLS  '

                       AN OVERVIEW


      There are three isomers  of  cresol:   o-cresol,  m-cresoi,

 and o-cresol.,^All three isomers as  well as  mixtures are art-

 icles of commerce .>  Cresols are  solid or liquid at  room tem-

 perature (melting  points 11-35°C).   They are slightly soluble

 ia  water and soluble ±a"organic  solvents.

      Total annual  production  of  cresols  in the United States  is

 probably in. excess, of 100 million pouncs.  They are used for

 a wide variety of  purposes/ including uses as disinfectants,

 solvents,, in ore flotation, and  as intermediates in the pro-

 duction  of phosphate esters and  phenolic resins. The number

 of  persons occupationally exposed to cresols is estimated to

 be  two million.  They are also present in a  number  of con-

 sumer products.,, including disinfectants, metal cleaners,  ana

 motor oil additives.

      Cresols are manufactured both from  petroleum and from

'coal.  The composition of the commercial products depends

 on  the method  of production and  upon the degree of.  refining.

 Cresols  are sold in a wide variety of grades,- varying- in com-

 position,  'color, and boiling  ranger   Technical grade cresols
                                             f
 commonly contain xylenols and phenol.  A less refined pro-

 duct  called creosote oil contains 10-20% by  volume  of tar from

 the coking process.

-------
     Cresols are relatively easily metabolized by mammals 'and
                                  *

micro-organisms and are unlikely to undergo significant bio-


accumulation.  They are moderately toxic to mammals by ingestion


and dermal exposure, and are corrosive to skin and other tissues.


No data are available on their toxicity by inhalation.  Little

             11
information is available on effects of chronic exposure.
                • *

     In one experiment all 'three isomers of cresol were re-


ported to promote the carcinogenicity of dimethylbenzanthracene


on mouse skin.  m-Cresol caused developmental abnormalities in*


toad embryos.  Otherwise, no significant information is avail-


able on the potential carcinogenicity, mutagenicity, or terato-


genicity of cresols.


     Cresols have a broad spectrum of toxicity to micro-organisms


and are used as disinfectants and fungicides.  There is little


other information on their potential toxicity to wildlife.

-------
                           CTESQLS

                            BART I

                             .INFORMATICS?
 I.  'Cresol  (mixed isomers)

 1.1  Identification      CAS No.  001319773
                       -NIOSHNo.  G059500

 1.2  Synonyms and»tTrade Names

      Cresylic acid;  methyl phenol;  hydroxytoiuene;
      trieresol;  cresylol
                                                           (G23,G21,G16)

.1..3  Chemical Formula and Molecular Weight

            OH

                                C7HgO     Mol. Wt.  108.15


                                                           (G23)

 1.4  Chemical and Physical Properties                •

      1..4.1   Description;       Admixture of isomers -in which
               .                 m-isomer predominates, obtained
                                rrom coal tar or petroleun;
                                colorless,  yellow or pinkish
                                liquid;  phenolic odor; combustible;
                                becomes  darker with age and on
                                exposure.to light.
                                                           (G21,G23)

      1.4.2   Boiling  Point;     191   - 203° C              (G21)

      1.4.-3   Melting  Point;  .    11   -  35° C '     '        (G21)

      1.4.4   Absorption Spectrometry;

                                No information found in  sources searched
                                                 y
      1.4.5   Vapor Pressure;    No information found in  sources searched

      1.4.6   Solubility;         Soluble  in alcohol,  glycol,
                      "          dilute alkalis,   ether,  chloro-
                                form;
                                Slightly soluble in water

                                                           (G21,G2S)

      1.4.7   Octanol/Water Partition Coefficient;

                      Log ?-..+. s 2.70'    (estimate)

-------
1.5  Production ana Use
     1,5.1  Production:
                          60      Million Ibs    (1968)
                          80      Million Ibs    (1973)
                                                             (G25)
     1.5,2  Use:
                As  a  disinfectant;  intermediate  in manufactur-
                ing of  phenolic  resins,  tricresyl  phosphate,
                salicylaldehyde,  coumarin,  and herbicides;  as
                an  ore  flotation agent;  as  a  textile  scouring  .^.
                agent;  as  an  organic  intermediate;  as a- -^-~""'
                factant
            Quantitative Distribution af Uses
                     Phosphate esters
                     Magnet wire
                     Antioxidants
                     Resins
                     Exports
                     Cleaning and disinfectant
                       compounds
                     Ore flotation
                     Miscellaneous
                                            Percent
                                               22
                                               15
                                               15
                                               15
                                               10
                                                6

                                                6
                                               11
                                              100
            Consumer Product Information;

                   .  Cresol is present in:

                     automotive parts cleaner
                     metal cleaner, stripper, degreaser
                     disinfectant
                     motor oil additive
                     carbon remover
                     embalming supplies
              Estimates
     1,S.J,  Release Rate;
                         30.4  Million Ibs
l.£,2  HOHS Occupational Exposure :

                Rank:  105

                Estimates no. of persons exposed t
                                                             (G21)
                                                            (G25)
                                                        (G35)
(G2S)
                                                        1,9 14, 000
                                                             6

                                                            (G29)

-------
                                    C3ESOT.S
H.  m-Cresol

1.1  Identification    CAS No. :  000108394
                     NIOSH No. :  G061250

1.2  Synonyms and Trade Names
                         i
     ra-Cresylic acid; n«ethylphenoi; 3-roethylphenol; l-hydroxy-3-^nethyl-
     benzene; nt-kresoi; ro-oxytoluene
              ~                                       '                  (G16)
                                 i>                                         *
1.3  Chemical Formula and Molecular Weight

            CH
                                 C-H-0         M3l. wt.  108.15


                                                                        (G22)
                                  *
1.4  Chemical and Physical Properties

     1.4.1  Description;      Colorless to yellowish liquid; phenol-like
                              odor    '
     1.4.2  Boiling Point;    202.2° C                '     .             (G22)

     1.4.3  Malting Point;     -11.5° C                       '"          (G22)

     1.4.4  Absorption Spectronstry:
                                      =214, 271,277,

                              logfc   =3.79,3.20,3.27  '              (G22)

     1.4.5  Vapor Pressure;    1 ma at 52.08 C                           (G22)

     1.4.6  Solubility;       Slightly soluble in water;  *
            •             •   Soluble in- hot water,  organic solvents;
                 . .   '  '       Soluble in all proportions in alcohol, ether.,
                              acetone, benzene and carbon' tetrachloride

                                                                        (G22)
                                                                         »
     1.4.7'  OctanolA?ater Partition Coefficient;

                              log' P^. = 2.37

-------
     Production and Use
                     No information  found in  sources  searched
     1.5,2  Use;     In disinfectants and fuaicants;.  in photographic
                     developers, explosives                              (G22)
                     •t
1.6  Exposure Estimates
                          i
     1.6.1  Release Hate;   .
                     No information  found in  grn_gr!ag  ^^gchgd
   .  1.6.2.  NOES Occsatlcna?. 5c»sure;
                     Rank:  2731   '
                               no. o£ r*>i'5j.iins exccsed:  9,000*
                            estimate                                     (G29)
1.7  Manufacturers
                     Kappers Co., Inc..                         .          (G24)

-------
                             CRESOLS



m.  oHZresol

1.1  Identification     CAS No.   .000095487
                       NIOSH No.   G063000

1.2  Synonyms  and  Trade Names

     o-Cresylic  acid';  o-methyl phenol;  2-nethyl phenol?
     orthocresol;  l-hydroxy-2-raethylbenzene;  o-hydroxy-
     toluene;  o-methylphenol;  o-oxytoluene;  2-hydroxy-  '
     toluene                   ~~
                                                          (G16)
                 5
1.3  Chemical  Formula  and Molecular Weicht
                          C7HgO         Mol. Wt.   108.15


                                                          CG22)

1.4  Chemical and Physical Properties

     1.4.1  Description;       White crystals; phenol-like odor;
                               combustible; becomes dark with age
                               and exposure to air and  light.

                                                          (G23,G21)

   .  1.4.2  Boiling Point;-     190.95°  C                  (G22)

     1.4.3  Melting Point;      30.94°  C    '              (G22)

     1.4.4  Absorption Spectrometry;

                         \ Wcl uSZT   A «•. A  •> M c MM*
                         A Max   s 219' 275 m*

                           log i = 3.71, 3.22             (G22)

     1.4.5  Vapor Pressure:    1 mm at  38.2° C            (G22)

     1.4.6  Solubility;        Soluble  in water and ordinary^
                     '.'         organic  solvents;
                               Very soluble Jn alcohol  and ether;
                               Soluble  in' all proportions ir.
                               acetone, benzene, caraon tetracnloride

                                                          (G22)

-------
     1.4.7  Octanol/Water Partition .Coefficient:
1.5  Production and Use
     I.S.I  Production:
                            Poct =3.40
      49..70U  Million Ibs
      20.481  Million ibs
      22.IS7  Million Ibs
(1972)
(1975)
(1976)
     1.5.2  User
Disinfectant; solvent
1.6  Exposure Estimates
     1.6.1  Release Rate:  15.b  Million Ibs
                                        (CIS)
(G28)
(G24)
(G24)
                                                             (G23)
                                        (G28)
     1.6.2  NOHS Occupational Exposure:
                     Rank:  1480
                     Estimates no. of persons exposed:  52/000*
                     *rough estimate                         (G29)
1.7  Manufacturers
              from coal tar:
                     Koppers Co., Inc.            *
                     Perro Corp.
              from petroleum:
                     Mericnem Co.
                     Ferro Corp.
                     Sherwin-Williams Co.
                                                             (G24J

-------
                             CSESOLS
IV.  £-Cresol

1.1  Identification    CAS No.:  000106445
                     NIOSH NO.:  G064750

1.2  Synonyms and frrade Names
                      i
     4-Cresol; £-cresylic acid; l-hydroxy-4-roethylbenzene; £-
     hydroxy toluene; 4 -hydroxy toluene; £-Kresol; l-methyl-4-
     hydroxybenzene; £-methylphenol; 4-methyiphenol; £-oxyto-
     luene; para-cresol; pa^ramethyl phenol           "~
                                                             (G16)

1.3  Chemical Formula and Molecular Weight

          OH

                  '         C HO         Mol. wt.  108.15
                            7 8
          CH
            3                                                (G22)

1.4  Chemical and Physical Properties

     1.4.1  Description;   '   Crystalline mass? phenol-like
                  "            odor
                                                             (G21)

     1.4.2  Boiling Point;    201.9° C '                      (G22)

     1.4.3  Melting Point;     34.8° C                       (G22)

   •  1.4.4  Absorption Spectrometry ;
                     log £        » 3.23                     (G22)
                                                y
     1.4.5  Vapor Pressure:   1 mm at 53.0° C                (G22)

     1.4.6  Solubility;       Slightly soluble in water;
                     '         Soluble 'in hot water, organic solvents;
                              Soluble in all proportions in. alcohol,
                              ether, acetone, benzene and carbon
                              tetrachloride
                                                             (G22)

     1.4.7  Octanol/Water Partition Coefficient

                         poct = 2-35                        '

-------
1.5  Production and Use
     1.5.1  Production;
                     No information found in sources searched  -
     1.5.2.  Use;     As a chemical- intermediate              (G24)
1.6  Exposure Estimate
     1.6.1  Release Rate;
                     No information found in sources searched
     1.6.2  NOES Occupational Exposure
                     Rank:  2466
              . •     Estimated no. of persons exposed:.  14,000*
                     •rough estimate
                                                             CG29)
1.7  Manufacturers
                     Sherwin-Williams Co.
                                                             (G24)

-------
                                                        CBFSOIfi

                                              SUMMMTC OF QIARAOTERISTICS
    Name
  Solubility
  Cresol          s in ale, glycol,
  (mixed isomers) Ail. alk, eth,
                  chl.
                  ss  in II-O
   o-Cresol
   m-Cresol
                                      LogP
                        oct
                     2.70
ci
s in H20 and COS,
vs in ale and eth.
oo in ace, bz, OCl..
                     3.40
ss in 1!2O; s in hot  2.17
lUO, os;^0 in ale,
eth, bz, aoe, OCl.
 ss in I120| s in
 hot II2O, bsf?o in
 ale, eth, bz, ace,
   L4
                                        '2.35
  Estimated
Environmental
  Release
(Million Ibs)

   30.4
   15.6
  Production
(Million Ibs)
          t

~60   (1968)
— 80   (1973)
  49.7  (1972)
  20,481(1975)
  22.187(19761
Estimated no.
of persons
exposed
 (occupational)

 1,914,000
    52,000
                                                                      9,000
                                                                      14,000
          Use

Disinfectant; phenolic
resins; tricresyl «^x>s-
pliate; ore flotation;
textile scouring agent;
organic intermediate;
mfg.  of salicylaldehyde
coumarin, and herbicides
surfactant

Disinfectant, solvent
                                                    In disinfectants,  fumi-
                                                    gants,  pliotographic
                                                    developers,  explosives

                                                    cyclic intermediate
      No information found in sources searched.

-------
                         CRESOLS
                         PART  II.
                  BIOLOGICAL PROPERTIES
                         ^
2.1  Bioaccumulation
     Log octahol/water partition,  coefficients  are 3.40,  2.37,  and
2.35 for the a-, m-, and £-isomers,  respectively (CIS).  The high
partition coefficient of the £-isomer  is  due to the steric effect
of the methyl group on the hydroxyl  group.   The high octanol/   .
water partition coefficients of the  cresols  indicate that bio-
accumulation in aquatic  organisms is a possibility, but specific
data on such bioaccumulation are  not available. . By analogy with
phenol, which appears to be completely eliminated from the body
within 24 hours  (G19), it is expected  that cresols would not be
bioaccumulated in mammals'.  Cresols  in waste waters near indust-'
rial plants are reported to undergo  rapid biodegradation (G14),
which indicate-s that cresols, like phenol, are  relatively easily
metabolized.
2.2  Contasanants and Envircroental Degradation or Conversion
     Products
     Cresols are sold in a wide variety of technical and special
grades, classified by color and distillation range (G2S).  The
composition of the various materials depends upon the starting
material and the method  of production.  A major source of cresols
is the. tar-acid oil obtained as a by-product of coking of. coal (G25)
     Cresols (boiling above 204°C)/  available  as a mixture of  o-,
m-, and p_-isbmers from tar acids,  are called  cresylic acid.  A  less
refined product called creosote- oil  contains i.0-20% by volume  of
the tar from the coking  process;  it  is used  as a wood preservative
(G2S).  Creosote oil may contain  polynuclear aromatic hydrocarbons.
Xylenols and phenol are  common impurities (or  ingredients) of  tech-
nical grade cresols  (G25).

-------
     The high environmental stability of the cresols in soils

 (owing to their antimicrobial properties) contributes to their
widespread use as wood perservatives.  £-Cresol is degraded by
the hydroxyl radical and ozone in air and by organic peroxide
radicals in water; half life estimates are less than 1 day in
air and 10 days in water  (G14) .  The m- and p_-isomers are ex-
pected to behave similarly.  Environmental degradation is likely
to be by air oxidation to give quinones and dihydroxybenzenes  (G14)
               '»

     Biodegfadation'products of cresols by sewage microorganisms
include carbon dioxide, methane, 3-methylcatechol, 2-hydroxy-6-
oxahepta-2,4-dienoic acid, oxalic acid, pyrocatechol,carboxylic
acid, and salicylic acid  (G14).  By analogy with phenol, cresols  •
may be methylated in tije environment to form the corresponding

anisoles.      •             • .
2.3  Acute Toxicity

     The NIOSH Registry of Toxic Effects of Chemical Substances
(G16) reports the acute toxicity of cresols as follows:
Substance   Parameter
Cresol

o-Cresol
"^*









LD50
LD50
LD50
LD50
LD50 •
LDLo
LDLo-
LDLO
LD50
LDLo
LDLo
LDLo
LDLo
m-Cresol
LD50
LD50
LD50
LD50
LDLo
LDLo
LDLO
LD50
LDLO
LDLo
LDLO
LDLo
  Dosage

1454 mgAg
 861 mgAg

 121 mgAg
1100 mgAg
 344 mgAg
 410 mgAg
  55 mgAg
 940 mgAg
1380 mgAg
 450 mgAg
 180 mgAg
 360 mgAg
 200 mgAg

 242 mgAg
 620 mgAg
 350 mgAg
 828 mgAg
 450 mgAg
 180 mgAg
1400 mgAg
2050 mgAg
 500 mgAg
 280 mgAg
 100 mgAg
 250 mgAg
  Animal

   rat
  mouse

   rat
   rat
  mouse
  mouse
   cat
  rabbit
  rabbit
  rabbit
  rabbit
guinea pig
   frog •*

   rat  '
   rat
   rat
  mouse
  mouse
   cat
  rabbit
  rabbit
  rabbit
  rabbit
guinea pig
   frog
     Route

     oral
     oral

     oral
     skin
     oral
  subcutaneous
  subcutaneous
     oral
     skin  '
  subcutaneous
  intravenous.
intraperitoneal
  subcutaneous

     oral
     skin
    unknown
     oral »
  subcutaneous
  subcutaneous
     oral
     skin
  subcutaneous
  intravenous
intraperitoneal
 .subcutaneous

-------
 (continued)
 Substance     Parameter      Dosage        Animal  .      Route

 p_-Cresol        LD50        207 mg/kg        rat          oral
                LD50        705 mg/kg        rat       '   skin
                LD50        344 mg/kg       mouse    .     oral
                LOLo  •      150 mg/kg       mouse      subcutaneous
                LD50        160 mg/kg       mouse        unknown
                LD.LO  '   _   80 mg/kg        cat       subcutaneous
                LDLo     *   620 mg/kg       rabbit     .   oral
                LD50  •      301 mg/kg      .rabbit        skin
                LDLo        300 mg/kg       rabbit     subcutaneous
                LDLo        180 mg/kg       rabbit     intravenous
                LDLo        100 mg/kg   '  guinea pig intraperitoneal
                LDLo   • •   150 mg/kg        frog      subcutaneous

      Cresols are rated as moderately toxic to humans (G4).   Acute
 exposures can cause  muscular weakness, gastroenteric  disturbances,
 severe depression, collapse,  and death (G38).   Organs attacked by
 cresols include the  central nervous system, liver, kidneys,  lungs,
 pancreas, spleen, eyes, heart, and skin  (G38)..  The type of exposure
 to cresols determines,  in  part,, the toxic effects. Cresols  are highly
 corrosive to  any tissues they contact (G5)  and are readily absorbed
 by skin and mucous membranes.   Systemic  effects,  including death,
 occur after dermal exposure-.   Because  their vapor pressure is low
 at 25°C, cresols do .not usually constitute an  acute inhalation
 hazard.  No-data are available on the toxicity of cresol vapors to
 humans (G39).

     - In animals, cresol toxicity varies with  the isomer, the species
 and the route  of exposure.   Reported LDSOs- vary from  a low of 121
mg/kg ia the  rat (oral,  pj-cresol)  to a high of 2050 mg/kg in the
 rabbit (skiiu  m-cresol)  (G16).   Evidence for different biological.
 effects of the three isomers includes the observation that, the ratios
between the LDSOs of the least toxic and most  -toxic isomexs  vary from
 as low as 1.8  (cutaneous,  rat)  to as high as 6.8  (cutaneous,'rabbit).
Furthermore, £-cresol,  but neither o- nor m-cresol, produced.
permanent, pigment loss  in  the hair of mice (1).

 2.4  Other Toxic Effects

      Chronic  poisoning from absorption  of cresols through the skir.,

-------
 mucous membranes or  respiratory tract has  not bean well studied.
 Campbell  (2) presented  incomplete  studies  showing that  exposure
 of mice to an atmosphere  saturated with cresylic acid vapors for
 1 hr/day on consecutive days  caused  irritation of the nose and
 eyes./ and death in some animals.   Uzhdavini  e£ al.   (3)  performed
 poorly documented studies on  the chronic effects of oj-cresol in-
 halation.  In mice,  £hey  found  evidence for:  tail necrosis;  slowed
 weight gain; cellular degeneration of the  CNS;  respiratory tract
 hyperemia, edema, proliferation of cellular  elements, and  hemor-
 rhagic patche's; myocardial fiber degeneration;  and protein deposits
 in liver and kidney  cells.  In  rats,  they  reported alterations in
 a conditioned reflex, and alterations in both peripheral blood and
 bone marrow elements.

       The Threshold  Limit Value established  by  the  ACGIH for cresols
 is 5 ppm (Gil).

 2.5  Carcinogenicity
      o,  m, and p_-Cresol have  been  reported to promote the  carcino-
 genicity of dimethyIbenzanthracene (DMBA)  in skin tests  with mice
 (4).  They were slightly less active  as promoters than phenol  in
 this experiment (see table below).
                        No. mice         Avg.  no.         %  survivors
                         survivors/        papillomas       with
      Promoter*         original no.      per  survivor     papilloma

   Benzene Control         12/12             0               0
   20% phenol              22/27              1.50            64
   20% o-cresol            17/27              1.35            59
'   20% m-cresol            14/29             0.93            50
   20% £-cresol            20/28              0.55            35  - '

   *  Initiator:   0.3% DMBA in acetone.   Promoter  in benzene.
      Data at 12 weeks.

      No  carcinogenicity tests conducted  with  cresols  alone have been
 found in the searched literature.

-------
 2.6   Mutagenicity

      In onion  root  tips,  however,  m- and p_-cresol' produced cyto-
 logical abnormalities  including  stickiness,  erosion,,  pycnosis,
 C-mitosis, polyphoidy,  and chromosome fragmentation(5).   o-Cresol
 did not appear as active  (5).  These chromosomal  effects do not
 necessarily imply that the cresols will  have genetic  activity in
 mammals.  No other mutagenicity  studies  were found  in the searched
 literature.
                   •                  .    -.            •

 2.7   Tera'togenicity

      No systematic  studies of  the  teratogenic  potential  of the
 cresols have been found.  The  only information available is
 on the effect  of m-cresol on embryos of  a toad (Xenopus  laevis)
 at the neural  tube  stage  of  development  (6).  Concentrations of
 20 to 80 ppm,  m-cresol caused  two  developmental- abnormalities:
 edema, and tail flexion..

 2.8   Metabolic Information

      Very little is known about  the  metabolic  fate  of cresols
 in mammals. .One study showed  that the cresols are  excreted in
 rabbit urine primarily as oxygen conjugates:  60-72%  as
 ether glucuronides  and 10-15%  as ethereal sulphates (7).
 Paper chromatography shoved  that o-  and  m-cresol  are
 hydroxylated and that  pj-cresol forms £-hydroxybenzoic acid
 p_-Cresol glucuronide was  isolated  from the. urine  of rabbits
 dosed by stomach tube with pj-cresol,  whereas^o- and m-cresol
were metabolized to  2,,5-dihydroxytoluene (7) .  No  studies
have  been traced of the biological effect of these  and other
possible metabolites of the  cresols.

-------
 2.9  Ecological  Effects

     The  96-hour  LC50 of  o-cresol to  channel catfish (Ictalurus
 punctatus) is reported to  be  67 mg/1  (8).   In tests with
 perch and sunf^.sh,.lethal  concentrations  (not LCSOs)  were
 determined in 1  hgur  exposures.   In perch (Perca fluviatilis),
 lethal concentrations for  o-, m-  and £-cresols were in the
 range 10-20 ppm  (9).  The  Aquatic .Toxicity Rating (96-hour
 TLm, species unspecified)  for cresols  is  listed as LO-1 ppm
 (G16).  Although o-cresol  is  less toxic to juvenile Atlantic
 salmon (Salmo salar) than  p_-cresol, the salmon avoided
 o-cresol  more efficiently  (10).
     Cresols have  a broad  spectrum of  toxicity to microorganisms,
They are  used as disinfectants and as  fungicides to protect
materials such as  wood.  They are also reported to be active
 against mycoplasmas  (11),  viruses (12), and .plant galls (13).

2.10 Current Testing and Evaluation

     A criteria  document on cresols is planned for completion
in 1977 by NIOSH.

-------
                            REFERENCES
  1.   Shelley,  W.  B.  o-Cresol:  cause  of  ink-induced hair depitaent-
      ation  in  mice.  ""Brit.  J.  Dematol.   90:169-174  (1974).

  2.   Campbell,  J.  Petroleum cresylic acids - a study of their toxi-
      city and  the* toxicity  of  cresylic  disinfectants.  Soap Sanit.
      Chem.   17:103-111 (1941).

  3.   Dzhdavini/ E.R.,  Astafyeva,  l.K.,  Mamayeva,  A.A. and Bakhtizina,
      G.Z.   Inhalation  toxicity of o-cresol.   Tr.  Ufiia.  Nauchno-Issled
      Inst.  Gig. Profzabol.   7:115-119  (1972).   (Russian)

  4.   Bontwell,  R.K., and Bosch, O.K.  The tumor-promoting action of
      phenol'and related compounds for mouse skin.   Cancer Res.
      19:413-424 .(1959).

  5.   Sharma, A.K.  and  Ghosh, S.   Chemical basis of the  action of
      cresols and  nitrophenols  on  chromosomes.   The Nucleus  8:183-
      190  (1965).

  6.   Johnson,  D.A.  The effects' of meta-cresol on the embryonic
      development  of the African.Clawed  Toad,  Xenoous  laevis.
      J. Ala. Acad. Sci.  44:177   (1973).

  7.   Bray,  E.G., Thorpe, W.V.,  and White,  K.   Metabolism of
   -   derivatives  of toluene..   4.   Cresols..   Biochem.  J.   46:275-
      278  (1950).                                   .             v

  8.   Clemens,  H.P., and Sneed,  K.E.  Lethal dose  of several com-
      mercial chemicals for  fingerling channel catfish.   U.S.  Fish.
      Wildlife  Serv. Spec. Sci.  Rep. Fisheries  316 (1959).  .

  9-.   Jones, J.R.E. Fish'.and River Pollution.   Butterworths, London
      (1964).  Pp 118-153.

10.   Zitko, V., and Carson, W.G.   Avoidance of organic  solvents
      and substituted phenols by juvenile  Atlantic  salmon.   Fish-
      eries  Res.. Board Can.  MS*  Rep.  1327  (1974)..
            .-       '                            >
11..   Kihara/K., Sasaki, T., and  Arima, S.   Efeect of antiseptics
      and detergents on Mycoplasma.  Igaku 7.Q  Seibutsugaku, 83:5-8
      (1971).

12.   Sellers, R. F.  The inactivation of  foot-and-mouth disease
     virus by chemicals and disinfectants.  Vet. Rec.,  83:504-506
      (1963).

13.  Schrothr M.N. and Hildebrand, B.C.  A chemotherapeutic treatment
     for selectively eradicating  crovm gall  and olive knot neoplasms.
      Phytopath.  53':848-854  (1954).

-------
                       GENERAL REFERENCES
  Gl.   Browning,  E.   Toxicity and Metabolism of Industrial Solvents.
       Elsevier,  Amsterdam (1965).
               '•
  G2.   Browning,  E.   Toxicitv of Industrial  Metals,  2nd ed.   Apoleton-
       Century-Crofts,  New York  (1969).

  G3.   Fairhall,  L.T.   Industrial' Toxicology,  2nd  ed.   Williams •
       & Wilkins  Co.   (1969).
                  •                                   -
  G4.   Sax, N.I.   Dangerous  Properties of  Industrial Materials,
       3rd-«d.  Reinnold Publishing  Corp., New York  (1975).

  G5.   Chemical Safety  Data  Sheets.  Manufacturing Chemists  Asso-
       ciation, Washington,  D.C.

  G6.   Industrial Safety Data  Sheets.  National Safety  Council,
       Chicago, Illinois.

  G7.   Shepard, T.H,  Catalog  of  Teratogenic Agents.  Johns  Eopkins
       University Press, Baltimore  (1973).

  G8.   Thienes, C.L..  &  Haley,  T.J.   Clinical Toxicology.   Lea &
       Febiger, Philadelphia (1972).

  G9.   IARC Monographs  on  the  Evaluation of  Carcinogenic Risk of
       Chemicals  to Man.   Lyon, France.  WHO,  International  Agency
       for Research on  Cancer.

G10.   Debruin, A.  Biochemical Toxicology of  Environmental  Agents.
       Elsevier/North-Holland,  Inc., New York  (1976).

Gil.   Threshold  Limit  Values  for Chemical Substances^and  Physical
      Agents in  the Workroom  Environment with Intended Changes
       for 1976.  American Conference of Government Industrial
      Hygienists.
                                               Jr
G12.   Chemicals  Being-  Tested  for Carcinogenicity  by the Bioassay
      Program, DCCP.  National Cancer Institute (1977).

G13.  Information Bulletin on the Survey of Chemicals  Being Tested
      For Carcinogenicity, No. 6.  WHO, Lyon,  France (1976) ,

G14.  Brown,  S.L., et_  al_.   Research Program on Hazard  Priority
      Ranking of Manufactured Chemicals, Phase II - Final Report
      to National' Science Foundation.   Stanford Research  Institute,
     'Menlo Park, California  (1975).

-------
 G15.   Dorigan,  J.,  et al.   Scoring of Organic Air Pollutants,
       Chemistry,  Production and Toxicity of Selected Synthetic
       Organic Chemicals.   MITSZ,  MTR-7243 (1976)t

.G16.   NIOSH Registry of Toxic Effects of Chemical Substances (1976).

 G17.   Kirk-Othmer Encyclopedia of Chemical  Technology.   Edited
       Standen,A(ed.),Interscience Publishers,  New York  (1963,  1972).  .
                  >,
 G18.   Survey of Compounds  Which Have Been Tested  for Carcinogenic
       Activity  Through 1972-1973  Volume.  DHEW Publication No.
       NIH73-453,  National  Cancer Institute,  Rockville,  Maryland.

 G19.   Criteria  for  a Recommended Standard - Occupational Exposure
       to  ....  / praparea ny NIOSH .
          :                                      .
 G20.   Suspected Carcinogens - A. subfile  of  the NIOSH Toxic Sub-
       stance List (1975).

 G21.   The Condensed Chemical. Dictionary,  9th ed.   Van Nostrand
       Reinhold  Co.,  New York (1977).

 G22.   Handbook  of Chemistry and Physics    ,  57th ed.   The  Chemical
       Rubber Company,  Cleveland,  Ohio (1976).

 G23.   The Merck Index,  9th ed.  Merck &  Co.,  Inc.,  Rahway,  N.J.
       (1976) .

 G24.   Synthetic Organic Chemicals, United States  Production and
       Sales.  1966-76.    ' U.S.  International  Trade Commission,  U.S.
       Government  Printing  Office,  Washington,  D.C.

 G25.   Lowenheim,  F.A.  & Moran,  M.K..   Faith.  Keyes,  and  Clark's
       Industrial Chemicals,  4th ed.   John wiley & Sons,  New York
       (1975).

G25.   Gosselin, Hodge,  Smith &. Gleason.  -Clinical Toxicology of
       Commercial Products,  4th  ed.  The Williams  and Wilkins Co.,
       Baltimore (1976).

G27.   Chemical Consumer Hazard  Information  System.   Consumer Product
       Safety Commission, Washington,  D.C. (1977)^

G23.  A Study of Industrial  Data on Candidate  Chemicals  for Test-
       ing.  Stanford Research  Institute,  Palo  Alto,  California  (1976,7)

G29.  National Occupational  Hazards Survey  (NOHS).   National
       Institute for"Occupational Safety and Health,  Cincinati  '
      Ohio  (1976).

G30.  The Aldrich Catalog/Handbook of Organic  and 3lochs-teals.
      .Aldrich' Chemical  Co.,  Inc.  (1977-78).

-------
G31.  McCutcheon's  Functional Materials 1977 Annual.  McCutcheon
      Division, MC  Publishing  Co.  (1977).
G32.  Hampel  & Hawley.   The Encyclopedia of Chemistry.  3rd ed.
      Van Nostrand  Reinhold Co.,  New YorK 11973} .
G33.  Casarett, L.  J.  &  Doull, J.  Toxicology, the Basic Science
      of Poisons.,  Macmillan Publishing Co." Inc., New York   (1975).
G34. "EPA/Office  of Research and Development, Chemical Production.
G35.  CTCP/Rochester Computer Service.  (See Reference No. G26.)
G36.  Leo, A., Hansch, C.  & Elkins, D.  Partition coefficients.
      and their uses.  . Chem. Rev. 71:525-616 (1971).
G37.  1977-78 OPD Chemical Buyers Directory.
G38.  Patty,  F.A. Industrial Hygiene and Toxicology, Vol. 2, 2nd ed.
      Wiley Interscience,  New York (1963)..
G39.  Directory of  Chemical Producers.  Stanford Research Institute,
      Menlo Park, California  (1977).

-------
                                      No. 55
           Crotonaldehyde


  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.

-------
                          CROTONALDEHYDE








SUMMARY



     Crotonaldehyde is not expected to  be overly persistent  in



water or the atmosphere.   It is not expected to bioconcentrate.



It has been detected in finished drinking water and  in  sewage



treatment plant, effluents.



     An increased incidence of malignant neoplasms has  been



observed in workers at an aldehyde factory who were  exposed  to



crotonaldehyde, among other substances.  There is, however,  no



indication that crotonaldehyde was the  causative factor in the



excess incidence of cancer.



     Pathologic change was observed in  the testes of mice receiv-



ing crotonaldehyde in the drinking water (0. 2 g/1) for  one month.







I.   INTRODUCTION



     Crotonaldehyde (CH3CH=CHCHO; molecular weight 70.1) is  a



water-white, mobile liquid with a pungent, suffocating  odor



(Hawley, 1977).  It has the following physical/chemical



properties (U.S. EPA, 1979a; Hawley, 1977):



                   Boiling Points       102"C



                   Melting Point:       -60°C



                   Vapor Pressure:      19 mm Hg at 20"C



                   Solubility:          very soluble  in  water;



                                        also soluble  in  many



                                        organic solvents.

-------
     A review of the production range  (includes  importation)

statistics for crotonaldehyde  (CAS No. 4170-30-3) which was

listed in the initial TSCA Inventory  (1979b) has shown that

between 1 million and 8 million pounds of this chemical were

produced/imported in 1977.—'

     Crotonaldehyde is used as an intermediate in the manufacture

of n-butanol and crotonic and  sorbic acids; solvent in the

purification of mineral oil; intermediate in resin and rubber

antioxidant manufacture; and in organic syntheses (NCI, 1978).

Other uses.are as a warning agent in  fuel-gas, insecticides,

leather tanning, production of rubber accelerators, and as an

alcohol denaturant (Hawley, 1977).



II.  ENVIRONMENTAL FATE

     Formaldehyde, the simplest aldehyde, is almost entirely

hydrated in water, thus it is  nonvolatile and is inactive toward

photochemical dissociation.  Higher aldehydes, such as crotonal-

dehyde, are less hydrated in water, more volatile, and somewhat

active toward photochemical degradation  (Calvert and Pitts,

1966).  Crotonaldehyde is expected to be oxidized in water at the

double bond to form keto aldehydes and cleavage products  (U.S.

EPA, 1977).  Crotonaldehyde biodegrades at a slow to moderate
   This production range information does not include any pro-
   duction/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 Inven-
   tory, including production range information, are subject to
   the limitations contained in the Inventory Reporting Regula-
   tions (40 CFR 710).

-------
rate; acclimated bacteria can speed the degradation  rate  (U.S.



EPA, 1979a).  In general, neither crotonaldehyde  nor its



oxidation products are expected to be overly persistent in  water



(U.S. EPA, 1977).



     In air, aldehydes are expected to photodissociate to RCO and



H atoms rapidly and competitively with their oxidation by HO



radical.  The projected half-life is on the order of 2 to 3 hours



(Calvert. and Pitts, 1966).  Oxidation of crotonaldehyde by  HO



radical should result in addition at the double bond to form a.



keto aldehyde (U.S. EPA, 1977).  Crotonaldehyde is a. reactive



component of auto exhaust and may contribute to smog (Dimitriades



and Wesson, 1972).



     B.   Bioconcentration



     Crotonaldehyde is not expected to bioconcentrate (based on



its similarity to acrolein) (U.S. EPA, 1977).



     C.   Environmental Occurrence



     Crotonaldehyde has been detected in finished drinking  water,



sewage treatment plant effluents (U.S. EPA, 1976), in wastewater



used for irrigation of potatoes (Dodolina _et_ _al_.,  1976),  and the



atmosphere (IARC, 1976).



     Crotonaldehyde occurs naturally in essential oils extracted



from the wood of oak trees (Egorov, 1976).  It has also been



found in the volatiles from cooking mutton  (Nixon _et> _al_., 1979)



and in tobacco and tobacco smoke constituents  (Pilott, 1975).

-------
III. PHARMACOKINETICS



     Although no information was found specifically on the metab-



olism of crotonaldehyde, it is probably oxidized to an acid and



subsequently to CC^ in the same manner as other small aliphatic



aldehydes.  Crotonaldehyde is a potential alkylating agent by the



metabolic formation of an activated epoxy derivative at the



double bond and via reaction with amino groups of cellular



macromolecules (NCI, 1978).








IV.  HEALTH EFFECTS



     A.   Carcinogenicity



     An increased incidence of malignant neoplasms has been



observed in workers at an aldehyde factory who were exposed to



acetaldehyde, butyraldehyde, crotonaldehyde, aldol, several



alcohols, and longer chain aldehydes.  Crotonaldehyde was found



in concentrations of 1-7 mg/m .  Of the 220 people employed in



this factory, 150 had been exposed for more than 20 years.  Dur-



ing the period 1967 to 1972, tumors were observed in nine males



(all of whom were smokers).  The tumor incidences observed in the



workers exceeded incidences of carcinomas of the oral cavity and



bronchogenic lung cancer expected in the general population and,



for the age group 55-59 years, the incidence of all cancers in



chemical plant workers.  There is no indication that crotonalde-



hyde was the causative factor in the excess incidence of cancer



(Bittersohl, 1974,  1975).

-------
     B.   Mutagenicity

     Schubert (1972) reported chromosome breakage  in human  lymph-

ocytes exposed to crotonaldehyde in vitro.  When tested  in

Salmonella typhimurium (tester strains TA1535, TA1537, TA1538,

TA100, and TA98) both in the presence and absence  of a metabolic

activation system, crotonaldehyde was nonmutagenic.  It  also

failed to increase the incidence of mitotic recombination in

Saccharomyces cerevisiae D3 in the presence and absence  of  a

metabolic activation system (NCI, 1978).

     C.   Reproductive Effects

     Pathologic change was observed in the testes  of mice one

month following a single intraperitoneal injection of crotonalde-

hyde  (1 mg/mouse).  In a related study, similar changes  were

observed in the testes of mice receiving crotonaldehyde  in  the

drinking water (0.2 g/1) for one month (Auerbach _et_ al. , 1977;

Moutschen-Dahmen et al., 1975; Moutschen-Dahmen et al.,  1976).

     D.   Other Toxicity

     Skog (1950) studied the effects of lower aliphatic  aldehydes

in rats and mice.   When administered subcutaneously or by

inhalation, crotonaldehyde caused lung edema and mild narcosis.

Death was delayed and probably resulted from the lung damage.

     With cats, similar effects were seen, with death due to lung

edema or bronchial pneumonia occurring within 24 hours for  injec-

tion and between 6 and 48 hours for inhalation studies (Skog,

1950).
                                                          »
     The oral 1^50 for crotonaldehyde in the rat is 300  mg/kg;

the 30-minute LC5Q in the rat is 4000 mg/kg.   The  rabbit dermal

LD5Q is 380 mg/kg (NIOSH, 1979).

-------
     E.   Other Relevant Information



     A case of apparent sensitization to crotonaldehyde has been



reported in a laboratory worker who handled "small" amounts of



the material (ACGIH, 1971).



     Crotonaldehyde is a strong mucous membrane irritant (NIOSH,



1978).








V.   AQUATIC EFFECTS



     The 96-hour LC^Q (partial flow-through system) for crotonal-



dehyde in bluegill sunfish is 3.5 ppm; in tidewater silversides



the 96-hour LC5Q is 1.3 ppm (Dawson, 1975/1977).








VI.  EXISTING GUIDELINES



     The OSHA standard for crotonaldehyde in air is a time



weighted average (TWA) of 2 ppm (39CFR23540).
                                i

-------
                            References
ACGIH. American Conference  of Governmental and Industrial
Hygienists, Documentation of the threshold limit values,
Cincinnati, Ohio.  1971.

Auerbach, C. _et_ al.  Genetic and cytogenetical effects of
formaldehyde and related compounds.   Mut.  Res.  39, 317-362, 1977.

Bittershol, G. Epidemiological investigations on cancer in
workers exposed to aldol and other aliphatic aldehydes. Arch.
Geschwalstforsch.  43,  172-176,  1964.

Bittersohl, G. Env. Qual. Safety _4,  235-238, 1975. (as. cited in
NCI, 1978).

Calvert, J.G. and J. N.  Pitts.   Photochemistry.  Wiley and Sons,
New York, 899 pp.  1966.   (as cited  in U.S.  EPA, 1977).

Dawson, G. W. _et_ aL.  The acute toxicity of 47 industrial chemi-
cals to fresh and  salt  water fishes.   J.  Hazardous Materials _1_,
303-318, 1975/1977.

Dimitriades, B. and T. C. Wesson.   Reactivities of exhaust
aldehydes.  J. Air Poll. Contr.  Assoc.. 2(1), 33-38, 1972.

Dodolina, V. T. _et_ _al_.   Vestn.  S-Kh.   Nauki (Moscow) _6_, 110-113,
1976.   (as cited in NCI, 1978).

Egorov, I. A. _et_ _al_.  Prikl.  Biokhim.  Mikrobiol.   12(1), 108-112,
1976.   (as cited in NCI, 1978).

Hawley, G. G. 1977.  Condensed Chemical Dictionary, 9th edition.
Van Nostrand Reinhold Co.

IARC  (International Agency  for Research on Cancer).  IARC mono-
graphs on the evaluation of carcinogenic risk of chemicals to
man. 13, 311, 1976.

Moutschen-Dahmen, J. _et_ _al.  Genetical hazards of aldehydes from
mouse  experiments. Mut. Res.  29(2),  205,  1975.

Moutschen-Dahmen, J. et^ ^1^.  Cytotoxicity and mutagenicity of two
aldehydes:  Crotonaldehyde  and butyraldehyde in the mouse.   Bull.
Soc. R. Sci. , Liege _45_, 58-72,  1976.  (as cited in NCI, 1978).

NCI (National Cancer Institute).   Chemical Selection Working
Group.  September  28, 1978.                                '

NIOSH  (National Institute for Occupational Safety and Health).
Information Profiles on Potential Occupational Hazards-Classes of
Chemical. 1978

-------
NIOSH  (National  Institute  for  Occupational Safety and Health).
Registry of Toxic  Effects  of Chemical Substances.  1979.

Nixon, L. N. _et_ _al_. Nonacidic constituents of volatiles from
cooked mutton.   J. Agric.  Food Chem.  27(2),  355-359, 1979.

Pilott, A. _et_ _al_.  Toxicology _5_,  49-62,  1975.  (as cited in NCI,
1978).

Schubert, J.  et_  ai.  EMS  Newsletter _6_, 17, 1972.  (as cited in NCI,
1978).

Skog, E. A toxicological investigation of lower aliphatic alde-
hydes I. Toxicity  of  formaldehyde, acetaldehyde, propionaldehyde,
and butyraldehyde; as well as  of acrolein and crotonaldehyde.
Acta Pharmacol. j6, 299-318, 1950.   (as cited in NIOSH, 1978).

U.S. EPA.  Frequency  of  organic compounds identified in water.
PB-265 470, 1976.

U.S. EPA.  Review  of  the Environmental Fate of Selected Chemi-
cals.  EPA-560/5-77-003, 1977.

U.S. EPA. Oil  and  Hazardous Materials.  Technical Assistance Data
System (OHMTADS  DATA  BASE), 1979a.

U.S. EPA. Toxic  Substances Control Act Chemical Substances Inven-
tory, Produciton Statistics for Chemicals Listed on the Non-
Confidential  Initial  TSCA  Inventory,  1979b.
                                 Sf

-------
                                      No,  56
              Cyanides


  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.

-------
                           CYANIDES
                           SUMMARY
     Cyanide is well-known as an acute, rapidly acting poison
which has caused numerous deaths, primarily in occupational
situations.  The mechanism of cyanide intoxication is attrib-
utable to the biochemical inhibition of cellular respiration,
which produces a condition resembling acute hypoxia.  De-
spite the considerable potency of cyanide as an acute poison,
repeated sublethal exposures do not result in cumulative ad-
verse effects in animals or man.  In a chronic feeding study
in rats, a no observable adverse effect level (NOAEL) was
found to be 12 mg/kg/day.  Extrapolation of this value to
humans, using the application of a safety factor of 100,
results in an acceptable daily intake for man (ADI) of 8.4 mg.
     Cyanide exists in water in the free form (CN~ and HCN),
which is extremely toxic, or in a form bound to organic
or inorganic moieties which is less toxic.  Cyanide is lethal
to freshwater fishes at concentrations near 50 ;ig/l and
has been shown to adversely affect invertebrates and fishes
at concentrations near 10 pq/1.  Very few saltwater data
have been generated.  Cyanide affects fish and invertebrates
by inhibiting utilization of available oxygen for metabolism
                                            *•
at the cellular level of respiration.

-------
                           CYANIDES

I.   INTRODUCTION
   c^
     This profile is based primarily upon the Ambient Water
Quality Criteria Document for Cyanides  (U.S. EPA, 1979).
The National Institute for Occupational Safety and Health
(NIOSH, 1976) has also prepared a  recent comprehensive review
of health hazards associated with  hydrogen cyanides  (HCN)
and commercially important cyanide salts (NaCN, KCN, and
Ca(CN)2).
     The toxicologic effects of cyanides are based upon
their potential for rapid conversion by mammals to HCN.
Cyanide production in the United States is now over  700
million pounds per year and appears to be increasing steadily
(Towill, et al. 1978).  The major  industrial users of cyanide
in the United States are the producers of steel, plastics,
synthetic fibers and chemicals, and the electroplating and
metallurgical industries (NIOSH, 1976; Towill, et al. 1978).
II.  EXPOSURE
     A.   Water
          Cyanide exists in water  in the free form (CN~
and HCN), or bound to organic or inorganic moieties.  Cya-
nide is not commonly found in United States water supplies.
Among 2,595 water samples tested,  the highest cyanide con-
centration found was 8 ppb (Towill, et al.  1978).  The vola-
tility of HCN, the predominant form in water, accounts in   '
part for the low levels usually measured.  The U.S.  EPA
(1979)  has estimated the bioconcentration factor -of  cyanide
at 2.3.
                              t

-------
     . y
     B.   Food
          Except for certain naturally occurring organoni-
triles in plants (e.g., cyanogenic glycosides, such as  amyg-
dalin), it is uncommon to find cyanide in foods.
     C.   Ambient Air
          There is insufficient information available to
estimate population exposures to cyanide via ambient air
(U.S. EPA, 1979).
Ill  PHARMACOKINETICS
     A.   Absorption
          The common inorganic cyanides are rapidly absorbed
across the skin (Drinker, 1932; Potter, 1950; Tovo, 1955;
Walton and Witherspoon, 1926), stomach and duodenum, and
lungs (Goesselin, et al. 1976).  Quantitative estimates
of the rate of penetration by various routes of exposure
are unavailable, however.  The rapid absorption of cyanide
is evidenced by the fact that death may be produced within
a matter of minutes following inhalation or ingestion.
     B.   Distribution
          Cyanide is distributed to all organs and tissues
via the blood, where its concentration in red cells is greater
than that in plasma by a factor of two or three.  This may
be due, at least in part, to a preferential binding of cya-
nide to methemoglobin  (Smith and Olson, 1973.) .  Although
quantitative data are lacking, it is predicted that cyanide
may readily cross the placenta.

-------
     C.   Metabolism
          By far, the major pathway for the metabolic detoxi-
fication of cyanide involves its conversion to  thiocyanate
via the enzyme rhodanase  (deDuve, et al. 1955).  A minor
pathway for cyanide metabolism involves nonenzymatic conjuga-
tion with cysteine, a reaction which accounts for no more
than 15 percent of cyanaide metabolism in the rat (Wood
and Cooley, 1956).  Very small amounts of cyanide can be
excreted unchanged (as HCN) or converted to carbon dioxide
(Friedberg and Schwarzkopf, 1969).
     D.   Excretion
          Among rats given 30 mg of sodium cyanide intra-
peritoneally over eight days, it was estimated  that 80 per-
cent of the total dose was excreted in the urine in the
form of thiocyanate (Wood and Cooley, 1956).  Cyanide does
not appear to accumulate significantly in any body compart-
ment with chronic exposures.
IV.  EFFECTS
     A.   Carcinogenicity
          Pertinent data confirming the carcinogenicity
of cyanide were not found in the available literature.
     B.   Mutagenicity
          Pertinent data concerning the mutagenicity of
cyanide were not found in the available literature.
     C.   Teratogenicity
          Cyanide is not known to be teratogenic.  However,
thiocyanate, the major metabolic product of cyanide in vivo,

-------
has produced developmental abnormalities  in  the  chick  (Nowinski
and Pandra, 1946) and ascidian embryo  (Ortolani,  1969)  at
high concentrations.
     D.   Other Reproductive Effects
          Pertinent information regarding  the possible  ef-
fect of cyanide on fertility or reproductive success was
not found in the available literature.
     E.   Chronic Toxicity
          Human inhalation of 270 ppra HCN  brings  almost
immediate death, while 135 ppm is fatal after 30  minutes
of exposure '(Dudley, et al. 1942).  The mean lethal dose
of HCN and its alkali metal salts by ingestion in humans
is in the range of 50 to 200 mg  (1 to 3 mg/kg), with death
coming in less than one hour (Gosselin, et al. 1976) .   In
non-fatal poisonings, recovery is generally  rapid and com-
plete.  The mechanism of acute cyanide intoxication can
be attributed to the biochemical inhibition  of cytochrome
c oxidase, the terminal enzyme complex in  the respiratory
electron transport chain of mitochondria  (Gosselin, et  al.
1976).  The major feature of cyanide poisoning resembles
the effects of acute hypoxia, which results  in a  decreased
utilization of oxygen by the tissues.  Cyanide poisoning
differs from other types of hypoxia in that  the oxygen  ten-
sion in peripheral tissues usually remains normal or may
even be elevated (Brobeck, 1973).
          Despite the high lethality of large single doses
or acute inhalation exposures to high vapor  concentrations

-------
of cyanide, repeated sublethal doses do not result  in cumula-
tive adverse effects (Hertting, et al. 1960; Hayes, 1967;
American Cyanamid, 1959).
     F.   Other Relevant Information
          Since cyanide acts by inhibiting cytochrome c
oxidase, it is reasonable to assume that any other  inhibitor
of the same enzyme (e.g. sulfide or azide) would have toxic
effects synergistic with (or additive to) those of  cyanide.
This has not been demonstrated experimentally, however.
          Cyanide poisoning is specifically antagonized
by any chemical agent capable of rapidly generating methemo-
globin Ln vivo, such as sodium nitrite, or other aromatic
nitro and amino compounds (Smith and Olson, 1973).
V.   AQUATIC TOXICITY
     A.   Acute Toxicity
          There have been numerous studies investigating
the toxicity of cyanide in freshwater fish.  Free cyanide
concentrations in the range of about 50 to 200 ug/1 have
eventually proven fatal to most species.  Certain life stages
and species of fish appear to be more sensitive to  cyanide
than others.  Eggs, sac fry, and warmwater species  tended
to be the most resistant.
          Several authors have reported increased cyanide
toxicity with the reduction of dissolved oxygen or  with
a rise in water temperature.  However, water alkalinity,
hardness, and pH below 8.3 have not been shown to have a
pronounced effect on the acute toxicity of cyanide  to fish.
The reported range for LC5Q values for freshwater fish is

-------
from 52 >ig/l, for juvenile brook trout, to 507 jjg/1,  for
sac fry brook trout, Salvelinus fontinalis.  For  the  fresh-
water invertebrates, the results from 11 acute tests  on
6 species have shown a range of LC^Q values from  83 pg/1
for cladoceran, Daphnia pulex to 760,000 pg/1 for snail,
Goniobasis livescens.
          The only saltwater species to be studied  is the
oyster.  A short, exposure of an oyster to cyanide resulted
in supression of activity after 10 minutes of exposure to
150 ^ug/1  (U.S. EPA, 1979).
     B.   Chronic Toxicity
          Based on long-term tests with bluegills (embryo-
larval) and reproduction by brook trout and fatheads,  the
geometric mean of the chronic effect level concentrations
is 9.6 ug/1 (Koenst, et al. 1977; Lind, et al. 1977;  Kimball,
et al.  1978).  Life cycle tests on the scud, Gammarus pseudo-
limnaeus, and the isopod, Ascellus communis, show the chronic
values to be 18.3 and 34.1 ug/1, respectively  (U.S. EPA,
1979).  The chronic toxicity of cyanide in marine species
has not been reported.
     C.   Plant Effects
          In the only plant test reported, 90 percent of
the blue-green alga, Microcystis aerusinoss, was  killed
when exposed to a free cyanide concentration, of 7,790  /ig/1
(Fitzgerald, et al. 1952).
          There was an inhibition of respiration  in the
marine alga, Prototheca zopfi, at 3,000 ug/1 and  enzyme

-------
inhibition in Chlorella sg. at 30,000 pq/1  (Webster and
Hackett, 1965; Nelson and Tolbert, 1970).
     D.   Residue
          No residue data is available for cyanide toxicity
in either salt or freshwater species.  The U.S. EPA (1979)
has estimated the bioconcentration factor of cyanide to
be 2.3.
VI   EXISTING GUIDELINES AND STANDARDS
     Neither the human health nor aquatic criteria derived
by U.S. EPA, 1979, which are summarized below, have gone
through the process of public -review; therefore, there is
a possibility that these criteria will change.
     A.   Human
          The U.S. Public Health Service Drinking Water
Standards of 1962 established 0.2 mg CN~/1 as the acceptable
level for water supplies.  A similar criterion has been
adopted by the Canadian government (Health and Welfare Canada,
1977).  In addition to defining the 0.2 mg CN~/1 criterion,
the U.S. Public Health Service (1962) has set forth an "objec-
tive" of 0.01 mg CN~/1 in water,  "because proper treatment
will reduce cyanide levels to 0.01 mg/1 or less."
          The U.S. Occupational Safety and Health Administra-
tion (OSHA)  has established a permissible exposure limit
for KCN and NaCN at 5 mg/m  as an eight-hour,time-weighted
average.  The National Institute for Occupational Safety
and Health (NIOSH) recommends 5 mg/m3 as a ten minute ceil-'
ing for occupational exposure to KCN and NaCN.

-------
          The OSHA permissible limit for exposure  to  HCN
is 10 ppm (11 mg/m )  as an eight-hour time-weighted average.
NIOSH recommends 5 mg/m  as a ten minute ceiling level  for
exposure to HCN.
          Based upon the results of a two year chronic  feed-
ing study in rats, the U.-S. EPA  (1979) has calculated an
acceptable daily intake (ADI) of cyanide for man to be  8.4
mg/kg.  This value was derived from the no observable adverse
effect level (NOAEL)  for rats of 12 mg/kg/day and  the applica-
tion of a safety factor of 100.  The corresponding draft
water quality criterion derived  from these data is 4.11
mg/1.  However, the U.S. EPA  (1979) has recommended that
the U.S.  Public Health Service Drinking Water Standard
of 200 jig/1 be retained as a safe level for man.
     B.   Aquatic
          For free cyanide (expressed as CN), the  draft
criterion to protect freshwater aquatic life is 1.4 ug/1
as a 24-hour average, and the concentration should not  exceed
38 ug/1 at any time  (U.S. EPA, 1979).
          Draft saltwater criterion is not available  for
cyanide toxicity, because of the paucity of valid  data  (U.S.
EPA, 1979).

-------
                           CYANIDES

                          REFERENCES


American Cyanamid Co.  1959.  Report on sodium cyanide:
30-day repeated feeding to dogs.  Central Med. Dep.

Brobeck, T.R.  1973.  Best and Taylor's physiological basis
of medical practice.  9th ed.  Williams and Wilkins Co.,
Baltimore.

de Duve, C., et al. 1955.  Tissue fractionation studies:
6.  Intracellular distribution patterns of enzymes in rat-
liver tissue.  Biochem. Jour. 60: 604.

Drinker, P. 1932.  Hydrocyanic acid gas poisoning by absorp-
tion through the skin.  Jour. Ind. Hyg. 14: 1.

Dudley, H.C.-, et al. 1942.  Toxicology of acrylonitrile
(vinyl cyanide): II. Studies of effects of daily inhalation.
Jour. Ind. Hyg. Toxicol. 24: 255.

Fitzgerald, G.P., et al.  1952.  Studies on chemicals with
selective toxicity to blue-green algae.  Sewage Ind. Wastes
24: 888.

Friedberg, K.D., and H.A. Schwarzkopf. 1969.  Blausaureexhala-
tion bei der Cyanidvergiftung  (The exhalation of hydrocyanic
acid in cyanide poisoning).  Arch Toxicol. 24: 235.

Gosselin, R.E., et al.  1976.  Clincial toxicology of com-
merical products. 4th ed. Williams and Wilkins Co., Baltimore.

Hayes, W.T. Jr. 1967.  The 90-dose LD5Q and a chronicity
factor as measures of toxicity.  Toxicol. Appl. Pharmacol.
11: 327.

Hertting, G., et al.  1960.  Untersuchungen uber die Folgen
einer chronischen Verabreichung akut toxicher Dosen von
Natriumcyanid an Hunden. Acta Pharmacol. Toxicol.  17: 27.

Kimball, G., et al.  1978.  Chronic toxicity of hydrogen
cyanide to bluegills.  Trans. Am. Fish. Soc. 107: 341.

Koenst, W., et al.  1977.  Effect of chronic exposure of
brook trout to sublethal concentrations of hydrogen cyanide.
Environ. Sci. Technol. 11: 883.

Lind, D., et al.  1977.  Chronic effects of hydrogen cyanide
on the fathead minnow.  Jour. Water Pollut. Control Fed.
49: 262.

-------
National Institute for Occupational Safety and Health. 1976.
Criteria for recommended standard occupational exposure
to hydrogen cyanide and cyanide salts (NaCN, KCN and Ca(CN)2).
NIOSH Publ. No. 77-108. Dep. Health Edu. Welfare. U.S. Govefn-
ment Printing Office, Washington, D.C.

Nelson, E.B., and N.E. Tolbert.  1970.  Clycolate dihydro-
genase in green algae.  Arch.  Biochem. Biophys. 141: 102.

Nowinski, W.W., and J.  Pandra. 1946.  Influence of sodium
thiocyanate on the development of the chick embryo.  Nature
157: 414.

Ortolani, G. 1969.  The action of sodium thiocyanate  (NaSCN)
on the embryonic development of the ascidians.  Acta Embryol.
Exp. 27-34.

Potter, A.L. 1950.  The successful treatment of two recent
cases of cyanide poisoning.  Br. Jour. Ind. Med. 7: 125.

Smith, R.P., and M.V. Olson.  1973.  Drug-induced methemo-
globinemia.  Semin. Hematol.  10: 253.

Tovo, S. 1955.  Poisoning due to KCM absorbed through skin.
Mineria Med. 75: 158.

Towill, L.E., et al.  1978.  Reviews of the environmental
effects of pollutants: V. Cyanide.  Inf. Div. Oak Ridge
Natl. Lab. Oak Ridge, Tenn.

U.S. EPA.  1979.  Cyanides:  ambient water quality criteria.
(Draft)  EPA PB296792.  National Technical Information Ser-
vice, Springfield, VA.

Walton, D.C., and M.G. Witherspoon. 1926.  Skin absorption
of certain gases.  Jour. Pharmacol. Exp. Ther. 26: 315.

Webster, D.A., and D.P. Hackett.  1965.  Respiratory chain
of colorless algae.  I.  Chlorophyta and Euglenophyta.
Plant Physiol. Lancaster 40': 1091.

Wood, J.L., and S.L. Cooley. 1956.  Detoxication of cyanide
by cystine.  Jour. Biol. Chem. 218: 449.
                              IXi

-------
                                     No. 57
         Cyanogen  Chloride


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

           APRIL  30, 1980
            5-7-1

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

-------
                               CYANOGEN CHLORIDE

 I.    INTRODUCTION
      Cyanogen chloride  is  a colorless gas at room  temperature  with  a molec-
 ular  weight  of  61.48,  a melting  point  of  -6.5°c,   a  boiling  point  of
 13.8°C,  and  a  specific  gravity  of  1.186.   It is  soluble  in  alcohol  or
 ether, and slightly soluble in water.  (Int. Teh. Inf.  Inst.,  1978).
      Cyanogen chloride  is  used as a  fumigant,  metal cleaner,  in ore refin-
 ing,  production  of  synthetic  rubber  and  in  chemical  synthesis   (Arena,
 1974).  Cyanogen chloride can be used  in the military  as a  poison  gas.
 II.   EXPOSURE   -
      The  major  sources  of exposure to  cyanogen chloride are  in the  above
 mentioned industrial uses.  The potentiality of  cyanogen chloride as  a  water
 pollutant has not been described in the available literature.
 III.  PHARMACOKINETICS
      The toxicity of cyanogen  chloride resides  very largely on  its pharmaco-
 kinetic property of yielding readily to hydrocyanic acid (also  called hydro-
 gen cyanide or  prussic  acid)  _in vivo.  The red  cells of whole  blood  rapidly
 convert cyanogen chloride  to cyanide,  while serum destroys cyanogen  chloride
 without forming hydrocyanic acid (Aldridge and Evans,  1946).
     Reference  should  be made  to  the EPA/ECAO  Hazard  Profile for  cyanides
 (U.S.   EPA,  1979)  for  a  general  discussion  on  absorption,  distribution,
metabolism  and  excretion.   Cyanogen  chloride,   like  HCN,   is  metabolically
converted to thiocyanate (HCNS) (Aldridge  and Evans, 1946).
                                5-7-3

-------
 IV.   EFFECTS
      A.   Carcinogenicity, Mutagenicity,  Teratogenicity,-and  Other
          Reproductive Effects
          Pertinent  information  could not be located in the  available  liter-
 ature.
          B.  Chronic Toxicity
          Inhaling  small  amounts  of  cyanogen  chloride  causes  dizziness,
 weakness, congestion of  the  lungs,  hoarseness,  conjunctivitis, loss of appe-
 tite, weight'loss,  and  mental  deterioration.   These effects are  similar to
                                                    \
 those found from  inhalation  of  cyanide (Dreisbach, 1977).  Cyanogen chloride
 is an irritant to both eyes.and throat (Int. Tech. Inf. Inst., 1978).
          Cyanogen chloride  acts as  a chenical  asphyxiant,  releasing cyanide
which causes  internal asphyxia  by  inhibiting  cellular respiration.  Cyano-
hemoglobin may also be formed slowly, but the toxicity is  mainly  due to the
inhibition of  cytochrome oxidase,  an enzyme which utilizes molecular oxygen
 for cell respiration (Dreisback, 1977).
     C.   Acute Toxicity
          Ingestion  or  inhalation  of  a  lethal   dose  of  cyanogen  chloride
 (LD5Q  = 13  mg/kg),  as  for cyanide or  other  cyanogenic  compounds,  causes
dizziness, rapid  respiration, vomiting,  flushing,  headache, drowsiness, drop
in blood  pressure,  rapid pulse, unconsciousness,  convulsions with  death oc-
curring within 4 hours (Dreisbach,  1977).
     By  subcutaneous   route,   the   LDLQ  for  cyanogen   chloride   are  as
follows:  mouse,  39  mg/kg;  dog,  5 mg/kg;  and  rabbit,  20 mg/kg.   By inhala-
tion, an |_CLQ  in the dog  was  found  to  be 79 ppm/8 hours.   Also  by inhala-
tion, the  LC50's in terms  of ppm  for 30  minute exposures  are:   rat,  118;
mouse, 177;  rabbit,  207;  and guinea pig, 207 (Int. Teh.  Inf. Inst.,  1978).

-------
V.   AQUATIC TOXICITY



     Pertinent  information could  not be  found in  the .available literature



pertaining  to  the toxic effects  of cyanogen chloride  to aquatic organisms.



The  reader  is  referred  to EPA/ECAO  Hazard  Profile for  cyanides (U.S. EPA,



1979).



VI.  EXISTING GUIDELINES AND STANDARDS



     A.  Human



          Threshold limit  values .for cyanogen chloride have  been set at 0.3



ppm and 0.6 mg/m3 for an 8-hour workday. (ACGIH, 1979).

-------
                               CYANOGEN CHLORIDE
                                  REFERENCES
Aldridge, W.N. and Evans,  C.L,   1946.   The  physiological effects and fate of
cyanogen chloride.  Quart. Jour. Expl. Physiol.  33: 241.
American  Conference  of  Governmental Industrial  Hygienists.  1979.   Thres-
hold-limit-values for  chemical  substances and physical  agents in  the  work-
room environment for 1979.  Cincinnati,  Ohio.
Arena,  J.M.   1974.    Poisoning.   Clark  C.  Thomas  Company.   Springfield,
Illinois, p. 210.
Deischmann,  W.B.  and  Gerarde,  H.W.   1969.   Toxicology of  drugs  and  chem-
icals.  Academic Press, New York, p.  641.
Oreisbach,  R.H..  1974.   Handbook  of Poisoning,  IX edition.  Lange  Medical
Publications, Los Altos,  California,  p.  221.
International  Technical  Information  Institute.   1978.   Toxic and  hazardous
chemicals safety manual.   Tokyo, Japan,  p. 142.
U.S. EPA..  1979.   Environmental Criteria and Assessment Office.   Cyanides:
Hazard profile.  (Draft).
                                   57-6

-------
                                      No. 58
                ODD
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

-------
                         Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.

-------
                                      ODD
                                   Summary

     ODD can  exist in  two  forms, the  o,p'- or  the  p,p'-isomers.  p,p'-ODD
[l,l-(2,2-dichloroethylidlene)-bis-4-chlorobenzene]    is    a    contaminant
(^0.330  of  commerical  preparations  of  DDT  [ 1,1 '-(2,2,2-trichloroethyli-
dene)-bis-4-chlorobenzene]  as  well  as  being a metabolite  of DDT.   It has
also been  used as  an insecticide in its own  right  under  the  names  TDE or
Rhothane.  p,p'-ODO is the  first  metabolite  of  p,p'-ODT leading to the even-
tual elimination of p,p'-ODT from the body  as p,p'-ODA [2,2-bis(4-chlorophe-
nyl) acetic  acid].   The  residency  time  of  ODD  in  the  body  is relatively
short.   There is some evidence  that  DDD is  carcinogenic in mice; however, in
other species,  it  appears  to be  non-carcinogenic.   p,p'-OOD  has been shown
to be mutagenic in Drosophila, but  not in  yeast or  bacteria.   In cell cul-
ture, p,p'-ODD causes chromosomal breaks.
     The only  available p,p'-OOD  toxicity  data involves  saltwater  fish and
invertebrates  and   freshwater   invertebrates.   The  96-hour  LC_Q value  for
two  invertebrates  and  three  fish range  from  1.6  to  42.0  ug/1.   p,p'-OOD
appears to be one-fifth to one-seventh as acutely toxic as p,p'-ODT.

-------
                                      ODD
I.   INTRODUCTION
     This  profile  is based  on the  Ambient  Water Quality  Criteria Document
for DDT (U.S. EPA, 1979a).
     ODD is  a  contaminant of technical p,p'-DDT [l,l'-(2,2,2-trichloroethyl-
idene)-bis-4-chlorobenzene].  It has  also  been  utilized as an insecticide in
its  own right  under the  common  names  TDE  or  Rhothane.   Its  two isomers,
p,p'-ODD   [l,l'-(2,2-dichloroethylidene)-bis-4-chlorobenzene]  and  o,p'-ODD,
make up approximately 0.3 and  0.1  percent,  respectively,  of technical DDT.
Between 1970 and 1973 (the  EPA banned DDT  in  1972),  a significant  drop in
residues of  ODD  and  DDT  occurred  in the U.S.A., constituting decreases of 89
and 86 percent, respectively.
II.  EXPOSURE
     Little  information  is available  on exposure to  ODD, although the gener-
al exposure  pattern  probably  follows  that  of DDT,  as outlined in DDT: Hazard
Profile  (U.S.  EPA,  I979b).   ODD appears  to be disappearing from  the U.S.
environment  at  approximately the same  rate  as   DDT  as  a result  of the 1972
ban  on  DDT  (U.S. EPA, 1975).   Wessel  (1972) calculated the  daily intake of
p,p'-DDD to  be  0.012  mg/man/day;  this  was  about half  the daily  intake of
p.p'-OOT.
III. PHARMACOKINETICS
     A.  Absorption
         Pertinent data could not be located in the available literature.
     B. • Distribution
         The distribution of DOD is the  same  as  that  described  for  DDT in
DDT: Hazard  Profile  (U.S. EPA,  1979b).   The  human adipose  storage  of ODD is
less than  that  of either DDT  or  ODE [l,l'-(2,2-dichloroethenylidene)-bis-4-
chlorobenzene].

-------
     C.  Metabolism
         p,p'-ODD  is  the first metabolite  in the multistep  pathway of  con-
verting  p,p'-ODT  to  p,p'-ODA  [ 2,2-bis(4-chlorophenyl) -acetic   acid],   the
metabolite  which  is  eventually excreted  by rats  and by  man (Peterson  and
Robinson  (1964).  Urinary  p,p'-ODA excretion  and serum  ODD  concentrations
showed  increases  with  DOT  dosage  in  man and  declined after dosing ended
(Morgan  and Roan, 1977).   The enzymes  for converting  p,p'-ODT  to  p,p'-ODD
are  present in all tissues, while  the  enzymes  for further metabolism  of ODD
appear to be absent  in -brain,  heart,  pancreas, and muscle  of  rats  (Fang,  et
al.  1977).
     0.  Excretion
         Doses  of o.p'-OOD  yield  o,p'-OOA and ring hydroxylation  products  of
o,p'-QDA  in the urine and  feces  of rats  in addition to  serine  and glycine
conjugates  in urine (Reif and Sinsheimer, 1975).
         ODD  is further  metabolized to  DOA,  which is excreted in the urine
(U.S. EPA,  1979a).
IV.  EFFECTS
     A.  Carcinogenicity
         Only  two  studies have been performed  to assess the  Carcinogenicity
of p.p'-ODD.   In a lifespan study, CF1  mice were fed 37.5  mg/kg/day 000  in
their  diet  (Tomatis,  et  al. 1974).  DOO-exposed animals  showed  slight  in-
creases in  liver tumors  in males only,  but lung adenomas  were markedly in-
creased in  both sexes. In a National  Cancer Institute study  (1978),  Osborne-
Mendel rats and B6C3F1 mice  were dosed with p.p'-OOQ, for 78 weeks.   In rats,
ODD  had  no  carcinogenic  effects  in the  females, (43 or 85 mg/kg/day),  but
caused a  significant  increase of  follicular cell adenomas  in the  low dose
males  (82 mg/kg/day).  Carcinomas  of  the  thyroid  were also  observed.  Be-

-------
cause of high  variation  of  thyroid  lesions in control male rats, these find-

ings are considered  only suggestive of a  chemical-related  effect.   In mice,

p,p'-OOD was not carcinogenic.

     B.  Mutagenicity

         p,p'-ODD  has  been  shown  to  be  non-mutagenic  in  E.  coli  Pol-A

strains (Fluck, et al.  1976)  and Escherichia marcescens (Fahrig, 1974).  The

only positive  result  found  in any of  the bacterial test systems was reported

by Buselmaier, et al. (1972)  upon the  administration of p,p'-ODO to mice and

assaying for  back  mutation  of Salmonella  typhimurium  and  E.  marcescens fol-

lowing incubation  in  the peritoneum in the  host-mediated  assay.   Yeast host

mediated assays using Saccharomyces cerevisiae were negative (Fahrig, 1974),

along  with an X-linked  recessive  lethal  assay  in  Drosphila  melanogaster

(Vogel, 1972).  In mammalian systems,  the mutagenic  activity  of p,p'-ODD is

relatively  weak.   This   is  evidenced  by  the fact  that,  depending  upon  the

dose  and  route of administration  and the  species sensitivity of  the test

organism,  reported studies  are  negative or  marginally positive  (U.S.  EPA,

1979a).  Some chromosomal  aberrations  and inhibition  of  proliferation have

been observed  with p,p'-000 in cell culture  (Palmer,  et al.  1972;  Mahr  and

Miltenburger,  1976).  The o,p'-isomer  is less active  with  regard  to chromo-

some damage (Palmer, et al.  1972).

     C.  Teratogenicity, Other Reproductive Effects, and Chronic Toxicity

         Pertinent data could not be located in the available literature.

     0.  Other Relevant Information

         Since ODD is a metabolite of DDT,  as well as a contaminant of com-

mercial preparations  of DDT, many  of  the effects  of  DDT could be  mediated
                                                                        9
through ODD.   Information on DOT is  presented in  DDT: Hazard  Profile  (U.S.

EPA, 1979b).

-------
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         The most  insensitive  freshwater invertebrate was the scud, Gammarus
lacustris.  with a  96-hr.  LC5Q  static value  of  0.60 ug/L  (Sanders,  1969).
Of the Cladoceran,  the Daphnia pulex  species  was the most,  sensitive  with a
static LC50 of  3.2 pg/1,  while the  Simocephalus  serrulatus was  the least
sensitive  with  a  LC5Q of  5.2  ug/1  (Sanders  and  Cope,   1966).   p,p'-OOD
toxicity  has  been  investigated  for several saltwater  species.   LC-g values
for  two  invertebrates, the  Eastern oyster, Crassostrea virqinica.  and the
Korean shrimp,  Palaemon  macrodactylus (Schoettger,  1970),. are  25 ug/1 and
1.6  jug/1, respectively,  in 96-hr  flow-through exposures.   In   flow-through
exposures  to  three species  of saltwater fish, 96-hr  LC5Q  values range  from
2.5  to 42 ug/1  for the stripped bass,  Morone saxatilis, Korn  and Earnest,
1974).  Two  species,  Morone saxatilis  (Korn and  Earnest,  1974)  and Fundulus
similis (U.S. EPA,  1979a),  were exposed to both  p,p'-OOD and p,p'-ODT under
similar conditions.   A comparison of  the results  indicates  that p,p'-OOD  is
one-fifth  to  one-seventh  as acutely  toxic  to  these species as  is p,p'-ODT.
However,   four  to five  week  old tadpoles of the  freshwater  toad (Bufo wood-
huusei fowleri) were  much  more sensitive, having 96-hr.  LCg_  values  of
160  ug/1  compared  with  1,000  pg/1  for p,p'-ODT.   The DOT  sensitivity  in-
creased with age (Sanders, 1970).
     B.  Chronic Toxicity, Plant Effects and Residues
         Pertinent data could not be located in the available literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     Neither the  human health nor  the aquatic criteria  derived by U.S.  EPA
(1979a),  which are  summarized  below,  have gone through the  process of'public
review;  therefore,   there  is  a  possibility  that  these criteria will  be
changed.

-------
     A.  Human
         In  1972,  the  U.S.  EPA banned  the agricultural  use  of DOT  in the
United States.  There are no  other  specific guidelines or standards for ODD.
However, for  the protection of  human health with respect to ODD, criteria of
0.98,  0.098,  and 0.0098  ng/1 have  been proposed  for DDT  corresponding  to
risk  levels  of 10,  10  ,  and  10" , respectively.   If  water  alone  is
consumed, the water concentration should be less than 0.36  pg/1 to keep the
lifetime cancer risk below 10~ .
     B.  Aquatic
         The  criteria for DDT and its metabolites  are proposed for the pro-
tection  of  aquatic  life from the  effects of ODD.   The 24-hour average for
the  protection  of  freshwater aquatic  life is  0.00023  ug/1,   not  to exceed
0.41 yg/1 at  any time.   For  saltwater  aquatic  life,  the  24-hour  average  is
0.0067 pg/l, not to exceed 0.021 jjg/1 at any time.

-------
                                      ODD

                                  REFERENCES
Buselmaier,  W.,  et  al.   1972.   Comparative  investigations  on  the  muta-
genicity  of pesticides  in  mammalian  test systems.   Eur. Environ.  Mutagen
Soc. 2nd Ann. Meet., Ziukovy Castle, 25.

Fahrig, R.   1974.   Comparative mutagenicity  studies with  pesticides.   Page
161  In:  R. Montesano and L.  Tomatis,  eds.  Chemical  carcinogenesis essays,
WHO.  IARC Sci. Publ. No. 10..

Fang,  S.C.,  et al.   1977.   Maternal  transfer  of 14C-p,p'-ODT  via placenta
and milk and its metabolism in  infant  rats.   Arch.  Environ. Contam. Toxicol.
5: 427.

Fluck, E.R., et al.  1976.   Evaluation of a  ONA polymerase-deficient mutant
of  E.  coli  for the  rapid detection  of  carcinogens.   Chem.   Biol.  Inter-
actions"~l5: 219.

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

Mahr,  U.  and   H.G. Miltenburger.   1976.   The  effect  of insecticides  on
Chinese hamster cell cultures.  Mutat.  Res.  40: 107.

Morgan,. O.P.  and C.C.  Roan.   1977.   The  metabolism of DOT in  man.  Essays
Toxicol.  5: 39.

National  Cancer Institute.   1978.   Bioassays  of DOT,  TOE and  p,p'-OOE for
possible carcinogenicity.  Cas No.  50-29-3, 72-54-8,  72-55-9,  NCI-CG-TR-131.
U.S. Dept. Health Edu. Welfare.

Palmer, K.A.,  et  al.  1972.  Cytogenetic  effects of DDT  and derivatives of
DDT in a cultured mammalian cell line.   Toxicol. Appl.  Pharmacol.  22: 355.


Peterson,  J.E.  and  W.H. Robison.   1964.   Metabolic products of p,p'-C~DT in
the rat.  Toxicol. Appl. Pharmacol.  6: 321.

Reif,  V.O.   and   J.E.  Sinsheimer.    1975.     Metabolism  of   1-10-chloro-
phenyl)-l-(p-chlorophenyl)-2,2-dichloroethane   (o.p^-OOD)   in   rats.   Drug.
Metals. Disp.  15.

Sanders,  H.O.   1969.   Toxicity  of Pesticides to  the Crustacean  gammarus
lacustris.  Bur. Sport Fish Wildl. Tech. Paper.   25:, 18.

Sanders, H.O.  1970.  Pesticide toxicities to tadpoles  of the western chorus
frog.   Pseudocris   triseriata  and Fowler's  toad,  Bufo  woodhousei  fowleri.
Copeia No. 2: 246.                                                    ~""~~~~

Sanders, H.O. and O.B. Cope.  1966.  Toxicities of  several  pesticides to two
species of cladocerans.   Trans.  Am. Fish Soc.   95:  165.
                                   58-10

-------
Schoettger, R.A.   1970.   Progress in sport  fishery  research 1970.  Research
Publ. NO. 106.  U.S. Dept. Interior.

Tomatis, L.,  et al.   1974.   Effect of  long-term exposure  to 1,1-dichloro-
2,2-bis(p-chlorophenyl)  ethylene,  to  l,l-dichloro-2,2-bis  (p-chlorophenyl)
ethane, and to  the two chemicals combined on  CF-1  mice.   Jour.  Natl. Cancer
Inst.  52:  883.

U.S. EPA.   1975.   Preliminary assessment of suspected  carcinogens in drink-
ing water.   Interim report to  Congress,  U.S. Environ.  Prot.  Agency, Washing-
ton, D.C.

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

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

Vogel, E.   1972.   Mutagenitatsuntersuchungen mit  DDT und  den DDT-metaboliten
DDE, ODD, DOOM and DDA an Drosphila melanogaster.   Mutat.  Res.  16: 157.

Wessel,  J.R.  ' 1972.   Pesticide  residues in  foods.  Environmental contami-
nants in foods.  Spec. rep. No. 9. N.Y.  State Agric. Exp.  Sta., Geneva.

-------
                                    No. 59
               DDE
  Health"and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.   20460

          APRIL 30, 1980
               Sf-l

-------
                          DISCLAIMER
     This report represents a  survey  of  the  potential  health
and environmental hazards from exposure to the subject  chemi-
cal.  The information contained in the report is drawn chiefly
from secondary  sources  and   available  reference  documents.
Because of the limitations of such sources, this short profile
may not reflect  all  available  information including all  the
adverse health  and  environmental  impacts presented  by  the
subject chemical.  This  document has  undergone scrutiny  to
ensure its technical  accuracv.
                            S7-9-

-------
                                      DDE
                                    Summary

     DDE  exists  as two  isomers, o,p'-  and  p,p'-ODE. [l,l'-(2,2-dichloroeth-
enylidene)-bis-4-ehlorobenzene]  is  the  major contaminant (ca.  4 percent) of
commercial preparations  of p,p'-ODT  [l,l'-(2,2,2-trichloroethylidene)- bis-
4-chlorobenzene], as well  as  being  a metabolite of  p,p'-ODT.   p,p'-ODE is a
highly lipophilic compound which undergoes  no further metabolism.  Its resi-
dency time in the body  is extremely  long.   p,pMDOE  has  been  shown  to be
carcinogenic  in mice but not  in  rats.   In cell culture it causes chromosomal
breaks.
     The only aquatic toxicity data available on p,p'-OOE involve acute tox-
ic  flow-through  exposures  to  two saltwater invertebrates.   The 48-hr. LC-0
for a shrimp is 28 pg/1; the 96-hr.  LC-g for the Eastern oyster is 14 jjg/1.

-------
                                      DDE



I. '  INTRODUCTION



     This  profile  is based  on the  Ambient  Water Quality  Criteria Document



for DDT and metabolites (U.S. EPA, 1979a).



     DDE is  a  contaminant of technical l,l'-(2,2,2-trichloroethylidene)-bis-



4-chlorobenzene (DDT).  Its  two  isomers,  p,p'-ODE [!,!'-(2,2-dichloroetheny-



lidene)-bis-4-chlorobenzene]  and  o,p'-ODE make up approximately  4.0 and 0.1



percent, respectively,  of technical  grade DDT.   Between 1970  and  1973 (the



EPA banned DDT in 1972),  a significant drop  in  the residues  of DDT in the



U.S. occurred,  constituting a .decrease of 86  percent.   However,  during this



time period,  residues of  DOE  decreased only  27  percent.   In fact, p,p'-DDE



residues comprise  most  of  the  biological residues  (ca.  71 percent) arising



from DDT application  (U.S. EPA, 1979a; Kveseth, et al. 1979).



II.  EXPOSURE



     Little  information is available on exposure  to  DDE, although the gener-



al exposure  pattern  probably follows that of DDT, as outlined  in DDT:  Haz-



ard Profile  (U.S.  EPA,  1979b).  DDE  residues  appear to be disappearing from



the environment at  a slower rate  than DDT  following  the  1972  ban  on DDT



(U.S.   EPA,  1975).   Wessel  (1972)  calculated  the   daily  dietary  intake  of



p,p'-DDE to  be 0.018 mg/man/day,  as  compared  with  a value  of  0.027 mg/man/



day for DDT.   A recent  study by  de Campos and Olszyne-Marzys (1979) based on



studies  in Latin  American countries  still  using DDT  indicates that  human



milk contains  more p,p'-OOE  than  p,p'-DDT  (up  to  3 pg/1 whole milk) in every



sample taken.

-------
III. PHARMACQKINETICS"
     A.  Absorption
         DDE is absorbed  from  the  gastrointestinal tract with high efficien-
cy characteristic  of dietary fat.   Maximum lipid  solubilities reach 100,000
ppm.
     8.  Distribution
         The distribution of ODE is  similar to that described for DDT in the
EPA/ECAO Hazard Profile on DDT  (U.S.  EPA,  1979b).   Serum and  adipose concen-
trations of p,p'-ODE rise slower than DDT, with the% peak some months in fol-
lowing  termination of  dosing.  The  human  adipose storage  of  p,p'-ODE  is
greater  than  that  for  DDT,  and p,p'-DDE is  eliminated from the  body very
slowly.   This  is  also  true  for  the  Rhesus  monkey  (Durham,  et  al.  1963).
Storage loss data  predict that, if dietary intake were eliminated, it would
take an entire lifespan to eliminate the  average  human  body  burden of p,p'-
DDE.  It has been  shown that tissue  storages of p,p'-ODE in the general pop-
ulation originate  almost  entirely  from dietary p,p'-ODE rather than DOT con-
version  (U.S.  EPA, 1979a).   However,  this may not be  the  case  for p,p'-ODE
residues in human milk (de Campos and Olszyne-Marzys, 1979).
     C.  Metabolism
         The end product  of  the metabolism of  DDT which proceeds via reduc-
tive dehydrochlorination  is  p,p'-DDE.   In addition,  p,p'-ODE is  the  major
storage product of DOT in animals  [apart from hamsters  (Agthe, et al. 1970)]
and humans:  The enzymes for metabolizing  DDT to  p,p'-ODE are present in all
tissues (Fang,  et al. 1977).
         In humans given  p,p'-OOT orally,  no more  than  one-fifth of  the
absorbed DDT ultimately  undergoes  conversion  to  p,p'-ODE  (Morgan  and  Roan,
1977).    p,p'-ODE  does not  undergo  further metabolism  to  2,2-bis(4-chloro-
phenyl)-acetic acid (DDA), the urinary excretion product of DDT.

-------
     0.  Excretion


         Excretion of  p,p'-ODE has not  been demonstrated in  man.   In mice,


p,p'-ODE is excreted in  the urine (Wallcave, et  al.  1974).   The o,p'-isomer


is more easily excreted than the p,p'-isomer (Morgan and Roan, 1977).


IV.  EFFECTS


     A.  Carcinogenicity


         Only  two  studies have been performed  to assess the carcinogenicity


of p,p'-ODE.   In  a lifespan study, CF-1  mice  were fed  37.5 mg/kg/day p,p'-


DDE  in  their  diet  (Tomatis,  et  al.  1974).   p,p^-DDE  increased liver tumor


incidence  from  1  percent  in  controls  to   90  percent in  treated  female


animals,  and.  from  34  to  74  percent  in  male  animals.   The combination


p,p'-DDE/ODD produced more  tumors than either  constituent alone at the same


concentration  in  the  combination.   In  a  National  Cancer  Institute study


(1978), Osborne-Mendel rats and  B6C3F1 mice  were  dosed  with p,p'-OOE for 78


weeks.  In  rats,  p,p'-  DDE had no carcinogenic effect on either females (22


mg/kg/day)  or  males (42  mg/kg/  day),  although hepatotoxicity  was evident.


In  mice,   hepatocellular  carcinomas  were  significantly increased  in  the


animals   fed   p,p'-QDE   (22  and  39   mg/kg/day  for   females   and  males,


respectively).  •


     B.  Mutagenicity


         p,p'-DDE has been  shown  to  be nonmutagenic in §_._ coli  Pol-A  strains


(Fluck, et  al. 1976), Escherichia  marcescens (Fahrig,  1974), and in the host


mediated  assay using Salmonella  typhimurium and  §_._  marcescens  (Buselmaier,


et al.  1972) and  Saccharomyces cerevisiae (Fahrig, 1974).  Vogel (1972) mea-
                                                    *

sured  X-linked  recessive lethal  mutations  in Drosophila  melanoqaster  and


found no activity  for p,p'-ODE.   In  mammalian systems, the mutagenic  activi-


ty of  p,p'-ODE is relatively weak.  This  is evidenced by the fact that, de-

-------
pending upon the  dose  and  route of administration4 and the  species  sensitivi-
ty of  the  test organism,  reported  studies are negative  or marginally posi-
tive (U.S. EPA,  1979a).  Some chromosomal aberrations and  inhibition of pro-
liferation have been observed with p,p'-ODE in cell  culture (Palmer, et al.
1972;  Mahr and Miltenburger,  1976).  The o,p'-isomer causes fewer  chromosom-
al aberrations (Palmer, et al.  1972).
     C.  Teratogenicity, Other  Reproductive Effects and Chronic Toxicity
         Pertinent information  could  not be  located in the available litera-
ture.
     D.  Other Relevant Information
         Since p,p'-ODE  is a metabolite of DDT,  as well as a contaminant of
commercial preparations of DDT, many  of the  effects of DDT could be mediated
through p,p'-ODE.   Information on  DDT  is presented  in  DDT:  Hazard Profile
(U.S.  EPA,  1979b).   Oral  acute  LD5Q  values  for  p,p'-ODE  in rat  are  380
mg/kg  for males but 1,240 mg/kg for females (Hayes, et al.  1965).
V.   AQUATIC TOXICITY
     A.  Acute Toxicity
         The  96-hr.  LC5Q  value  for  p,p'-ODE  for the  comparatively resis-
tant freshwater planarian  (Polycelis  felina)  was  1,050 ;jg/l (Kouyoumjian and
Uglow,  1974).  The  acute toxicity of p,p'-OOE  has  also been investigated in
two  saltwater  invertebrates.   The  48-hr.  LC,-n  for the  brown  shrimp, Penae-
                                             2U
us aztecus,  was  28 Jjg/l;  the  96-hr. LC-_ for the Eastern oyster, Crassos-
trea virqinica.  was 14  jug/l  ('U.S.  EPA,  1979a).   Both  studies were  flow-
through exposures.
     B.  Chronic Toxicity and Plant Effects
         Pertinent data could not be located in the available literature.

-------
     C.  Residues
         p,p'-DDE  is  a major metabolite  of DDT in  aquatic  ecosystems.  One
study  involving  bird  eggshells  and DDT  showed p,p'-DDE to  comprise 62 per-
cent  of the  DDT metabolites  (U.S.  EPA,  1979a).   Average  residues in egg-
shells  of  the great  black-backed  gull ranged  from 14  to 68 ng/g  of lipid
(Cooke, 1979).   p,p'-ODE  in fat and muscle  of the white-faced ibis in 1974/
75 were as high as 65 ng/g  lipid  (Capen and Leiker, 1979).   No  studies are
available, however, involving p,p'-DDE specifically.
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
         In  1972,  the U.S.  EPA banned  the agricultural  use of DDT  in the
United  States.   There  are  no  other  specific guidelines or  standards  for
DDE.   However,   for   the  protection  of   human  health with  respect to DDE,
criteria of  0.98,  0.098  and 0.0098 ng/1  have  been  proposed  for  DDT corres-
ponding  to   risk   levels  of  10" ,  10"  ,   and   10" ,   respectively.   If
water  alone  is  consumed, the  water concentration  should  be  less  than 0.36
pg/1 to keep the lifetime cancer risk below 10~ .
     B.  Aquatic
         The  criteria for  DDT  and  its metabolites  are proposed for  the
protection of aquatic life  from the effects  of DDE.   The 24-hour average for
the  protection  of  freshwater  aquatic life is 0.00023  pg/1, not  to  exceed
0.41 pg/1  at any time.  For saltwater aquatic life, the  24-hour average is
0.0067 |jg/l, not to exceed 0.021 ;jg/l at  any time.

-------
                                      DDE

                                  REFERENCES


Agthe, C.,  et al.  1970.   Study  of the potential  carcinogenicity of DDT in
the Syrian Golden Hamster.  Proc. Soc. Biol. Med. 134: 113.

Buselmaier, W., et  al.   1972.   Comparative investigations on the mutagenici-
ty of pesticides  in mammalian test systems.  Eur.  Environ.  Mutagen Soc. 2nd
Ann. Meet., Ziukovy Castle, 25.

de Campos,  M. and  D.E.  Olszyna-Marzys.   1979.   Contamination  of human milk
with chlorinated  pesticides in  Guatamala  and in El Salvador.  Arch. Environ.
Contam. Toxicol.  8: 43.

Capen, O.E. and T.J. Leiker.   1979.   DDE  residues in blood and other tissues
of white-faced ivis.  Environ. Pollut.  19: 163.

Cooke,  A.S.  . 1979.  Eggshell  characteristics  of  gannets  (Sula bassoud),
shaps (Phalacrocorax aristotelis) and  great black-packed gulls (Larus marin-
us)  exposedto  DOE and other  environmental pollutants.   Environ.  Pollut.
19: 47.

Durham, W.F.,  et  al.   1963.  The effect  of various dietary levels of DDT on
liver function, cell morphology and DOT storage in the Rhesus monkey.  Arch.
Int. Pharmaccdyn. Ther.   141: 111.

Fahrig, R.   1974.  Comparative  mutagenicity studies  with pesticides.   Page
161  In:  Montesano  and  L.  Tomatis,  (eds).   Chemical  carcinogenesis  essays,
WHO.  IARC Sci. Publ.  No. 10.

Fang,  S.C.,  et al.   1977.   Maternal  transfer  of  14C-p,p'-DDT  via placenta
and milk and  its  metabolism in  infant  rats.  Arch. Environ. Contam. Toxicol.
5: 427.

Fluck, E.R.,  et  al.  1976.  Evaluation of  a DNA polymerase-deficient mutant
of E.  cqli for  the rapid  detection  of  carcinogens.   Chem.  Biol. Interac-
tions.  15: 219.

Hayes, W.J.,  Jr., et al.   1965.   Chlorinated hydrocarbon  pesticides  in the
fat of people in New Orleans.   Life Sci.  4: 1611.

Kouyoumjian,  H.H.  and R.F. Uglow.   1974.   Some aspects of  the  toxicity of
p,p!-OOT,   p,pl-ODE  and  p,p!-ODO  to  the  freshwater  planarian  Polycelis
felina (Tricladida).  Environ. Pollut.  7: 103.

Kveseth,  N.J.,  et al.    1979.   Residues  of DDT  in  a  Norwegian fruit  growing
district two  and  four years after termination of  DDT  usage.   Arch. Environ.
(Contam.  Toxicol.).  8:  201.

Mahr, U.  and  H.G.  Miltenburger.   1976.   The effect of  insecticides  on Chi-
nese hamster cell cultures.  Mutat.  Res.   40: 107.

-------
Morgan, D.P.  and C.C.  Roan.   1977.  The  metabolism  of DDT in  man.   Essays
Toxicol.  5: 39.

National Cancer Institute.   1978.   Bioassays of DDT,  TDE and  p,p'-ODE for
possible carcinogenicity.  NCI-CG-TR-131.  U.S. Dep. Health Edu. Welfare.

Palmer, K.A.,  et al.   1972.   Cytogenetic  effects of DDT  and  derivatives of
DDT in a cultured mammalian cell line.  Toxicol. Appl. Fharmacol.  22: 355.

Tomatis, L.,  et al.   1974.   Effect  of  long-term exposure  to 1,1-dichloro-
2,2-bis(p-chlorophenyl)  ethylene,   to l,l-dichloro-2,2-bis  (p-chlorophenyl)
ethane, and  to the  two chemicals combined on CF-1  mice.   Jour.  Natl. Cancer
Inst.  52: 883.

U.S. EPA.   1975.  DDT.  A  review  of scientific and  economic  aspects of the
decision  to ban  its use as  a  pesticide.   EPA52Q/1-75-022.  U.S.  Environ.
Prot. Agency, Washington, D.C.

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

U.S. EPA.   1979b.   Environmental Criteria and  Assessment  Office.   DDT: Haz-
ard Profile (Draft).

Vogel, E.   1972.  Mutagenitatsuntersuchungen  mit  DDT  und den DDT-metaboliten
DDE, ODD, DOOM and DDA.  an Drosohila melanogaster.   Mutat. Res.   16: 157.

Wallcave, L.,  et al.-  1974.   Excreted metabolites of l,l,l-trichloro-2,2-bis
(p-chlorophenyl)  ethane  in  the  mouse  and  hamster.    Agric.   Food  Chem.
22: 904.

Wessel,  J.R.   1972.   Pesticide  residues  in  foods.  Environmental  contami-
nants in foods.  Spec. Rep.  NO. 9.   N.Y. State Agric.  Exp. Sta., Geneva.

-------
                                    No. 60
               DDT
  Health and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.   20460

          APRIL 30, 1980
              60-1

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

-------
                      SPECIAL NOTATION









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



DDT and  has found sufficient evidence to  indicate that this



compound is carcinogenic.
                            60-3

-------
                                      DDT
                                    Summary

     .The most  commonly 'used  DDT was a technical formulation and usually con-
sisted of a mixture  of  p,p'-ODT (77.1 percent), o,p'-DDT (14 percent), p,p'-
DDD  (0.3 percent),  o,p'-ODD  (0.1  percent),  p,p'-DDE  (4 percent),  o,p'-OOE
(0.1 percent and  3.5 percent unidentified compounds.   Pure  DDT is the p,p'-
isomer  [l,l'-(2,2,2-trichloroethylidene)-bis-4-chlorobenzene].   Unless spe-
cifically identified,  the term  DDT will refer  tcr- the pure  form.   Prior  to
being banned in the  U.S.  in  1972, DDT was used  extensively as a pesticide.
     Due to  the high lipid  solubility  of  DDT,  it has  a  long  residency time
in  the  body.   DDT has  produced adverse reproductive  effects  in rodents  and
birds,  but  adverse  effects  have not  been noted  in man.  The lowest acute
oral  to—  value  was found  for  the dog (60-75  mg/kg).   There is  suggestive
evidence that  DDT might be a carcinogen, and weak  evidence  that it might  be
a  teratogen.   Chromosomal  breaks  have  been observed  with DDT  exposure  in
vitro and in_ vivo.
     DDT is acutely  toxic to freshwater fish at concentrations as  low as  0.8
jug/1 and to invertebrates at 0.18;ug/l.  Chronic toxicity has  been manifest-
ed  in the  fathead  minnow  in the  range of 0.37  to 1.48 jug/1.    A  weighted
average  bioconcentration  factor of  39,000  has been  estimated  for  DDT  for
consumed fish  and shellfish.  For saltwater fish and invertebrates,  DDT con-
centrations  as low  as  0.2 jug/1 and  0.14 /jg/1, respectively,  have been  re-
ported  to  be  acutely toxic.  Chronic toxicity  data^ for saltwater organisms
are  not available.

-------
                                      DDT
I.   INTRODUCTION
     This profile  is  based primarily  on  the Ambient  Water Quality Criteria
Document for DOT (U.S. EPA, 1979a).
     DDT has been  used extensively  world-wide for public health and agricul-
tural programs as  a broad  spectrum insecticide.  It has  played a large role
in  the  world-wide control  of the  malaria  mosquito.  In  1972, following an
extensive review of health  and  environmental hazards of  the  use of DDT, the
U.S. EPA  decided to  ban  any  further  use of DDT. .. Prior  to  this, technical
grade DDT had been widely  used  in the U.S., with a peak  usage  in 1959 of 80
million  pounds.    This  amount  decreased  steadily  to  less than  12  million
pounds by 1972.  Since the 1972 ban, the use  of DDT  in the U.S. has been ef-
fectively discontinued.  However,  technical grade DDT is  still used  in many
other countries  and  widespread  contamination  still occurs.    Since  ODD and
DDE are also  metabolites  of DDT, it  is  sometimes difficult to separate con-
tamination from  metabolic  accumulation.   The compounds of  DOT  are extremely
persistent and are so widespread  that levels as high as 15 ppb have been de-
tected in feed for laboratory animals  (Coleman  and Tardiff, 1979).
II.  EXPOSURE
     The primary route  of human  exposure  to DDT is from ingestion of small
amounts in the diet.  Biological  magnification  of DDT  in the food chains oc-
curs by two routes:   (1) direct absorption  from contaminated water by aquat-
ic  organisms;  (2)  transfer of residues through sequential  predator feeding.
Meats,  fish,  poultry,  and dairy products  are the primary  sources  of DDT
                                                     t
residues in the  human diet.   The  U.S.  EPA  (1979a) has  estimated the weighted
average  bioconcentration   factor  of  DDT at 39,000  for  consumed fish  and
shellfish.  Due  to the banned  usage  of DDT  in the U.S.,  there  has  been a

-------
continual decline in the DDT  residue  in  food.   These decreases are reflected
in the  changing amounts of estimated dietary intake:   1965  - 0.062 mg/man/
day;   1970  -  0.024  mg/man/day;  1973  -  0.008 mg/man/day  (U.S.  EPA,  1975).
Levels  of  DDT- found in  the air are  far below  levels  that add significantly
to total human  intake.   Stanley, et  al.  (1971)  sampled air  in nine locali-
ties,  and   found DDT  in  the  ranges  of  1  ng/m   to  2520  ng/m  of  air.
Wolfe and Armstrong  (1971) showed  that  industrial workers not wearing respi-
rators  could  be exposed to significant  levels of  DDT in the  air (up to 34
mg/man/hour), particularly in  the  formulating  plants.   Exposure for agricul-
tural spray operators may be  as high  as 0.2 mg/man/hour (Wolfe, 1967).  Der-
mal  exposure  'for formulators   was  estimated to range  from 5  to  993 mg/man/
hour  (Wolfe  and Armstrong,  1971).  Little DDT was  found  in  the urine,  how-
ever.  Dermal absorption of DDT is minimal.
     Dermal toxicity in  rats  occurs at  3,000  mg/kg (U.S. EPA,  1979a).  Hayes
(1966) estimated the intake of DDT to be in the following proportions:  food
-  0.04 mg/man/day;  water  -   4.6  x  10~   mg/man/day;  and  air  - 9  x  10~
mg/man/day.  The actual dose for the  average  man  is now estimated to be 0.01
mg/man/day (U.S. EPA, 1979a).
III.  PHARMACOKINETICS
     A.  Absorption
         DDT  is  absorbed  from  the  gastrointestinal tract with efficiency ap-
proaching 95  percent when ingested with dietary  fat.   In  humans, Morgan and
Roan  (1971)  showed  that absorption of  an  oral dose of 20 mg DOT proceeded
faster  than  transport  out of  the  vascular compartment  into  tissue storage.
Studies concerning  the  kinetics of absorption of  DOT  via inhalation or der-
mal routes were not found in the available  literature.

-------
     B.  Distribution
         DDT has been  found  in virtually all body  tissues,  approximately in
proportion to respective  tissue content of extractable  lipid.   The adipose/
blood  ratios  of DDT have  been recently estimated  to  be approximately 280:1
(Morgan and  Roan,  1977).  DOT concentrations  in  body  tissues  were highest
for  fat  tissue, followed  by reproductive organs,  the  liver  and  kidney to-
gether,  with lowest  concentrations  found  in  the  brain  (Tomatis,  et  al.
1971).  Elimination  of  very low  levels of DOT  from storage  proceeds much
more slowly than that  of  the large stores of DDT ^accumulated by occupation-
ally exposed workers or dosed  volunteers (Morgan  and Roan, 1971).  The aver-
age North American adult,  with 17 kg of body fat,  contains  approximately 25
mg of  DDT.   It is predicted from storage loss data that,  if dietary intake
were eliminated, most  of  the  DDT would  be  lost within one or  two decades
(U.S.  EPA, 1979a).   Trace metals in the  diet,  particularly  cadmium, may af-
fect the mobilization of DDT in tissues' (Ando, 1979).
     C.  Metabolism
         The metabolism of DDT in man  appears  to  be the same as the pathways
reported by Peterson and Robison  (1964)  for  the mouse.  Generally, two sepa-
rate reductive  pathways produce  the primary endpoint metabolites, p,p'-CDE
and p,p'-ODA.  The predominant  conversion is of DDT to p,p'-ODD via dechlor-
ination.  This  is the  first  product  in a series which results in metabolites
which  are later excreted.   The other primary pathway  proceeds via reductive
                                                                           /
dehydrochlorination  which results  in  the  formation  of p,p'-ODE  the major
storage product in animals  and humans.  Fant,  et  al.  (1977)  suggest that
enzymatic activity  for the  dehydrochlorination and reductive dechlorination
                                                                        •
reactions transforming DDT to  DDO and  DDE is present in all tissues, whereas
the  enzymes  involved  in  the hydrogenation and hydroxylation  steps changing
                                    66-7

-------
ODD to DDA are absent  in  the  brain,  heart, pancreas, and muscle  of the rat.

Metabolic conversion of DOT to DDA proceeds more  rapidly than conversion to

the storage metabolite of DDE.   For  additional information  regarding the DDT

metabolites ODD  and DDE,  the reader is  referred  to the Hazard  Profile for

those chemicals (U.S. EPA, 1979b,c).

     D.  Excretion

         The excretion of DDT  was  investigated in  human volunteer studies of

Hayes, et al. (1971) and Roan,  et  al.  (1971).   Urinary excretion predominat-
                                                   ».
ed, with 13  to  16 percent of  the  daily  dose being excreted as p,p'-DDA, and

was shown to correlate with exposure levels of individuals  working in a for-

mulating plant  (Ortelee,  1958).   p,p'-DDE and DDT are  the  predominant com-

pounds excreted and  p,p'-DOD  and p,p'-DDA are excreted  in  the least amounts

(Morgan and  Roan,  1977).   p,p'-DDE  was  found  in  slightly  higher concentra-

tions in exposed  workers  versus the general population.  Gut microorganisms

have demonstrated a capacity for degradation of DDT to p,p'-DDO and p,p'-ODA.

IV.  EFFECTS

     A.  Carcinogeniity

         Lifetime and  multigeneration  exposures to DDT  in  the diet of rats,

mice, and  fish  have produced significant increases in  the  formation  of  a

number of  tumor  types  (U.S. EPA,  1979a).  The predominant  lesion appears to

be hepatoma.  Also,  Tomatis,  et al.  (1974) demonstrated that short-term ex-

posure to  technical grade  DDT  (37.5  mg/kg/day for  15 or   30 weeks),  using

CF-1 mice, resulted  in an  increased  incidence and early appearance of hepa-

tomas, similar  to that caused  by  lifespan exposure.  "'Mice  appear much more

susceptible than rats  (U.S. EPA, 1979a)  and  the use of  the  mouse  as an ani-
                                                                         «
mal model  for humans has  been criticized  (Deichmann,  1972).  In these stud-

ies contaminants p,p'-ODD and  p,p'-ODE were present,  both of which have pro-

-------
duced liver tumors in  CF-1  mice (Tomatis, et  al.  1974).  Also, the  combina-
tion of p,p'-ODD/DDE was  found to  produce more tumors than  and equal concen-
tration of  either  compound  alone.   Tarjan and Kemeny (1969) noted  leukemias
and pulmonary  carcinomas  in Bald-C mice  fed  3 ppm DDT in the  diet.   Hepato-
mas have been observed in rainbow trout (Halver, et al.  1962).
         A  number  of  other studies  have shown  no  significant increase  in
tumor formation  following DDT  exposure.   Lifetime feeding studies with  Syri-
an  Golden  Hamsters (Agthe,  et al.  1970) and  a number  of long term  feeding
studies with  various  strains of rats  have  shown .no  significant increase  in
tumor incidence  (Cameron  and Cheng, 1951; Fitzhugh and Nelson, 1947; Radom-
ski, et al. 1965; Deichmann, et al.  1967).   In a 78-week  National Cancer In-
stitute study  (1978),  Osborne-Mendel rats given  16 and 32  mg/kg/day  (males)
or  11  and  21  mg/kg/day  (females)  showed no  tumors.   B6C3F1  mice given  3.3
and  6.6 mg/kg/day (males)  or  13 and  26 mg/kg/day  (females)  also showed  no
tumor development.  Durham,  et al.  (1963) found no liver  pathology  in Rhesus
monkeys fed  100 mg/kg/day or  less  DDT for  up  to  7.5 years.  At the  present
                                                                       i
time, no evidence  of  neoplasia has been found in the  studies performed  in
occupationally exposed or dosed volunteer subjects  (U.S. EPA,  1979a).
     B.  Mutagenicity
         DDT  has not  shown  mutagenic  activity in  any  of the  bacterial  test
systems thus  far studied:   Salmonella  typhimurium (McCann,  et  al. 1975;  Mar-
shall,  et  al. 1976);  §_._ coli  Pol-A  strains   (Fluck, et al. 1976);  Bacillus
subtilis (Shirasu, et  al.  1976).   Tests on eukaryotic  yeast cells have  been
uniformly  negative,  with Fahrig (1974)  using Saccharomyces  cerevisiae  and
                                                    •*          ^^^^^••^^^^^^^^^^
Clark (1974)  using Neurospora  crassa.   Vogel   (1972) and  Clark (1974)  found
positive mutagenic activity  in Drosophila melanoqaster by measuring  x-»linked
recessive lethal mutations.  In mammalian systems,  the mutagenic activity  of

-------
DDT is relatively weak.  This  is  evidenced by the  fact  that,  depending upon
the dose and route  of  administration  and the species sensitivity of the test
organisms,  reported  studies are negative  or only marginally  positive (U.S.
EPA, 1979a).  In vivo  and  in vitro cytogenetic studies seem to indicate that
DDT is a clastogenic (chromosome  breaking) substance.   The metabolites p,p'-
DDE, p,p'-ODD,  p,p'-DDA and p,p'-DDOH were  also  non-mutagenic except possi-
bly for  p,p'-DDD  (U.S. EPA,  1979a).   Chromosomal aberrations  in cell lines
of  the kangaroo rat occurred more often  with  p,p'-isomers than o,p'-isomers
(Palmer,  et al. 1972).
     C.  Teratogenicity
         Only •minimal  teratogenic effects have been reported  following high
dosages  of  DDT.  Sprague-Oawley  rats receiving  200 ppm  DDT  in  their diet
showed a significant increase in ring tail, a constriction of the tail fol-
lowed by amputation, in the offspring (Ottoboni, 1969).
     D.  Other Reproductive Effects
         Hart,   et  al.   (1971)  showed  that DDT has  an effect  on prematurity
and causes an  increase in the number  of fetal resorptions  in rabbits given
50  mg/kg on  days  7, 8, and  9  of  gestation.   Chronic exposure  (less than 200
mg/kg) of rats  and  mice produced  no adverse effects on  survival  of the off-
spring (Ware and Good,  1967;  Ottoboni,  1969).   Krause,  et al.  (1975) noted a
damaging effect on  spermatogenesis in  rats  following acute exposure  to DDT
(7,200 mg/kg).   Also,  DDT  has  been shown to  possess  estrogenic activity in
rodents and birds (Welch,  et al. 1969; Bittman, et al. 1968).
     E.  Chronic Toxicity
         A number  of pathological  changes have  been  noted in  rodents;  the
most consistent finding in  lifetime feeding studies has  been  an increase in
the size  of liver,  kidneys,  and  spleen;  extensive degenerative  changes  in

-------
 the  liver;  and an  increased  mortality  rate .(U.S'.  EPA,  1979a).  In contrast
'to  the rodent models,  Rhesus monkeys fed  diets  with up  to  200 ppm DDT did
 not  show liver histopathology, decrease  in weight gain or food consumption,
 or clinical  signs  of illness  (Durham, et  al. 1963).
      F.   Other Relevant Information
          DDT is a  strong inducer  of  the  mixed function oxidase system; this
 could potentially  enhance the biological  effects of other chemicals by  acti-
 vation,  or diminish their activities through detoxification mechanisms  (U.S.
 EPA,  1979a). Exposure to DOT has caused enhanced €umor incidence in N-fluor-
 enacetamide-treated  rats  (Weisburger  and  Weisburger,  1968)  and  decreased
 phenobarbital-induced sleeping times  (Conney,  1967).  Acute  oral  LD-g val-
 ues  in rats typically  range  from  100 to 400  mg/kg and 40 to 60 mg/kg i.v.
 The  oral LD5Q values in other animals are:   60 to  75  mg/kg  (dogs);  250  to
 400  mg/kg (rabbits); approximately 200 mg/kg (mice).  For p,p'-ODE, the val-
 ues  are  330 and 1,240 mg/kg in male and  female rats,  respectively; for  p,p'-
 ODA  in  rats,  the  values are  740 and  600 mg/kg,  respectively  (U.S.  EPA,
 1979a).   Symptoms  of DOT poisoning in humans include  the  following:  convul-
 sions,  parasthesia of extremities and vomiting  (at high doses), convulsions
 and  nausea  (less than  16 mg/kg),  dizziness,  confusion and most characteris-
 tically,  tremors  (Hayes,  1963).   In rats, the liver shows changes at dietary
 doses less than 5  ppm  (Laug,  et  al.  1950).  No permanent injury to .man from
 DDT  has  been recorded (U.S. EPA, 1979a).
 V.    AQUATIC TOXICITY
      A.   Acute Toxicity
          The acute  toxicity  of DDT  to  freshwater  organisms  has  been well
 documented.   Data  are  available   for 25  species of  fish.   The 96-hour LC5Q
 values are available for the following freshwater fish:  rainbow trout  (Sal-
                                   Co//

-------
mo qairdneri),  1.7  to 42 pg/1; fathead minnow  (Pimephales promelas),  7.4 to
58 pg/1;  channel catfish  (Ictalurus  punctatus),  16  to 17.5  pg/1;  bluegill
(Lepomis macrochirus),  1.2  to  210 pg/1.  The most  sensitive of fish was the
yellow perch  (Perca  flavesceus)  with a  96-hour  LC5Q of  0.6  pg/1 (Marking,
1966).  Invertebrate  freshwater species  are more sensitive than  fish.   For
Daphnia maqna,  48-hour LC5Q values of  1.48 pg/1  have  been reported (Pries-
ter,  1965).   One  week  old  crayfish  (Orconectus nais) had a  96-hour  LC5Q
value  of  0.18 pg/1  (Saunders,  1972).  LC5Q  values for nine  saltwater  fish
species range  from  0.2  to  4.2 pg/1.   Saltwater  invertebrates  were  slightly
more  sensitive,  with LC5Q values  ranging from 0.14 to 10.0 pg/1  (U.S.  EPA,
1979a).
         Concentrations  as  low as 8 pg/1 elicited  hyperactive locomotor re-
sponses in bluegill  (Lepomis macrochirus) over  16 days  old (Ellgaard,  et al.
1977).  The  acute  LD_Q  in  adult  summer frogs  (Rana  temporaria)  was  only
7.6 mg/kg.  Though adipose tissues contained most of  the DOT,  the  ovaries of
females contained as  much of the  compound as  did bones and spleen (Harri, et
al. 1979).
     B.  Chronic Toxicity
         Only  one  chronic  freshwater  fish value  is  available (Pimephales
promelas). indicating that  the chronic toxicity  value is  0.74 pg/1 (Jarvi-
nen,  et al.,  1977).   Freshwater  invertebrate  chronic toxicity  data  are not
available.  Concentration of DDT  affecting  three  saltwater invertebrate  spe-
cies in chronic studies are similar in LC5Q values (U.S. EPA, 1979a).
     C.  Plant Effects
         Four  species of freshwater  algae  (Calovella sp.)  have evidenced  a
wide  range  of  sensitivities,  0.3  to 800 pg/1 (Sodergren, 1968).   Wu'rster
(1968) investigated the  effects of  DDT  on four species of  marine algae.   The

-------
data showed  reduced  rates of photosynthesis•at  10 /ug/1, indicating  that  al-

gae are much less  sensitive to DOT  than  are  fish  and  invertebrates.

     0.  Residues

         DOT is  bioconcentrated  to a  very  high  degree in  aquatic  organisms.

An average bioconcentration  factor (BCF) of 640,000  has been  calculated from

31  experimental  measurements  of  bioconcentration  done   on  26  species  of

freshwater  fish.  Individual  BCF's  ranged  from  490 to  2,236,666.   In  the

field,  BCF  factors have  been observed which are seven times  higher  than  the

average values derived from  laboratory data.  This discrepancy may be due to

the  many  additional  trophic  levels  involved  and  the  possibly higher  lipid

content of  the  organisms in  the field.   In saltv/ater species,  the  BCF  for

DOT  ranges  from  800 to 76,300  times  for fish  and shellfish  (U.S.   EPA,

1979a).  The lowest observed allowable  maximum  tissue concentration was  0.5

jug/kg  for  domestic animals in animal feed (U.S. FDA, 1977) and in the  brown

pelican  (Pelecanus occidentalis)  for eggshell thinning (Blus,  et al.  1972,

1974).

VI.  EXISTING GUIDELINES  AND STANDARDS

     Neither  the human health nor the  aquatic  criteria derived by  U.S.  EPA

(1979c), 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 existing  guidelines and  standards for DDT are:

                                                     V*
     YEAR     AGENCY/ORG.          STANDARD       REMARKS

     1971     WHO                   0.005 mg/kg     Maximum Acceptable Daily
                                    body weight     Intake  in food

     1976     U.S. EPA             0.001 ug/1      Ambient Water Quality
                                                    Criteria

-------
     1977     Natl.  Acad.  Sci.,          -          In light  of carcinogenic
              Natl.  Res.  Counc.                     risk projection,  suggested
                                                   strict criteria  for  DDT
                                                   and DDE in  drinking  water
     1978     Occup. Safety         1 mg/m2        Skin exposure
              Health Admin.
     1978     U.S. EPA              0.41,ug/l      Final acute and  chronic
                                    0.00023 ,ug/l    values for  water quality
                                                   criteria  for protection of
                                                   aquatic life (freshwater)

         The  U.S.  EPA  (1979a)  is  in  the  process  of establishing ambient
                                                  «.
water quality criteria.  Based on the potential carcinogenicity of DDT,  cur-
rent  draft  criteria  are   calculated  on the  estimate  that 0.98 jug/man/day
would result in an  increased additional  lifetime  cancer  risk  of no more  than
1/100,000.  Since  man and  the  rat  appear  to  be  less  sensitive  than mice,
greater levels may be tolerable.
     B.  Aquatic
         For DDT, the proposed draft  criterion to protect freshwater aquatic
life is 0.00023jug/1  as a  24-hour  average;  the concentration  should not ex-
ceed 0.41 yug/1  at any time.  For  saltwater aquatic  species,  the  concentra-
tion is 0.0067^ug/l as a 24-hour average and should  not  exceed 0.021yug/l at
any time (U.S. EPA,  1979a).
                                           /
                                  Co-If

-------
                                     DDT

                                  REFERENCES
Agthe, C.,  et al.  1970.  Study  of the potential carcinogenicity  of  DDT in
the Syrian Golden hamster.  Proc.  Soc. Exp. Biol. Med.  134: 113.

Ando, M.  1978.   Transfer of 2,4,5,2',4',5'-hexachlorobiphenyl and 2,2,-bis-
(p-chlorophenyl)-l,l,l-trichloroethane(p,p'-ODT)  from  maternal  to  newborn
and suckling rats.  Arch. Toxicol.  41: 179.

Bittman, J., et al.  1968.   Estrogenic  activity  of  o.,p'-ODT in the mammalian
uterus and avian oviduct.  Science  162: 371.

Blus, L.J., et al.   1972.  Logarithmic relationship of DOE  residues  to egg-
shell thinning.  Nature  235: 376.

Blus, L.J.,  et al.  1974.   Relations of the brown pelican  to certain envi-
ronmental pollutants.  Pestic. Monit. Jour.  7: 181.

Cameron,  G.R.,  and K.  Cheng.  1951.   Failure of oral  DDT to  induce toxic
changes in rats.  Br. Med. Jour. 819.

Clark, J.M.   1974.  Mutagenicity  of DDT in mice,  Drosophila melanoqaster and
Neurospora crssa.  Aust. Jour. Biol. Sci.  27: 427.

Coleman,  w.E.  and R.G. Tardiff.   1979.   Contaminant levels in  animal feeds
used for toxicity studies.  Arch.  Environ. Contam. Toxicol.  3: 693.

Conney, A.M.   1967.   Pharmacological  implications  of microsomal  enzyme in-
duction.  Pharmacol.  Rev.  19: 317.

Deichmann, W.8.  1972.   The debate on DDT.  Arch. Toxicol.  29: 1.

Deichmann, W.B.,  et  al.  1967.   Synergism among oral carcinogens.   IV.  The
simultaneous  feeding of four tumorigens to  rats.   Toxicol.  Appl.  Pharmacol.
11: 88.

Durham, W.F.,  et  al.   1963.   The effect  of various  dietary levels of DDT on
liver function, cell morphology and  DDT storage  in  the  Rhesus  monkey.   Arch.
Int. Pharmacokyn. Ther.  141: 111.

Ellgaard,  E.G., et al.   1977.  Locomotor hyperactivity induced  in the blue-
gill sunfish,  Lepomis  macrochirus, by  sublethal  corrections of DDT.   Jour.
Zool.  55: 1077.

Fahrig, R.   1974.  Comparative mutagenicity studies with  pesticides.   Page
161  in  R. Montesano and L.  Tomatis,  eds.  Chemical carcinogenesis  essays,
WHO.  IARC Sci. Publ. No. 10.
                                                                       »
Fang, S.C.,  et al.  1977.   Maternal transfer  of 14C-p-p'-ODT  via placenta
and milk and  its metabolism  in  infant rats.   Arch.  Environ.  Contam. Toxicol.
5: 427.
                                      60'

-------
Palmer, K.A.   1972.  Cytogenic  effects of DDT  and  derivatives of  DDT  in a
cultured mammalian cell line.  Toxicol. Appl. 'Pharmacol.  22: 355.
Peterson,  J.E.  and  W.H. Robison.   1964.   Metabolic products of  p,p'-ODT in
the rat.  Toxicol. Appl. Pharmacol.  6: 321.
Priester,  E.L.,  Jr.  1965.   The accumulation and  metabolism of  DDT,  para-
thion,  and  endrin by aquatic  food-chain  organisms.   Ph.D.  Thesis.   Clemson
Univ.  Clemson, S.C.  74 p.
Radomski,  J.L., et  al.   1965.   Synergism  among oral carcinogens.   I. Results
of  the simultaneous  feeding  of four  tumorigens to  rats.  Toxicol.  Appl.
Pharmacol.  7: 652.
Roan, C.,  et  al.  1971.  Urinary excretion of ODA following ingestion of DDT
and DDT metabolites in man.  Arch. Environ. Health  22: 309.
                                                   •.
Shirasu,  V.,  et  al.   1976.   Mutagenicity  screening  of  pesticides  in  the
microbial system.  Mutat. Res.  40: 19.
Sodergren,  A.  .1968.  Uptake  and accumulation  of  C^-DDT by  Chlorella  sp.
(Chlorophyceae) Oikos  19: 126.
Stanley,  C.W.,  et  al.   1971.   Measurement  of atmospheric levels  of pesti-
cides.  Environ. Sci. Technol.  5: 430.
Tarjan, R.  and T.  Kemeny.   1969.  Multigeneration  studies on DDT  in mice.
Food Cosmet. Toxicol.  7: 215.
Tomatis,  !_.,  et  al.  1971.  Storage levels  of DDT  metabolites  in mouse tis-
sues following long-term exposure to technical DDT.  Tumcri  57: 377.
Tomatis,  L.,  et al.   1974.   Effect  of  long-term exposure to l,l-dichlor-2,2-
bis(p-chlorophenyl)   ethylene,  to l,l-dichloro-2,2-bis  (p-chlorophenyl)  eth-
ane,  and  to  the  two chemicals  combined  on  CF-l mice.   Jour. Natl. Cancer
Inst.  52: 883.
U.S. EPA.   1979a.  DDT: Ambient Water Quality Criteria.  (Draft).
U.S. EPA.   1979b.   Environmental Criteria and Assessment  Office.   DDE:  Haz-
ard Profile.  (Draft).
U.S. EPA.   1979c.   Environmental Criteria and Assessment Office.   ODD:  Haz-
ard Profile.  (Draft)
U.S. FDA.   1977.  Administrative Guidelines Manual 7426-04, Attachment E.
Vogel, E.   1972.  Mutagenitatsuntersuchungen  mit DDT und den DDT-metaboliten
DDE, ODD,  DOOM und DDA. an Drosphila melanoqaster.  Mutat. Res.   16: 157.
Ware, G.W. and E.E.  Good.  1967.  Effects of insecticides on reproduction in
the  laboratory  mouse.   II.  Mirex,  Telodrin  and DDT.   Toxicol.  Appl.  Phar-
macol.  10: 54.

-------
Weisburger,  J.H.  and* E.K. Weisburger.  1968,   Food  additives and chemical
carcinogens:  on   the  concept  of  zero  tolerance.   Food  Cosmet.  Toxicol.
6: 235.

Welch, R.M.,  et al.   1969.  Estrogenic action  of DDT  and  its analogs.  Toxi-
col. Appl.  Pharmacol.  14: 358.

Wolfe, H.R. and J.F. Armstrong.  1971.  Exposure of  formulating plant work-
ers to DDT.   Arch. Environ. Health  23: 169.

Wolfe, H.R.,  et al.  1967.  Exposure  of workers  to pesticides.  Arch. Envi-
ron. Hlth.   14: 622.

Wurster,  C.F.,  Jr.  1968.  DOT reduces photosynthesis by marine phytoplank-
ton.  Science.   159: 1474.
                                       60-/7

-------
                                       No.  61
        DibroraochloroTTiethane


  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.

-------
                      DIBRCMOCHLORCMETHANE








SUMMARY



     Dibromochlorome thane has been detected  in drinking  water in



the United States.   It is believed to be formed by the haloform



reaction that may occur during water chlorination.  Dibromochlo-



romethane can be removed from drinking water via treatment  with



activated carbon.  There is a potential for  dibrcmochlorome thane



to accumulate in the aquatic evironment because of its resistance



to degradation.  Volatilization is likely to be an important



means of environmental transport.



     Very little toxicity information is available.   Dibromochlo-



romethane gave positive results in mutagenicity tests with



Salmonella typhinurium TA100.  It  is currently under test by the



National Cancer Institute.








I.   INTRODUCTION



     Dibromochlorome thane (CHBr2Cl, molecular weight 208.29)  is a



clear, colorless liquid.  It is insoluble in water,  but  is  solu-



ble in a number of organic solvents.  Its boiling point  is  119-



120°C and its density is 2.45 at 20°C (Weast, 1972).   At 10.5°C,



its vapor pressure is 15 torr (Dreisbach, 1952).



     A review of the production range (includes importation)



statistics for dibrcmochlorome thane (CAS No.'124-48-1) which is



listed in the initial TSCA Inventory (1979)  has shown that

-------
between 0 and 900 pounds  of  this  chemical were produced/imported

in 197 7._y

     Dibromochloromethane is used  as  a  chemical  intermediate in

the manufacture of fire  extinguishing agents, aerosol propel-

lants, refrigerants, and  pesticides (Verschueren, 1977).



II.  EXPOSURE

     A. .  Environmental  Fate

     No information was  found pertaining  to  the  rate of oxidation

of dibromochloromethane  in either  the aquatic or atmospheric

environments.  Dibromochlorome thane is  probably  like other halo-

genated aliphatics in that it is  not easily  oxidized in aquatic

systems because there are no functional groups which react

strongly with HO radical.  A maximum  hydrolytic  half-life of 274

years has been reported  for  dibrcmochloronethane at pH 7 and 25°C

(Mabey and Mill, 1978).

     The vapor pressure  of dibromochlorone thane, while lower than

that for chloroform and  other chloroalkanes, is, nonetheless,

sufficient to ensure that volatilization  will be an important

means of environmental transport.  The  concentration of dibromo-

chlorome thane present in water supplies has  been reported to
   This production range  information does no't 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).
                            th*

-------
decrease as a result of volatilization while flowing through open

channels (Rook, 1974).

     B.   Bio accumulation

     The log of the octanol/water partition coefficient (log P)

as calculated by the method of Hansch is 2.09  (Tute, 1971)  indi-

cating that dibromochloromethane is somewhat lipophilic.   As a

result, dibromochloromethane may exhibit a tendency to bioac-

cumulate in organisms.  No experimental data were found to

confirm this.

     C.   Environmental Occurrence

     Dibromochloromethane has been detected in finished drinking

water (Kleoper and Fairless, 1972; U.S. EPA, 1975), in drinking

water supplies (U.S. EPA, 1975), and in wastewater effluents

(Glaze and Henderson, 1975).  Dibromochloromethane is hypothe-

sized to be present in water supplies as a result of the  haloform

reaction which takes place during the chlorination of such  water

(Rook, 1974; U.S.  EPA, 1975; Glaze and Henderson 1975).



III. HEALTH EFFECTS

     A.   Carcinogenicity

     Dibromochloromethane is currently under test for

carcinogenicity by the National Cancer Institute.  No results are

available.

     B.   Mutagenicity

     Dibromochloromethane was found mutagenic  in Salmonella
                                                           »
typhimurium TA100  in the absence of metabolic  activation  (Simmon

1977) .

-------
     C.   Other Toxicity


     A long-term test conducted  by  administration of high doses


of the chemical by gavage  in  mice showed a dose-dependent


decrease in the activity of liver and  spleen phagocytes (Munson


ejt _al_. , 1978).


     The oral  LD5Q of dibroraochlororaethane in mice is 800 mg/kg


and 1200 mg/kg  for males and  females respectively.  Sedation and


anesthesia occurred within 30 minutes  of administration of the


compound and lasted 4 hours.  Necropsies were performed on ani-


mals that died.  Hemorrhaging was observed in the adrenals, the


kidneys were pale, and the liver appeared to have fatty infiltra-


tion (Bowman,  1978).




IV.  AQUATIC EFFECTS


     No information was found.




V.   EXISTING GUIDELINES


     The Maximum Contaminant  Level  (MCL) for total trihalometh-


anes (including dibromochloromethane)  in drinking water has been

set by the U.S. EPA at 0.10 mg/1 (44 FR 68624).  The concentra-


tion of dibromochloromethane  produced  by chlorination can be


reduced by treatment of drinking water with powdered activated


carbon (Rook,  1974).  This is the technology that has been pro-


posed by the EPA to meet this standard.
                               /
                               •«

                             Cl-t

-------
                            REFERENCES

Bowman, F.J. e_t _al_.  The Toxicity of Some Salome thanes in Mice.
Toxicology and Applied Pharmacology 44, 213-215, 1978.

Dreisbach, R.R.  Pressure-Volume-Temperature Relationships of
Organic Compounds,  Handbook Publishers, Inc. Sandusky, Ohio
1952.

Glaze, W.H. and J.E. Henderson, IV.  Formation of Organochlorine
Compounds from the Chlorination of a Municipal Secondary Efflu-
ent.  Journal Water Pollution Cont. Fed. 47, 2511-2515, 1975.

Kleopfer, R. D. and B.J. Fairless.  Characterization of Organic
Components in a Municipal Water Supply.  Environ. Sci. Technol.
6(12), 1036-1037, 1972.

Plabey, W. and T. Mill.  Critical Review of Hydrolysis of Organic
Compounds in Water Under Environmental Conditions J. Phys. Chen.
Ref. Data-7, 103, 1978.

Munson, A.Z. a_t _al_.  Retoculoendothelial System Function in Mice
Exposed to Four Kaloalkanes: Drinking Water Contaminants.
Toxicology and Applied Pharmacology 45(1), 329-330, 1978.

Rook, J.J.  Formation of haloforms during chlorination of natural
watars.   Journal of the Society of Water Treatment and Examina-
tion 23(Part 2), 234-243, 1974"

Rook, J.J.  Chlorination Reactions of Fulvic Acids in Natural
Waters. Environ. Sci. Technol. 11(5), 473-432, 1977.

Simmon, v.F.  Structural Correlations of Carcinogenic and
Mutagenic Alkylhalides, Proc. 2nd FDA Office of Science Summer
Sym. 163-171, 1977.

Tute, M.S.  Principles and Practices of Hansch Analysis.  A Guide
to Structure-Activity Correlation for the Medicinal Chemist.
Advances  in Drug Research 6, 1-77, 1971.

U.S. EPA.  Preliminary Assessment of Suspected Carcinogens in
Drinking Water.  EPA 560/4-75-003, 1975.

U.S. EPA.  Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-
Confidential Initial TSCA Inventory, 1979.
                                            .•
Verschueren, K.  Handbook of Environmental Data on Organic
Chemicals.  Van Nostrand Reinhold Co., New York. 1977.
                                                           »
Weast, R. C. , ed. 1972.  CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.                          '

-------
                                      No. 62
        Di~n-butyl Phthalate


  Heal-th and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, D.C.  20460

           APRIL 30, 1980
                     a.-'

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

-------
                          DI-n-BUTYL PHTHALATE




                                Summary





      Teratogenic effects in rats have been reported in testing of di-



n-butyl phthalate following i.p. administration, but not after oral



administration at high doses (0.600 g/kg/day).  Other reproductive




effects in rats following i.p.  administration include impaired implantation




and parturition.  Rats fed di-n-butyl phthalate or its monoester metabolite



have developed testicular damage and atrophy.




      Mutagenic or carcinogenic effects of di-n-butyl phthalate have




not been reported.



      One clinical study has indicated that workers exposed primarily,




but not exclusively, to di-n-butyl phthalate showed a higher incidence




of toxic polyneuritis.



      The only toxicity data available for review demonstrate that di-



n-butyl phthalate is acutely toxic to freshwater organisms at concentrations




as low as 730 _ug/l.

-------
                          DI-n-BUTYL PHTHALATE



I.    INTRODUCTION




      This profile  is based on  the  Ambient Water Quality  Criteria  Document




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




      Di-n-Butyl phthalate (DBP) is a diester of the ortho  form of




benzene dicarboxylic acid. The  compound has a molecular weight of  278.34,




specific gravity of 1.0465, boiling point of 340°C and a  solubility of




0.45 gms per 100 ml of water at  25°C (U.S. EPA, 1979a).




      DBP is used as a plasticizer  in polyvinyl acetate emulsions  and




as an insect repellent.




      Current Production:  8.3  x 103 tons/year in 1977 (U.S. SPA,  1979a).




      Phthalates have been detected in soil, air, and water samples, in




animal and human tissues, and in certain vegetation.  Evidence from in




vitro studies indicates that certain bacterial flora may  be capable of




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




additional information regarding the phthalate esters in  general,  the




reader is referred to the EPA/ECAO Hazard Profile on Phthalate Esters



(U.S.  EPA, 1979b).



II.   EXPOSURE




      Phthalate esters appear in all areas of the environment.  Environmental



release of phthalates may occur through leaching of the compound from



plastics, volatilization of phthalate from plastics, or the incineration



of plastic items.  Sources of human exposure to phthalates include



contaminated foods and fish,  dermal application, ,and parenteral administration




by use of plastic blood bags, tubings,  and infusion devices (mainly



DEHP release).   Relevant factors in the migration of phthalate esteVs



from packaging materials to food and beverages are: temperature,  surface



area contact, lipoidal nature of the food and length of contact (U.S.




EPA, 1979a).

-------
      Monitoring studies have indicated that most water  phthalate  concen-



trations are in the ppm range, or 1-2 pg/liter  (U.S.  EPA,  1979a).   Industrial



air monitoring studies have measured air levels of phthalates  from 1.7



to 66 mg/m3 (Milkov, et al. 1973).  Levels of DBF in  foods  have  ranged



from not detectable to 60 ppm (Tomita, et al. 1977).  Cheese,  milk,



fish and shellfish present potential sources of high  phthalate intake'



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



average bioconcentration factor for DBP to be 26 for  the edible  portions



of fish and shellfish consumed by Americans.  This estimate was  based



on the octanol/water partition coefficient.



III.  PHARMACOKINETICS



      A.    Absorption



            A human study in which subjects ate food  containing  DBP



leached from plastic containers shows significantly higher  levels  of



DBP found in the blood (Tomita, et al. 1977).



      B.    Distribution



            Pertinent data could not be located in the available literature.



      C.    Metabolism



            Monobutyl phthalate has been identified as a urinary metabolite



in rabbits administered DBP (Ariyoshi, et al. 1976).  This  metabolite



has also been detected in the urine of rats, hamsters, and  guinea  pigs,



as well as other metabolites with side chain oxidation, and phthalic



acid (Tanaka,  et al. 1978).

                                                      *

      D.    Excretion



            Pertinent data could not be located in the available literature.
                                                                        »


                                   i.

-------
IV.   EFFECTS


      A.     Carcinogenicity



             Pertinent data could not be located in  the available  literature.


      B.     Mutagenicity



             Mutagenic effects of DBF were not observed in the Ames



Salmonella assay (Rubin, et al. 1979) or in a yeast  (Saceharomyces)



assay system (Shahin and VonBorstel, 1977).


      C.     Teratogenicity



             Teratogenic effects were not produced by DBF, (0.600  g/kg/day),


following oral administration to pregnant rats (Nikonorow, et al.  1973)


while Singh, et ai. (1972) reported teratogenic effects of DSP following


i.p. injection of pregnant rats.



      D.     Other Reproductive Effects


             Intraperitoneal injection of DBF to pregnant rats showed


that adverse effects prior to gestation day six were primarily on  implanta-


tion, while after this day the effect was primarily on parturition



(Peters and Cook 1973).


      Testicular damage has been reported in rats fed DBF or its monoester


metabolite (Carter, et al. 1977).


      E.     Chronic Toxicity


             An increase in toxic polyneuritis has been reported by •



Milkov,  et al.  (1973) in workers exposed primarily to difautyl phthalate.


Lesser levels of exposure to dioctyl, diisooctyl, and benzylbutyl phthalates,
                                                   .•

and to tricresyl phosphate were also noted in these workers.

-------
V.    AQUATIC TOXICITY

                                          •.

      A.     Acute Toxicity               >



             Acute toxicity for di-n-butyl phthalate ranged from a 96-



hour static LC5Q of 730 jug/1 for the bluegill sunfish (Lepomis macrochirus)



to 6,470 ug/1 for the rainbow trout (Saline gairdneri) (Mayer and Sanders,



1973).  The freshwater scud (Gammarus pseudolimnaeus) was shown to



provide a 48-hour static LC5Q value of 2,100 ug/1 di-n-butyl phthalate.



Marine data were not available for review.



      B.     Chronic



             Pertinent data could'not be located in the available literature.



      C.     Plants



             Pertinent data could not be located in the available literature.



      0.     Residues



             Bioconcentrat-ion factors ranging from 400 to 1400 have been obtained



for the aquatic invertebrates Daphnia magna and Gammarus  pseudolimnaeus.



VI.   EXISTING GUIDELINES AND STANDARDS



      Neither the human health nor aquatic criteria derived by U.S. EPA (1979a),



which are summarized below, have gone through the process of review;  therefore.



there is a possibility that these criteria may be changed.



      A.     Human



             Based on "no effect" levels observed in chronic feeding studies



in rats or dogs, the U.S. EPA (1979a) has calculated an acceptable daily



intake (ADI) level of 12.6 mg/day.



             The recommended water quality criterion level for protection



of human health is 5 mg/liter for DBP (U.S.  EPA, 1979a).
                                                     «•


      B.     Aquatic



             The data base for toxic effects in both freshwater and marine



environments was insufficient for the drafting of a water quality criterion



to protect aquatic organisms.
                                 6J.-7

-------
                     DI-n-BUTYL PHTHALATE
                          REFERENCES

Ariyoshi, T.,  et  al.   1976.   Metabolism of dibutyl phthalate
and the effects of  its  metabolites on animals.   Kyushu Yaku-
gakkai Kaiho 30: 17.

Carter, B.R.,  et  al.   1977.   Studies  on  dibutyl phthalate-
induced testicular atrophy in  the  rat:   Effect on zinc metabo-
lism.  Toxicol. Appl. Pharmacol. 41:  609.

Engelhardt,  G.,  et  al.    1975.    The  microbioal  metabolism
of  di-n-butyl  phthalate  and  related  dialkyi  phthalates.
Bull. Environ. Contain. Toxicol. 17: 342.

Mayer, F.L.,  Jr.,  and  H.O.  Sanders.   1973.   Toxicology of
phthalic acid  esters  in aquatic organisms.   Environ.  Health
Perspect. 3: 153.

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

Nikonorow, M.,  et al.  1973.   Effect of orally administered
plasticizers and  polyvinyl chloride  stabilizers in  the rat.
Toxicol.  Appl. Pharmacol. 26:  253.

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

Rubin, R.J., et al.   1979.  Ames  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.

Shahin, M.,  and R.  Von  Borstel.   1977.   Mutagenic  and lethal
effects  of  a-benzene  hexachloride,  dibutyl  phthalate  and
trichloroethylene  in  Saccharomyces  cerevisiae.   Mutat.  Res.
48: 173.

Singh, A., et  al.   1972.   Teratogenicity of phthalate esters
in rats.   Jour. Pharm. Sci. 61: 51.

Tanaka, A.,  et al.   1978.   Biochemical studies  on phthalic
esters.   III.    Metabolism  of  dibutyl phthalate   (DBP)  .in
animals.   Toxicology 1: 109.

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

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

U.S.  EPA.    1979b.   Environmental  Criteria  and  Assessment
Office.  Phthalate Esters:  Hazard Profile  (Draft).

-------
                                      No. 63
       Dibenzo(a,h)anthracene


  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.
                            63-3-

-------
                      SPECIAL NOTATION










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



dibenzo(a,h)anthracene and has found sufficient evidence  to



indicate that  this compound is carcinogenic.
                            63-4

-------
                      DIBENZO(a,h)ANTHRACENE



                             Summary



     Dibenzo(a,h)anthracene  (DBA)  is  a  member of  the polycyclic



aromatic hydrocarbon  (PAH)  class.   DBA was  the  first pure chemi-



cal  shown  to produce  tumors  in  animals.   It  is  carcinogenic by



skin  application,  by  injection,  and  by  oral administration to



rodents.  Since humans are not exposed to only DBA in  the environ-



ment,  it  is  not possible  to  attribute  human cancers  solely to



exposure to DBA.  Furthermore,  it is not known how DBA may inter-



act  with  other  carcinogenic  and  non-carcinogenic  PAH  in  human



systems.

-------
                      DIBENZO(a,h)ANTHRACENE



I.    INTRODUCTION



     This profile  is  based  primarily on the Ambient Water Quality



Criteria Document for  Polynuclear  Aromatic Hydrocarbons  (U.S.  EPA,



1979a)  and the Multimedia Health Assessment  Document for Polycyclic



Organic Matter (U.S. EPA.  1979b).



     Dibenzo(a,h)anthracene  (DBA;  C22H14^  is one of the family of



polycyclic aromatic hydrocarbons (PAH)  formed, as  a  result of  incom-



plete  combustion  of  organic  material.   Other  than  a  reported



melting point of 266-266.5°C (U.S.  EPA.   1979b), its physical and



chemical properties have not' been well-characterized.



     PAH, including DBA are ubiquitous  in  the environment, being



found  in  ambient air, food, water,  soils  and sediment (U.S. EPA.



1979b).   The  PAH  class contains  a number  of  potent carcinogens



(e.g.,   benzo(a)pyrene),  moderately  active  carcinogens   (e.g.,



benzo(b)fluoranthene),  weak  carcinogens  (benz(a)anthracene),  and



cocarcinogens (e.g., fluoranthene), as well  as numerous non-carcin-



ogens  (U.S.  EPA.   1979b).



     PAH which contain .more  than  three  rings  (such  as DBA) are re-



latively stable  in the  environment,  and may be transported  in air



and water by adsorption to particulate matter. However, biodegrad-



ation and chemical treatment are  effective  in eliminating most PAH



in the environment.



II.  EXPOSURE



     A.   Water



          Levels of DBA  in water  have not been reported.  However,



the concentration of six representative  PAH  (benzo(a)pyrene,  fluor-

-------
anthene,  benzo( j) fluoranthene,   benzo(k). fluoranthene,  benzo(ghi)-
perylene, indeno(l,2,3-cd-pyrene)  in  United States drinking water
averaged 13.5 nanograms/liter (Basu and Sacena, 1977,  1978).
     B.    Food
          Based  on  limited monitoring  studies, DBA  has been  de-
tected  in  various foods,  such  as, butter  and smoked fish.    Al-
though,   it  is not possible  to estimate  the  human dietary intake
of DBA,  it has  been  concluded  (U.S. EPA.  1979b)   that  the daily
dietary  intake  of  all types  of PAH  is about  1.6 to  16  ug  per
day.   The  U.S.  EPA  (1979a)  has  estimated  the  weighted average
bioconcentration  factor  of DBA  to  be 24,000  for  the edible  por-
tions of fish and shellfish consumed  by Americans.  This estimate
is based on the octanol/water partition coefficient for  DBA.
     C.    Inhalation
          Levels  of  DBA have  not  been monitored  in  ambient  air.
However, it has been estimated that the average total  PAH level in
ambient air is about 10.9 nanograms/m  (U.S. EPA,  1979a). Thus the
total daily intake of PAH by  inhalation  of ambient  air  may be about
207 nanograms, assuming that  a human breathes 19 m   of  air per  day.
III. PHAPjyiACOKINETICS
     There are no data.available concerning the pharmacokinetics of
DBA, or  other PAH, in humans.   Nevertheless, it is  possible  to  make
limited  assumptions  based  on the  results of animal research  con-
ducted with several PAH, particularly benzo(a)pyrene.
     A.    Absorption
          The absorption of DBA  in humans or  other  animals has not
been  thoroughly  studied.   However, it  is  known (U.S.  EPA,  1979a)
that, as a class, PAH  are well-absorbed across  the  respiratory and
                                t

-------
gastrointestinal epithelia.  The  high  lipid  soluoility of compounds
  in the  PAH class  supports this observation.
       B.    Distribution
            Only limited  work  on distribution  of  DBA  in  mammals
  has  been  performed   (Heidelberger  and  Weiss,   1959).    However,
  it is  known  (U.S.  EPA,  1979a)  that  other  PAH become  localized
  in a  wide  variety of  body  tissues  following  their  aosorption
  in experimental  rodents.   Relative  to other  tissues, PAH  tend
  to localize in body fat and fatty tissues  (e.g.,  breast).
       C.    Metabolism
            The-mammalian metabolism of DBA has been well-character-
  ized  (Sims,  1976).   DBA,  like  other  PAH,  is  metabolized,  by  the
  microsomal mixed function  oxidase  enzyme  system in  mammals (U.S.
  EPA.   1979b) .   Metabolic  attack  on one or  more of  the aromatic
  rings leads  to the  formation of  phenols, and  isomeric dihydro-
  diols by the  intermediate formation of  reactive epoxides.  Dihydro-
  diols are  further  metabolized  by  microsomal mixed  function  oxi-
  dases to  yield diol  epoxides,- compounds  which are  known to  be
  ultimate  carcinogens for  certain PAH.  Removal of activated inter-
  mediates   by  conjugation   with  glutathione  or  glucuronic  acid,
  or Dy  further  metabolism  to tetrahydrotetrols,  is  a key  step
  in protecting the  organism from toxic interaction with cell macro-
  molecules.
       D.    Excretion
                                               .-
            There is no direct  information available  concerning  the
  excretion  of PAH in man.  The  excretion of  DBA however, by mic"e  was
  studied by Heidelberger and Weiss  (1959).   The excretion  of DBA was

-------
rapid and occurred mainly via  the  feces.   Elimination in the bile
accounts for a  significant percentage of all administered PAH (U.S.
EPA, 1979a).   It is unlikely that  PAH  will accumulate in the body
with chronic low-level exposures.
IV.  EFFECTS
     A.    Carcinogenicity
          DBA  was  the first pure  chemical ever  shown  to produce
tumors  in   animals.   DBA  has  considerable carcinogenic  potency
when applied to  the  skin of mice  (Iball,  19.39;  U.S.  EPA. 1979b) ,
injected  subcutaneously  in  mice  (U.S.  EPA.     1979b),  injected
into  newborn mice  (Beuning,  et al.  1979), injected  into  Strain
A mice  (Shimkin  and  Stoner,  1975)  or  administered  orally to mice
(Snell and  Stewart, 1962).
     B.    Mutagenicity
          DBA is a mutagenic in the Ames Salmonella  assay  (Andrews,
et al. 1978; Wood,  et  al.  1978)  in  cultured  hamster  cells  (Huberman
and Sacks,  1974) ,  and is positive  in the  ir± vivo sister-chroraatid
exchange  assay  in Chinese  hamsters   (Roszinsky-Kocher,  et  al.
1979).
     C.    Teratogenicity
          There are no data  available concerning  the possible tera-
togenicity  of  DBA  in man.  Other  related PAH apparently  are  not
significantly  teratogenic in mammals (U.S. EPA, 1979a).
     D.    Other Reprodutive Effects
          Pertinent information could  not be located  in the avail-
able literature.
                               63-*

-------
     E.   Chronic Toxicity

          As long ago as 1937,  investigators  knew  that carcinogenic

PAH, including DBA, could inhibit growth in rats  and mice  (Haddow,

et al. 1937) .   In early studies, DBA was  administered  to mice in

weekly subcutaneous  injections for  40  weeks, which  produced in-

creased reticulum  (stem) cells, dilation of lymph sinuses, and de-

creased  spleen  weights  in  comparison  to controls   (Hoch-Ligeti,

1941) .

          A  more  detailed study  of  subchronic effects  of DBA on

lymph nodes of male rats was reported in 1944  (Lasnitzki and Wood-

house, 1944).  Subcutaneous injections given  five times weekly for

several weeks caused  normal lymph nodes  to  undergo hemolymphatic

changes.

V.   AQUATIC TOXICITY

     Pertinent  information  could  not be located  in  the available

literature.

VI.  EXISTING GUIDELINES AND STANDARDS

     Neither  the  human  health nor  aquatic  criteria  derived  by

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

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

bility that  these  criteria may be changed.

     A.   Human

          There are no established exposure criteria  for DBA. How-

ever,  PAH  as a  class  are  regulated  by several authorities.  The

World Health Organization recommends that  the  concentration  of PAH
                                                              9
in drinking  water  (measured as the  total  of  fluoranthene,  benzo-

(g,h,i)perylene,   benzo(b)fluoranthene,  benzo(k)fluoranthene,  in


                                sf

-------
deno(l,2,3-cd)pyrene,  and benzo(a)pyrene)  not  exceed  0.2  ug/1.

Occupational  exposure criteria  have  been  established   for  coke

oven emissions,  coal tar products, and  coal tar pitch volatiles,

all  of  which  contain large  amounts  of  PAH including  DBA  (U.S.

EPA, 1979a).

          The  U.S.   EPA   (1979a)  draft  recommended  criteria  for

PAH in water are based upon the extrapolation of animal carcinogenicity

data for benzo(a)pyrene and DBA.  Levels for each compound are de-

rived which will result in specified risk levels  of human cancer as

shown in the table below.
                               BaP

Exposure Assumptions       Risk Levels and Corresponding Criteria

    (per day)                               ng/1

                               0      10"7       10"6       1Q~5

2 liters of drinking water
and consumption of 18.7
grams fish and shellfish       0      0.097      0.97       9.7

Consumption of fish and
shellfish only                        0.44       4.45       44.46
DBA
2 liters of drinking water 0 0.43
and consumption of 18.7
grams fish and shellfish
Consumption of fish and 1.96
shellfish only.
4.3 43
19.6 196
     B.   Aquatic
                                                              »
          The  criterion  for  freshwater  and marine  life  have not

been derived  (U.S. EPA, 1979a) .
                             C3-/0

-------
                      DIBENZO(a,h)ANTHRACENE

                            REFERENCES


Andrews, A.W., et al.   1978.   The  relationship between carcinogeni-
city and mutagenicity of  some polynuclear  hydrocarbons.   Mutation
Research 51: 311.

Basu and Saxena, 1977, 1978.  Polynuclear aromatic hydrocarbons in
selected  U.S.  drinking  waters  and  their  raw  water  sources.
Environ. Sci. Technol.  12: 795.

Beuning, M.K., et al.  1979.  Tumorigenicity of the dihydrodiols of
dibenzo(a,h)anthracene on mouse skin and  in  newborn  mice.   Cancer
Res. 39: 1310.
                                            %
Haddow, A.,  et  al.   1937.  The  influence  of certain carcinogenic
and other hydrocarbons on body growth  in  the  rat.  Proc. Royal Soc.
B.  122: 477.

Heidelberger, C.,  and  S.M.  Weiss.   1959.   The  distribution  of
radioactivity in mice following administration of 3,4-benzopyrene-
5C   and 1,2,5,6-dibenzanthracene-9, IOC  .  Cancer Res.  11: 885.

Hoch-Ligeti,  C.   1941.   Studies  on the  changes in  the  lymphoid
tissues  of mice  treated with  carcinogenic  and non-carcinogenic
hydrocarbons.  Cancer Res.  1: 484.

Huberman,  E. , and  L.  Sachs..  1974.   Cell-mediated  mutagenesis of
mammalian  cells  with  chemical  carcinogens.   Int.  Jour.  Cancer.
13: 326.

Iball, J.   1939.   The relative  potency of carcinogenic compounds.
Am. Jour. Cancer.  35: 188.

Lasnitzki, A.,  and  Woodhouse, D.C. 1944.   The  Effect of 1:2:5:6-
Dibenzanthracene on the lymph-nodes of the rat.  J.  Anat.  78: 121.

Roszinsky - Kocker, et  al.   1979.   Mutagenicity of PAH's.   Induc-
tion  of  sister-chromatid exchanges in  vivo.   Mutation Research.
66: 65.

Shimkin, M.B., and G.D.  Stoner.  1975.  Lung tumors  in mice:  appli-
cation  to  carcinogenesis bioassay.   In;   G. Klein  and S.   Wein-
house,  (eds.)   Advances  in Cancer Research,  Vol.  12 Raven Press,
New York.

Sims,  P.   1976.   The  metabolism of polycyclic hydrocarbons to di-
hydrodiols and diol epoxides  by human and animal  tissues.   Pages
211-224  in  R.  Montesano, et  al.  eds.  screening  tests in chemical
carcinogenesis.   IARC Publ. No.  12. Lyon, France.
                              6 3-II

-------
Snell,  K.C.,  and  H.L.  Stewart.   1962.   Induction  of  pulmonary
adenomatosis in DBA/2 mice by  the  oral  administration of dibenzo-
(a,h)anthracene.  Acta. Vn. Int. Cone.  19: 692.

U.S.  EPA.   1979a.   Polynuclear aromatic  hydrocarbons:   ambient
water quality criteria.  (Draft).

U.S. EPA.   1979b.   Health Effects Research Laboratory, Environment-
al Criteria and Assessment Office Research Triangle Park, N.C.

Wood, A.W., et  al.  1978.  Metabolic activation of dibenzo(a,h)-
anthracene  and  its  dibydiodiols to  bacterial  rautagens.   Cancer
Res.  38:  1967.

World Health Organization.   1970.  European Standards for drinking
water, 2nd ed.  Geneva.

-------
                                      No. 64
         1,2-Dichlorbenzene
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, B.C.  20460

           APRIL 30, 1980

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

-------
                     1,2-DICHLOROBENZENE



                           SUMMARY



     1,2-Dichlorobenzene is a lipophilic compound which



upon absorption into the body, deposits in the fatty tissues.



This compound is detoxified by the liver microsomal enzymes.



On chronic exposure to 0.1 mg 1,2-dichlorobenzene/kg, rats



developed anemia, liver damage, and central nervous system



depression.  There have not been studies available to deter-



mine the carcinogenic or teratogenic potential of 1,2-di-



chlorobenzene.  1,2-Dichlorobenzene was mutagenic when tested



with the mold Aspergillis nidulans and negative when tested



with the bacteria Salmonella typhimurium in the Ames assay.



     The toxicity of 1,2-dichlorobenzene appears to be simi-



lar for freshwater and marine organisms with reported LC5Q



values ranging between 1,970 and 27,000 ug/1.
                              X

-------
                     1,2-DICHLOROBENZENE

I.    INTRODUCTION

     This profile is based on the Ambient Water Quality

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

     1,2-Dichlorobenzene  (1,2-DCB or ODCB; CgH4Cl2; molecular

weight 147.01) is a liquid at normal environmental tempera-

tures.  1,2-Dichlorobenzene has a melting point of -17.6°C,

a boiling point of 179°C, a density of 1.30 g/ml at 20°c,

a water solubility of 145,000 ug/1 at 25°C,'- and a vapor

pressure of 1 mm Hg at 20°C (Weast, 1975).  The major uses

of 1,2-dichlorobenzene are as a process solvent in the manu-

facturing of toluene diisocyanate and as an intermediate
                                                 *
in the synthesis of dyestuffs, herbicides, and degreasers

(West and Ware, 1977) .

II.  EXPOSURE

     A.   Water

          1,2-Dichlorobenzene has been detected in rivers,

groundwater, municipal and industrial discharges, and drink-

ing water.  1,2-Dichlorobenzene has been reported entering

water systems at average levels of 2 mg/1 as a result of

its use by industrial wastewater treatment plants for odor

control (Ware and West, 1977).  In 4 out of 110 drinking

waters, 1,2-dichlorobenzene was detected at an average con-

centration of 2.5 pg/1 (U.S. EPA, 1979a).  Also, 1,2-dichloro-

benzene may be formed during chlorination of water contain-
                                                            #
ing organic precursor material (Glaze, et al. 1976).

-------
     B.    Food



          There are not enough data to state quantitatively



the degree of 1,2-dichlorobenzene exposure through total



diet (U.S. EPA, 1979a).   The U.S. EPA  (1979a) has estimated



the weighted average bioconcentration factor of 1,2-dichloro-



benzene  to be 200 for the edible portion of aquatic organisms



consumed by Americans.  This estimate is based on measured



steady-state bioconcentration studies in bluegill.



     C.    Inhalation



          1,2-Dichlorobenzene has been detected on airborne



particulate 'matter in California at concentrations between



8 and 53 ng/m  (Ware and West, 1977).  There is no other



available information on the concentration of this compound



in ambient air (U.S. EPA, 1979a) .



III. PHARMACOKINETICS



     A.    Absorption



          There is little information provided in U.S. EPA



(1979a)  on the absorption specifically of 1,2-dichloroben-



zene.  General information on the absorption of dichloro-



benzenes can be found in the Hazard Profile for Dichloro-



benzenes  (U.S. EPA, 1979b).  Reidel (1941) has reported



absorption of 1,2-dichlorobenzene through the skin of rats



in lethal amounts after five dermal applications under severe



test conditions (painting twice  daily directly on a 10 cm



area of  abdominal skin).  Also,  1,2-dichlorobenzene fed to



rats at  less than 0.4 to 2 mg/kg/day was absorbed and accu-

-------
raulated in various tissues indicating significant absorption
by the gastrointestinal tract even at low levels of exposure
(Jacobs, et al. 1974a,b).
     B.   Distribution
          After feeding rats low levels of 1,2-dichloroben-
zene, in combination with other trace pollutants found  in
the Rhine River, tissue accumulation was greater in fat
than in the liver, kidney, heart, and blood  (Jacobs, et
al. 1974a).
     C.   Metabolism
          The metabolism of 1,2-dichlorobenzene was studied
by Azouz, et al.  (1955) in rabbits.  1,2-Dichlorobenzene
was mainly metabolized by oxidation to 3,4-dichlorophenol
followed by the formation of conjugates with glucuronic
and sulfuric acids.  Minor oxidative metabolites and their
conjugates were also detected.
     D.   Excretion
          Excretion of the metabolic products of 1,2-dichloro-
benzene in the rabbit was mainly through the urine  (Azouz,
et al.  1955).
IV.  EFFECTS
     A.   Carcinogenicity
          Specific positive evidence of the carcinogenicity
of DCB's is lacking.  However, a sufficient collection of
varied data exist to suggest prudent regard of DCS as a
potential carcinogen (U.S. EPA, 1979a).

-------
     B.   Mutagenicity
          Treatment of the soil mold Asper_gj.llus nidulans
for one hour in an ether solution of 1,2-dichlorobenzene
increased the frequency of back-mutations  (Prasad, 1970).
In the Ames assay, 1,2-dichlorobenzene did not increase
the mutational rate of the histidine-requiring strains of
Salmonella typhimurium (Andersen, et al.  1972).
     C.   Teratogenicity
          Studies of the teratogenicity of '•!, 2-dichloroben-
zene could not be located in the available literature.
     D.   Other Reproductive Effects
          Information is not available.
     E.   Chronic Toxicity
          In an inhalation study, Hollingsworth, et al.
(1958) exposed groups of 20 rats, 8 guinea pigs, 4 rabbits,
and 2 monkeys to the vapor of 1,2-dichlorobenzene seven
hours per day, five days per week for six to seven months
at an average concentration of 560 mg/m .  No adverse effects
were noted in behavior, growth, organ weights, hematology,
or upon gross and microscopic examination of tissues.  In
a nine month chronic toxicity study, Varshavskaya (1967)
gave rats 1,2-dichlorobenzene at daily doses of 0.001, 0.01,
and 0.1 mg/kg.  The toxicological observations in the highest
dose group were anemia and other blood change-s, liver damage,
and central nervous system depression.  The highest no-observ-
able-adverse-effect level for 1,2-dichlorobenzene by Var-
shavskaya (1967) was 0.001 mg/kg/day, whereas the compar-

-------
 able  level  in  the  rat study by Hollingsworth, et al.  (1953)
 was 18.8  mg/kg/day.
      F.   Other  Relevant Information
          1,2-Dichlorobenzene can induce microsomal drug
 metabolizing enzymes (Ware and West, 1977).
 V.    AQUATIC TOXICITY
      A.   Acute  Toxicity
          For  freshwater fish, two 96-hour static bioassays
 have  produced  LCc* values of 5,590 and 27,0-00 ug/1 for the
 bluegill  (Lepomis  macrochirus) (U.S. EPA, 1978; Dawson,
 et al.  1977).  A single 96-hour static assay for the fresh-
 water invertebrate Daphnia magna provided an LCcQ value
 of 2,440  ug/1.   In marine fish, LCg0 values  reported were
 7,300 ug/1  for  the tidewater silverside (Menidia beryllina)
 and 9,560 ug/1  for the sheepshead minnow (Cypringdon. yariega-
 tus)  (U.S.  EPA,  1978).  An adjusted LC5Q value of 1,970
 ug/1  was  obtained  for the marine invertebrate  (Mysidopsis
 bahia).
      B.   Chronic
          The  only freshwater, organisms tested were embryo-
 larval stages  of the fathead minnow (Pimephales pcomelas),
 which produced a chronic value of 1,000 ug/1 for 1,2-dichloro-
.benzene.  No chronic data for marine organisms were avail-
 able  for  evaluation.
      C.   Plants
          The  freshwater algae Selenastrum capricornutum
 has been  tested  for the effects of 1,2-dichlorobenzene on

-------
chlorophyll a and cell numbers.  The EC^Q values were 91,600
and 98,000 pg/1, respectively, while comparable values of
44,200 to 44,100 pg/1 were reported for the marine algae
Skeletonema costatum  (U.S. EPA, 1978).
     D.   Residues
          A bioconcentration of 89 was obtained for the
bluegill.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.   Human
          The Occupational Safety and Health Administration
(OSHA, 1976) , and the American Conference of Governmental
Industrial Hygienists (ACGIH, 1977) threshold limit value
is 300 mg/m  for 1,2-dichlorobenzene.  The U.S. EPA (1979a)
draft water quality criterion for total dichlorobenzene
(all three isomers) is 160 ug/1.
     B.   Aquatic
          Criteria have been drafted for freshwater organisms
as 44 ug/1 for the 24-hour average concentration, not to
exceed 99 pg/1.  The marine draft criterion is 15 pg/1 not
to exceed 34 pg/1  (U.S. EPA, 1979a).

-------
                              1,2-OICHLORQBENZENE

                                  REFERENCES
American Conference  of Governmental Industrial  Hygienists.   1977.  Documen-
tation of  the  threshold limit  values  for  substances  in workroom  air (with
supplements  for those  substances  added  or  changed since  1971).   3rd  ed.
Cincinnati, Ohio.
                                                    >.
Andersen, K.J.,  et al.  1972.   Evaluation  of herbicides for  possible muta-
genic properties.  Jour. Agric. Food Chem.  20: 649.

Azouz, W.M., et al.    1955.   Studies  in detoxication,  62:  The metabolism of
halogenobenzenes.  Orthoand paradichlorobenzenes.  Siochem. Jour.  59: 410.

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

Glaze, W.H.,  et al.   1976.   Analysis of  new chlorinated  organic compounds
formed by  chlorination  of  municipal  wastewater.   In:  Proc.  Conf.  Environ.
Impact Water Chlorination.  Iss. Ccnf.-751096, pages 153-75. (Abstract)

Hollingsworth,   R.L.,  et al.   1958.  Toxicity  of o-dichlorobenzene.   Studies
on animals and  industrial experience.   AMA Arch. Ind. health  17: 180.

Jacobs,  A.,  et al.   1974a.   Accumulation  of  noxious  chlorinated substances
from  Rhine  River  water in the  fatty  tissue  of rats.   Vom  Wasser (German')
43: 259.  (Abstract)

Jacobs,  A., et  al.   1974b.   Accumulation  of organic compounds, identified as
harmful  substances in  Rhine water, in  the  fatty tissues  of  rats.   Kern-
forschungszentrum Karlsruhe (Ber.).  KFK 1969 UF, pp. 1. (Abstract)

National Academy of  Sciences.   1977.  Drinking water  and health.   U.S.  EPA
Contract No. 68-01-3169.  Washington,  D.C.

Occupational  Safety   and  Health  Administration.   1976.   General  industry
standards.  29  CFR 1910,  July  1,  1975;  OSHA  2206,  revised  Jan.  1976.  U.S.
Dep. Labor, Washington, O.C.

Prasad,  I.   1970.   Mutagenic effects  of  the  herbicide 3',4'-dichloropropio-
nanilide and its degradation products.  Can. Jour. Microbiol.  16: 369.

Riedel,  H.   1941.   Einige  beobachtungen  uber orrhodichlorbenzol.   Arch.
Gewerbepath. u  Gewerbehyg.   10: 546.  (German)

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

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

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

Varshavskaya,  S.P.   1967.   Comparative  toxicological  characteristics  of
chlorobenzene and  dichlorobenzene (ortho- and  para-isomers) in  relation to
the sanitary protection of water bodies.  Gig. Sanit. (Russian)  33: 17.

Ware, S.,  and W.L. West.   1977.   Investigation of  selected potential envi-
ronmental  contaminants:  halogenated  benzenes.   EPA-56072-77-004.   Rep.  EPA
Contract  No.  68-01-4183.   Off.  Toxic  Subst.   U.S.  Environ. Prot.  Agency,
Washington, O.C.

Weast,  R.C.,  et al.   1975.   Handbook  of chemistry and physics.   56th ed.
CRC Press, Cleveland, Ohio.

-------
                                       No.  65
         1,3-Dichlorobenzar.e


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

           APRIL 30, 1980

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

-------
                              1.3-OICHLOROBENZENE
                                    Summary
     1,3-Oichlorobenzene is not  used commercially and is  produced only as a
by-product  in  the  manufacture  of  chlorinated  benzenes.   This  compound  is
metabolized by  the  liver mixed function oxidase system.   Little is known of
the toxicological,  teratogenic, or  carcinogenic  properties of this compound.
1,3-Oichlorobenzene has  been  shown  to  be  mutagenic to  the soil mold Asper-
qillus  nidulans.    Since  1,3-dichlorobenzene  may be  a  contaminant  of the
other dichlorobenzenes,  some  of  the toxicologic  ptoperties ascribed to  these
isomers may be due  to the 1,3-isomer.
     For freshwater and  marine fish and invertebrates, acute toxicity values
ranged  from 2,414  to  4,248 pg/1,  but  the  freshwater invertebrate,  Daphnia
magna,  was more  resistant to  1,3-dichlorobenzene  with  an  acute  value  of
23,800 pg/1.

-------
                              1,3-DICHLORQBENZENE
I.    INTRODUCTION
     This  profile  is based  on the Ambient  Water Quality  Criteria Document
for Dichlorobenzenes (U.S. EPA, 1979a).
     1,3-Dichlorobenzene   (1,3-DCB;   MDCB;    C6H4C12;    molecular   weight
147.01)  is a  liquid at  normal  environmental  temperatures,  has  a  melting
point  of  -24.2°C,  a boiling point  of  172°C,  a  density of  1.29 g/ml  at
20°C,  a water  solubility of 123,000 ^ig/1  at  25°C,  and a  vapor pressure
of  5  mm Hg at  39°C  (Weast,  1975).  1,3-Dichlorobenzene may occur  as  a con-
taminant of 1,2- or 1,4-dichlorobenzene formulations (U.S. EPA, 1979a).
II.  EXPOSURE
     A.  Water
         1,3-Dichlorobenzene  has  been  detected  or quantified in groundwater,
raw water,  and  drinking water.  In two of  11C  drinking  water  samples,  1,3-
dichlorcbsnzene was  detected at  an average  concentration of  0.1 pg/1 (U.S.
EPA, 1979a).  Also,  1,3-dichlorobenzene may  be  formed  during chlorination of
raw  and waste  water containing  organic  precursor material  (Glaze,   et  al.
1576).
     8.  Food
         The  data  are'  insufficient to  state  quantitatively  the  degree  of
1,3-dichlorobenzene exposure  through total  diet (U.S.  EPA,  1979a).  1,3-Oi-
chlorobenzene  is  reported to be  among  several metabolites of gamma-penta-
chloro-1-cyclohexane  found  in  corn and  pea  seedlings   (Mostafa   and  Moza,
1973).    The    U.S.   EPA  (1979a)   has  estimated"  the   weighted  average
bioconcentration factor to  be 150 for  1,3-dichlorobenzene  for the  edible
                                                                      »
portions  of fish  and  shellfish  consumed by  Americans.   This estimate  is
based on measured steady- state bioconcentration studies  in bluegill.

-------
     C.  .Inhalation
         Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
     A.  Absorption
         Specific  information  on the  absorption of  1,3-dichlorobenzene was
not found  in the available  literature.   General information on  the absorp-
tion of the  dichlorobenzenes can  be  found in the Hazard Profile for Dichlor-
obenzenes (U.S. EPA, 1979b).  .
     8.  Distribution
         Specific information on  the distribution of 1,3-dichlorobenzene was
not found in the  available  literature.   Reference may be made  to the Hazard
Profile for  Dichlorobenzene  (U.S. EPA,  1979b) and  the  1,2-iscmer (U.S. EPA,
1979c).
     C.  Metabolism
         The metabolism of  1,3-dichlorobenzene  in  rabbits  was  studied  by
Parke  and  Williams  (1955).   1,3-Oichlorcbenzer.e  was mainly metabolized  by
oxidation  to 2,4-dichlorophenol  followed by  the formation of  the glucuro-
nides  and  ethereal  sulfates.  Minor  oxidative metabolites  and  their conju-
gates were also detected.
     0.  Excretion
         Excretion  of  the  metabolic  products of  1,3-dichlorobenzene  in the
rabbit is mainly  through the urine  with  excretion being essentially complete
within five days (Parke and Williams, 1955).
IV.  EFFECTS
     A.  Carcinogenicity
                                                                      *
         Reports of  specific Carcinogenicity tests of 1,3-dichlorobenzene in
animals or  of  pertinent epidemiologic studies in  humans  were  not  found  in
the available literature (U.S.  EPA, 1979a).

-------
     8.  Mutagenicity



         Treatment of the  soil  mold Asoeraillus nidulans  for  one hour in an



ether solution  of  1,3-dichlorobenzene increased the  frequency  of back muta-



tions (Prasad, 1970).



     C.  Teratogenicity and Other Reproductive Effects



         Studies  of  the  teratogenicity  and  other  reproductive  effects  of



1 ,'3-dichlorobe'nzene were not found in the available literature.



     0.  Chronic Toxicity
           ...   s


         Specific  information on  the chronic  toxiclty of 1,3-dichlorobenzene



was not found  in the available  literature.   However,  1,3-dichlorobenzene may



have been a contaminant of  the  1,2- and l,i-dichlorobenzenes used in toxico-



Icgical studies.   For further information on  the general toxicologic proper-



ties of  the  dichlorobenzenes,   refer  to the Hazard Profile  for Oichloroben-



zenas (U.S. EFA, I579b).



     E.  Other Relevant Information



         1,3-Dichlorobenzene  can  induce microscmal   drug  metabolizing  en-



zymes.   Changes in the  levels  of  microsomal  enzymes can  affect the metabo-



lism and  biological  activity   of  a  wide variety  of xenobiotics  (Ware  and



West, 1977).



V.    AQUATIC TOXICITY



     A.  Acute Toxicity



         For  the  bluegill  (Lepomis macrochirus),  a  96-hour static  LC-Q  of



5,020 jjg/1 has been obtained.  The freshwater  invertebrate,  Daohnia maqna,



has a  much higher LC50 of  28,100  ug/1  for  a 48-hour'static assay.   For the



sheepshead minnow,  an  acute LCcg  of 7,770  ug/1 has  been  obtained.   A ^value



of  2,850  pg/1  has been obtained  for  the  marine  mysid shrimp  (Mysidopsis



bahia)  (U.S.  EPA,  1978).

-------
     B.  Chronic
         Chronic  studies  with  either  freshwater or  marine species  are not
available.
     C.  Plant Effects
         The  freshwater  alga  Selenastrum caoricornutum  was tested  for the
effects  of  1,3-dichlorobenzene on  chlorophyll  a  and  cell  numbers.   The
EC50  values  ranged from  149,000-179,000 ug/1.   For  the marine  alga Skele-
tonema  costatum,  the  EC5Q  values  for cell  number  and  chlorphyll  a ranged
from 49,600-52,800 pg/1 (U.S. EPA, 1979a).
     D.  Residues
         A bioconcentration  factor of  66 was  obtained for the bluegill  (U.S.
EPA, 1979a).

VI.  EXISTING GUIDELINES AND STANDARDS
     A.  Human
         There  are  no existing standards  for 1,3-dichlorobenzene.   The U.S.
EPA  (1979a)  draft  water  quality  criterion  for  total  dichlorobenzene  (all
three isomers) is 160 ug/1.
     8.  Aquatic
         A  criterion   for  the  protection of  freshwater organisms  has  been
drafted as  310 ug/1  for  a  24-hour average concentration not to  exceed 700
jjg/1.   For  marine life,  the  criterion has been proposed as 22  ug/1 for 24-
hour average not to exceed 49 ug/1.

-------
                             1,3-DICHLOROBENZENE

                                  REFERENCES
Glaze, W.H.,  et al.   1976.   Analysis of  new  chlorinated organic  compounds
formed by  chlorination of  municipal wastewater.   _In Proc.  Conf.  Environ.
Impact Water Chlorination.  Iss.  Conf.-751096,  pages 153-75.  (Abstract)

Mostafa,   I.Y.  and  P.N.   Moza.   1973.  Degradation  of  gamma-pentachloro-1-
cyclohexane (gamma-PCCH)  in corn and  pea seedlings.   Egypt.  Jour.  Chem.  Iss.
Spec.: 235. (Abstract)

Parke, D.V. and  R.f.  Williams.   1955.  Studies in detoxication: The  metabo-
lism  of  halogenobenzenes. (a) Metadichlorobenzene  (b)  Further  observations
on the metabolism of chlorobenzenev  Biochem.  Jour.   59:  415.

Prasad, I.  1970.   Mutagenic  effects of the herbicide  3',4'-dichloropropio-
nanilide and its degradation products.  Can.  Jour.  Microbiol.   16:  369.

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

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

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

U.S.  EPA.   1979c.  Environmental  Criteria and  Assessment  Office.   1,2-Di-
chlorobenzene:  Hazard Profile.   (Draft)

Ware, S.  and  W. L. West.   1977.   Investigation of selected potential  envi-
ronmental  contaminants: halogenated  benzenes.   EPA  560/2-77-004.   Rep. EPA
Contract  NO.  68-01-4183.    Off.  Toxic  Subst.   U.S.  Environ.  Prot.  Agency,
Washington, D.C.

Weast, R.C.,  et  al.   1975.  Handbook  of  chemistry  and  physics.   56th ed.
CRC Press, Cleveland,  Ohio.
                                     C5-?

-------
                                      No.  66
        1,4-Dichlorobenzane


  Health and Environmental Effect3
U.S. ENVIRONMENTAL PROTECTION AGENCY
       WASHINGTON, B.C.  20A60

           APRIL 30, 1980

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

-------
                     1,4-DICHLOROBENZENE



                           SUMMARY



     1,4-Dichlorobenzene  is a lipophilic  compound  which,  upon



absorption into the body, deposits  in  the  fatty  tissues.



This compound is detoxified by the  liver  microsomal  enzymes.



Chronic intoxication produces increased liver  and  kidney



weights' and abnormal liver pathology.  Studies  to  determine



the carcinogenic or teratogenic potential  of 1,4-dichloroben-



zene could not be located in the available literature.   1,4-



Dichlorobenzene produces chromosomal aberrations  in  root  tips



and has been shown to increase the  mutation rate  in  the mold



Aspergillus nidulans.



     Acute values for freshwater and marine organisms  ranged



from 1,990 to 11,000 ug/1 for 1,4-dichlorobenzene.   Marine  in



vertebrates were most sensitive and freshwater  invertebrates



were most resistant to the effects  of  1,4-dichlarcbenzer.e.
                              t

-------
                     1,4-DICHLOROBEN ZENE




I.   INTRODUCTION



     This profile is based on the Ambient Water Quality  Cri-



teria Document for Dichlorobenzene  (U.S. EPA,  1979a).



     1,4-Dichlorobenzene  (CgH^C^; molecular weight  147.01)



is a solid at normal environmental temperatures.   1,4-Di-



chlorobenzene has a melting point of 53.0°C, a boiling point



of 174°C, a density of 1.25 g/ml at 20°C, a water  solubility



of.80/000 u.g/1 at 25°C, and a vapor pressure of 0.4  mm Hg  at



25°C (Weast, et al. 1975).  The primary use of 1,4-dichloro-



benzene is 'as an air deodorant and  insecticide.  This com-



pound is produced almost entirely as a byproduct during  the



manufacture of monochlorobenzene (Ware and West, 1977).




     For a more general discussion of dichlorobenzene, the



reader is referred co  the Hazard Profile for Dichlcrobenzene



(U.S. EPA, 1979b).



II.  EXPOSURE



     A.   Water



          1,4-Dichlorobenzene has been detected or quantified



in rivers, groundwater, municipal and industrial discharge,



and drinking water.  1,4-Dichlorobenzene enters wastewater



systems because of its use in toilet blocks (Ware  and West,



1977).  1,4-Dichlorobenzene may also be formed during chlori-



nation of raw and waste water containing organic percursor



material (Glaze, et al. 1976).  In 20 of 113 drinking water



samples, 1,4-dichlorobenzene was detected at an average  con-



centration of 0.14 ug/1 (U.S. EPA, 1979a) .

-------
     B.   Food

          There are not enough data  available  to  quantita-

tively state the degree of 1,4-dichlorobenzene  exposure

through total diet (U.S. EPA, 1979a).   Schmidt  (1971)  report-

ed the tainting of pork as a result  of  the  use  of an  odor

control agent-containing 1,4-dichlorobenzene  in pig  stalls.

Also, Morita, et al.  (1975) reported 0.05 mg/kg 1,4-dichloro-

benzene in fish from Japanese coastal waters.   The U.S EPA

(1979a) has estimated the weighted bioconcentration  factor of

1,4-dichlorobenzene to be 140 for the edible  portion  of fish

and" shellfish consumed by Americans.  This  estimate  is based

on measured steady-state bioconcentration studies in  blue-

gills.

     C.   Inhalation

          Merita and Chi (1975) measured 1,4-dichlorcbenzene

in the vapor phase, in and around Tokyo, by use of a  cold

solvent trap.  Urban levels were found  to range from  2.7 to

4.2 ug/m3, while suburban levels were lower,  ranging  from

1.5 to 2.4 ug/m^; indoor levels were considerably higher,

ranging 0.105 to 1.7 mg/m^.  No other information was  found

regarding the concentration of this  compound  in ambient air

(U.S. EPA, 1979a) .

III.  PHARMAKINETICS

     A.   Absorption

          In humans, toxic effects following  accidentally or
                                                           »
deliberately ingested 1,4-dichlorobenzene clearly indicate

significant absorption by the gastrointestinal  route  (Camp-

bell and Davidson, 1970;  Frank and Cohen, 1961; Hallowell,

-------
1959).  Also, Azouz, et al.  (1955) detected  no  1,4-dichloro-

benzene in the feces of rabbits dosed  intragastrically  with

the compound in oil.  This suggests virtually complete  ab-

sorption under these conditions.

     B.   Distribution

          The studies of Morita and Ohi  (1975)  and Morita,  et

al.  (1975) have shown 1,4-dichlorobenzene in adipose  tissue

(mean about 2 mg/kg) and blood  (about  0.01 ng/1)  of  humans

exposed to ambient pollution levels in the Tokyo  area.

     C.   Metabolism

          The metabolism of 1,4-dichlorobenzene  in rabbits

was studied by Azouz, et al. (1955).   1,4-Dichlorobenzene was

primarily metabolized by oxidation to  2,5-dichlorophenol,

followed by the formation of the glucuronides and ethereal

sulfates.  Minor oxidative metabolites and their  conjugates

were also detected.  Pagnatto and Walkley  (1966)  indicated

that 2,5-dichlorophenol was also the principal  metabolite of

1,4- dichlorobenzene in humans.

     D.'   Excretion

          Excretion of the metabolic products of  1,4-di-

chlorobenzene in the rabbit occurs mainly  through the urine

(Azouz, et al. 1955), with no mention made of fecal  excre-

tion.

IV.  EFFECTS

     A.   Carcinogenicity
                                                           »
          Mo reports of specific carcinogenicity  tests  of

1,4-dichlorobenzene in animals or of pertinent  epidemiologic

studies in humans were available. ' A few inconclusive experi-

-------
ments which indicate further investigation of  the  carcino-



genic potential of 1,4-dichlorobenzene  is warranted  are  re-



viewed in. U.S EPA (1979a).



     B.   Mutagenicity



          Various mitotic anomalies were observed  in  cells



and somatic chromosomes of 1,4-dichlorobenzene  treated  root



tips (Carey and McDonough, 1943; Sharma and Sarkar,  1957;



Srivastava, 1966).  Treatment of Aspergillus nidulans  (a  soil



mold organism) for one hour in an ether solution of  1,4-di-



chlorobenzene increased the frequency of back-mutations



(Prasad, 1970).



     C.   Teratogenicity and Other Reproductive Effects



          Pertinent data could not be located  in the  avail-



able literature.



     D.    Chronic Toxicity



          Effects observed in racs and guinea  pigs exposed to



a concentration of 2,050 mg/m3 1,4-dichlorobenzene for  six



months included: growth depression (guinea pigs);  increased



liver and kidney weights (rats); abnormal liver pathology



(cloudy swelling, fatty degeneration, focal necrosis,  cirrho-



sis) (Hollingsworth, et al. 1956).  In animals  exposed  to



4,800 mg/m^ 1,4-dichlorobenzene, up to 25 percent deaths



were noted; and in survivors, symptoms were noted  that were



similar to those observed at the lower dose.   Similar  pathol-



ogy was also observed in female rats, who received 376 mg/kg
                                                           »


dose of 1,4-dichlorobenzene by stomach tube 5 days a  week  for



a total of 138 doses.
                           6  -7

-------
     E.   Other Relevant Information


          1,4-Dichlorobenzene can induce microsoraal drug-


metabolizing enzymes.  Changes in the levels of microsomal


enzymes can affect the metabolism and biological activity of


a wide variety of xenobiotics (Ware and West, 1977).


V.   AQUATIC TOXICITY


     A.   Acute Toxicity


          Acute 96-hour LC^Q values for all aquatic species


tested were relatively similar.  For the freshwater fish, the


bluegill (Lepomis macrochirus), a LC50 of 4,280 ug/1 was


obtained, while the freshwater invertebrate Daphnia magna was


more resistant, with a LC50 value of 11,000.  An LC50


value of 7,400 ug/1 was obtained for the marine fish, the


sheepshead minnow (Cyprinodon variegatus);  and the myrid


shrimp (Mysidopsis bahia) had an LC50 valua of 1,990 ug/1


(U.S.  EPA,1973).


     B.   Chronic


          Pertinent data could not be located in the avail-


able literature.


     C.    Plants


          The freshwater alga, Selenastrum capricornutum,


when tested for the effects of 1,4-dichlorobenzene on chloro-


phyll _a and cell numbers, was shown to have had a range of


effective concentration of 96,700 to 98 ,100''ug/1, while the


marine alga Skeletonema costatum was more  sensitive, with an
                                                          »

effective concentration range of 54,800 to 59,100 ug/1.
                                    66-1

-------
       D.    Residues
            A  bioconcentration factor of 60 was obtained for
  the  freshwater  bluegill.
  VI.   EXISTING GUIDELINES  AND STANDARDS
       A.    Human\
            The Occupational Safety and Health Administration
  Standard  (OSHA,  1976),  and the American Conference of Govern-
  mental Industrial Hygienists (ACGIH,  1977)  threshold limit
  value are  450 mg/m^  for 1,4-dichlorobenzene.  The
  acceptable daily intake (ADI)  of 1,4-dichlorobenzene is 0.94
  mg/day (Natl. Acad.  Sci.,  1977).  The U.S.  EPA (1979a) draft
'  water quality criterion for total dichlorobenzene (all three
  isomers)  is  0.16 mg/1.
       B.    Aquatic
            A  criterion  for  the  protection of freshwater aqua-
  tic  life  has been drafted  as a 190 ug/1 24-hour average con-
  centration,  not  to exceed  440  ug/1 at any time.  For the pro-
  tection of marine life,  the criterion is 15 ug/1 as a 24-hour
  average,  not to  exceed  34  ug/1 at any time.

-------
                     1 , 4-DICHLOROBEN ZEN E

                         REFERENCES

American Conference of Governmental Industrial Hygienists.
1977.  Documentation of  the threshold  limit  values  for  sub-
stances in workroom air  (with supplements  for those  sub-
stances added or changed since 1971).  3rd ed. Cincinnati,
Ohio.

Azouz, W.M., et al.  1955.  Studies in detox ication,  62:  The
metabolism of halogenobenzenes.  Ortho- and  paradichloro-
benzenes.  Biochem. Jour.  59: 410.

Campbell, D.M., and R.J.L. Davidson.   1970.  Toxic  haemolytic
anaemia in pregnancy due to a pica for paradichlorobenzene.
Jour. Obstet. Gynaec. Br. Cmnwlth.  77: 657.

Carey, M.A. , and E.S. McDonough.  1943.  On  the production of
polyploidy .in Allium with paradichlorobenzene.

Frank, S.B., and H.J. Cohen.  1961.  Fixed drug eruption  due
to paradichlorobenzene.  N.Y. Jour. iMed.   61: 4079.

Glaze, W.H., et al.  1976.  Analysis of new  chlorinated
organic compounds formed by chlorination of  municipal waste-
water.  In: Proc. Conf.  Environ. Impact Water Chlorination.
Iss. Conf .-751096, pages 143-75. (Abstract).

Hallowell, M.  1959.  Acute haemolytic anemia following  the
ingestion of paradichlorobenzene.  Arch. Dis. Child.  34:
  ~
Hollingsworth, R.L., et al.  1956.  Toxicity of paradichloro-
benzene.  Determinations on experimental animals  and  human
subjects.  AMA Arch. Ind. Health  14: 138.

Morita, M., et al. . 1975.  A systematic determination  of
chlorinated benzenes in human adipose tissue.  Environ.
Pollut.  9: 175  (Abstract).

Morita, M. , and G. Ohi.  1975.  Para-dichlorobenzene  in human
tissue and atmosphere  in Tokyo metropolitan area.   Environ.
Pollut.  3: 269.

National Academy of Sciences.  1977.  Drinking water  and
health.  U.S. EPA Contract No. 68-01-3169. "Washington, D.C.

Occupational Safety and Health Administration.  1976.  Gener-
al industry standards.  29 CFR 1910, July 1, 1975;  OSHA 2206,
revised Jan. 1976.  U.S. Dep. Labor, Washington,  D.C.

-------
Pagnotto, L.D. , and J.E. Walkley.  1966.  Urinary dichloro-
phenol as an index of paradichlorobenzene exposure.  Ind.
Hyg. Assoc. Jour.  26: 137. (Rev. in Food Cosmet.  Toxicol.
4: 109.  (Abstract).

Prasad, I.  1970.  Mutagenic effects of the herbicide 3',4'-
dichloropropionanilide andd its degradation products.   Can.
Jour. Microbiol.  16: 369.

Schmidt, G.E.  1971.  Abnormal odor and taste due to p-di-
chlorobenzene.  Arch. Lebensmittelhyg.  (German)  22: 43.
(Abstract)'.

Sharma, A..K., and S.K. Sarkar.  1957.  A study on the compar-
ative effect of chemicals on chromosomes of roots, pollen
mother cells and pollen grains.  Proc. Indian Acad. Sci.
Sect. B.  45: 288.

Srivastava, L.M.  1966.  Induction of mitotic abnormalities
in certain genera of tribe Vicieae by paradichlorobenzene.
Cytologia  31: 166.

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.

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

U.S. EPA.  1979b.  Environmental Criteria Assessment Office.
Dichlorobenzene: Hazard Profile (Draft).

Ware, S.A., and W.L. West.  1977.  Investigation of selected
potential environmental contaminants: halogenated benzenes.
EPA 560/2-77-004.  Rep. EPA Contract No. 63-01-4183.  Off.
Toxic Subst. U.S. Environ. Prot. Agency, Washington, D.C.

Weast, R.C., et al.  1975.  Handbook of chemistry and
physics.  56th ed.  CRC Press, Cleveland, Ohio.

-------
                                   No. 67
         Dichlorobanzenes
  Health and Environmental Effects
U.S.  ENVIRONMENTAL PROTECTION AGENCY
      WASHINGTON, D.C.  20460

          APRIL 30,  1980
          £7--I

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

-------
                               DICHLOROBENZENES
                                    Summary

     Dichlorobenzenes  are  lipophilic  compounds  which, upon  absorption into
the body, deposit  in  the fatty tissues.  These  compounds  are metabolized by
the liver microsomal  enzyme  system to water  soluble  compounds.   Chronic ex-
posure to  any of  the "three  isomers  produces effects  on  the  liver,  blood,
central nervous system and respiratory^tract.   Studies to  determine the car-
cinogenic or  teratogenic potential of the dichlorobenzenes were  not located
in  the  available  literature.   In one  study  these compounds  have increased
the mutational rate of soil mold.
     The position  of  the chlorine atoms on the  benzene ring  appears to have
little   significant   effect   on   the  toxicity   of   the   1,2-,   1,3-,   or
Iji-dichlorobsnzsne isomsrs 'to  fish and invertebrates,  sxcept for the appar-
ent resistance  of  the freshwater  invertebrate  Daonnia maena  to  1,3-chloro-
benzene.   Marine   fish tend  -to  be slightly  mere  resistant  thar. freshwater
fish,  although the inverse is true for freshwater and marine invertebrates.

-------
                               DICHLOROBENZENES
I.   INTRODUCTION
     This profile  is based  on the Ambient  Water Quality  Criteria Document
for Dichlorobenzenes (U.S. EPA, 1979).
     The  dichlorobenzenes  (CgH4Cl2;   molecular  weight   147.01)   are   a
class  of halogenated aromatic compounds  represented by three structurally
similar  isomers:   1,2-dichloro-,  1,3-dichloro-,  and  1,4-dichlorobenzenes
(Weast, et al.  1975).   1,2-Oichloro- and 1,3-dichlorobenzene  are  liquids  at
normal environmental temperatures  while  1,4-dichlorobenzene is a solid.  All
the dichlorobenzenes  boil at  approximately  175°C and  have a  density close
to  1.28  a/ml.    The   solubilities  in   water  of  the   1,2-,   1,3-,  and
1,,4-dichlorobenzene  iscmers  at  25°C are  145,000 pg/1,  123,000 pg/1,  and
80,000   pg/1,    respectively   (Jacobs,    1957).    The   vapor   pressure   of
1,2-dichlorobenzene   at   20°C   is   1   mm   Hg;   the   vapcr   pressure   of
1,3-dichlorobenzene  at  39°C  is   3  mm  Kg;   and  the  vapor  pressure  of
1,4-dichlorobenzsns  at  25°C is  0.4  mm  Hg  (Jordan,  1954;  Kirk  and Othrr.er,
1963).
     The major  uses of 1,2-dichlorobenzene  are as a process  solvent in the
manufacturing of toluene  diisocyanate  and  as  an intermediate in  the syn-
thesis  of dyestuffs, ' herbicides,  and  degreasers.   1,4-Oichlorobenzer.e  is
used as  an  air deodorant  and  an insecticide.  1,3-Oichlorobenzene  is found
as a  contaminant of the other two isomers.   The  combined  annual production
of  1,2-,  and  1,4-dichlorobenzene  in  the  United States   approaches  50,000
metric tons (Ware and West, 1977).

-------
II.  EXPOSURE
     A.  Water
         Dichlorobenzenes have been detected  or  quantified in rivers,  ground
water, municipal  and industrial discharges,  and drinking  water.   Dichloro-
benzenes enter  the water  systems  from the  use  of 1,2-dichlorobenzene  as  a
deodorant   in   industrial  wastewater  treatment   and   from   the  use   of
1,4-dichlorobenzene  toilet  blocks  (Ware "and" West, "1977).  "Chlorinated  ben-
zenes  may  also be formed  during  chlorination  of raw  and wastewater  con-
taining  organic  precursor material  (Glaze,  efc  al.   1976).   In  two  case
studies  the  concentration of  dichlorobenzene in  finished  water was  higher
than in the raw water supply (Gaffney, 1976).
     8.  Food
         There  are not  enough data  to  state quantitatively  the degree  of
dichlcrcbenzer.e exposure through  total  diet.   Tainting  of  cork  has  been
reported due to the  use of an odor control  product  containing 1,4-dichloro-
benzene in pig  stalls  (Schmidt,  1971).  Also,  low .levels of contamination  of
plant  products  have been noted from the metabolism  of lir.dane and  garcma-
pentachlor-1-cyclohexane  (Balba  and  Sana,  1974;  Niostafa  and Moza,  1973).
Morita,  et  ai.  (1975)  reported  detectable  levels of  1,4-dichlorobenzene  in
fisn of  the  Japanese coastal  waters;  the  concentration  was  Q.Q5  mg/kg.  The
U.S. EPA  (1979) has estimated the weighted  average  bioconcentration  factors
for the edible  portion  of fish and shellfish consumed  by  Americans  for  1,2-
dichloro-,   1,3-dichloro-,  and 1,4-dichlorobenzene to  be 200, 150, and  140,
respectively.   These estimates  are  based on measured  steady-state  biocon-
centration studies in bluegills.
                            47-

-------
     C.  Inhalation
         1,2-Oichlorobenzene   has   been  detected  in  airborne  participate
matter  in' California  at  concentrations between  8 and  53 ng/m   (Ware and
West,  1977).   Merita  and  Ohi  (1975)  measured  1,4-dichlorobenzene  in the
vapor phase,  by the use of a  cold solvent  trap,  in and around Tokyo.   Urban
levels  were  2.7 to  4.2 /jg/nr5;  suburban levels  were lower  at 1.5  to 2.4
pg/m ;  however,  indoor levels  were  considerably higher  at  0.105  to 1.7
mg/m .
III. PHARMACOKINETICS
     A.  Absorption
         The  (jichicrcbenzsnss  may be  absorbed  through  the  lungs,  gastro-
intestinal  tract,  and  intact  skin  (Ware  and  West, 1977).  There  is  no data
on  the  quantitative efficiency  of absorption  of dichlorobenzenes; however,
as  indicated from  the  appearance  of  metabolites in  the  urine, respiratory
absorption  during  inhalation  exocsure  is  rapid  (Pagnatto  and  Walkley.
1966).   In humans,  toxic effects  following accidentally  or deliberately in-
gested  1,4-dichlorobenzene clearly indicate  significant  absorption  by the
gastrointestinal  route  (Campbell and Davidson, 1970;  Frank and Cohen,  1961;
Hallowell,  1959).   Also, 1,2-dichlorobenzene  fed  to rats at less than 0.4  to
2  mg/kg/day  was  absorbed  and  accumulated  in  various  tissues,  indicating
significant  absorption  by  the gastrointestinal  tract  even at  low  levels  of
exposure by ingesticn (Jacobs, et  al. 1974a,b).
     B.  Distribution
         After  feeding  rats low levels of 1,2-dichlorobenzene in combination
with other trace pollutants  found in  the  Rhine  River,  tissue accumulation
was greater in fat than in the liver, kidney, heart,  and  blood (Jacobs,  et
al. 1974a).   Studies of  Morita and Ohi  (1975)  and Morita,  et al. (1975) have

-------
shown 1,4-dichlorobenzene  in  adipose tissue  (mean  about 2 mg/kg)  and  blood
(about 0.01 mg/1) of humans exposed  to ambient pollution levels  in  the  Tokyo
area.
     C.   Metabolism
         Metabolism  of  the   1,2-  and  1,4-dichlcrobenzenes was  studied  by
Azouz,  et al.  (1955),  and   1,3-dichlorobenzene  was  studied  by  Parke  and
Williams  (1955) in  rabbits.   These compounds are mainly  metabolized  by.oxi-
dation  to  3,4-dichlorophenol,  2,5-dichlorophenol,  and  2,4-dichlorophenol
respectively,   which are subsequently  conjugated.   Other oxidation  products
are formed to  a  lesser extent, followed again by conjugation.   Pagnatto  and
Walkley   (1966)  indicated  that  2,5-dichlorophenol  was  also  the  principal
metabolite of 1,4-dichlorobenzene in humans.
     0.   Excretion
         In studies of rabbits,  Azouz,  et al. (1955)  and Parks  and wUliams
(1955) reported the excretion of metabolic products of  the dichiorobenzenes
in the urine.
IV.  EFFECTS
     A.   Carcinogenicity
         NO reports of carcinogenicity testing of  specific dichlorcbenzenes
cculd be  located  in  .the  available literature.   Inconclusive  experiments
reviewed  in U.S.  EPA  (1979)  indicate that further  investigation  of the  car-
cinogenic potential of the  dichiorobenzenes is warranted.
     8.   Mutagenicity
         Various  mitotic  anomalies  were  observed  in  cells  and  somatic
chromosomes  of  1,4-dichlorobenzene-treated  root  tips  (Srivastava,  1966;
Sharma   and   Sarkar,   1957;   Carey  and  McDonough,   1943).   Treatment   of
Aspergillus  nidulans   (a  soil mold  organism)   for one hour  in  an  ether
                                  67-7

-------
solution  of  any  of  the  three  isomers  of  dichlorobenzene   increased  the
frequency   of   back-mutations   (Prasad,   1970).    -In   the   Ames   assay,
1,2-dichlorobenzer.e   did   not   increase    the   mutational   rate  of   the
histidine-requiring  strains  of Salmonella   tvchircurium   (Andersen,  et  al.
1972).
     C.  Teratogenicity and Other Reproductive Effects
         Pertinent data could not be located in the available literature.
         Campbell  and  Davidson (1970)  reported  the  history  of a  woman who
was eating  p-OCS during her pregnancy, and  which  had no  apparent  effect on
the offspring.
     0.  Chronic Toxicity
         In humans, chronic  occupational  exposure  by inhalation has occurred
mainly from 1,4-dichlorobenzene  and to a  lesser  extent 1,2-dichlorobenzene.
Toxicity has  involved  the  following organs  and  tissues:   liver,  blood (or
reticulcsndothelial system, including bone marrow  and/or  immune components),
central nervous  system, respiratory tract,  and integument (U.S.  EPA,  1979).
In an  inhalation study, Hollingsworth,  et al. (1958)  exposed groups  of 20
rats,  eight  guinea  pigs,  four  rabbits,  and  two  monkeys  to  vapor  of
1,2-dichlorcbenzene for seven hours per day,  five  days per week  for  six to
seven months  at  an average  concentration  of  560 mg/m  .   NO  adverse effects
were  noted  in  behavior,  growth,  organ  weights,  hematology,  or  gross  and
microscopic examination of tissues.  In a nine-month chronic  toxicity study
Varshavskaya  (1967), gave  rats  1,2-dichlorobenzene at daily doses  of  0.001,
0.01,  and  0.1 mg/kg.   The  toxicological  observations in the highest  dose
group was anemia and other blood changes, liver damage, and  central nervous
system depression.  Liver  carnage has also  been observed with  rats and guinea
pigs exposed  to 1,4-dichlorobenzene at a concentration  of 2,050  mg/m   for

-------
six  months  (Hollingsworth,  et  al.   1956)'.   There  have  been  no  specific



studies  on the  chronic  effects  of  1,3-dichlorobenzene, although  this com-



pound may  'have been a contaminant in  the preparations of the other  two iso-



mers used  for  toxicological testing (U.S. EPA, 1979).



     E.  Other Relevant  Information



         Dichlorobenzenes  can  induce  the  microsomal drug  metabolizing en-



zymes.   Changes  in the  levels  of microsomal  enzymes can  affect the metab-



olism  and biological  activity of  a   wide  variety of xenobiotics  (Ware and



West, 1977).



V.   AQUATIC ' TOXICITY



     A.  Acute Toxicity



         Acute  studies  have  indicated  that  the  position of  the  chlorine



atoms  on  the  benzene ring  do not  dramatically  influence the  toxicity   of



dichlorcbanzenes  for  freshwater  fish.    In  56-hour  static  bioassays with



bluegills,  Leocrnis  ~acrohirus,  >-^=o  values  were  4,280,  5,590  and  5,020



,ug/l  for 1,4-,  1,2, and 1,3-dichlorobenzene,  respectively  (U.S.  EPA,  1973).



However,  Dawson,  et al.  (1977)  has  provided a  96-hour  static LCSg  value  of



27,000 pg/1  for 1,2-dichlorobenzene for  the  same  species.   A greater  range



Oi  toxicmiss was  obw2i,n.sc  rcr  the  \ resnwatcr  invsrteGrace  C5G~riia  iTiacna



tested  in 96-hour  static  bioassays.   LC5Q values  were:   2,440;  11,000; and



28,100 /jg/1  for  the   1,2-,  1,4-, and 1,3-dichlorobenzene  isomers,   respec-



tively  (U.S.  EPA,  1978).  Marine  fish  were slightly  more  resistant than



freshwater  fish  in  96-hour  static  assays with L.CCQ  values  ranging from



17,400 to  9,660  ug/1  for 1,4- and 1,2-dichlorobenzene, respectively,  for the



sheepshead minnow.   Marine invertebrates  were  the  most sensitive organisms

-------
tested with  LC5Q values of  1,970,  1,990, and 2,850 jug/1  obtained for 1,2-,
1,4-,  and 1,3-  dichlorobenzenes respectively  in  mysid  shrimp  (Mysidoosis
bahia) (U.S. EPA, 1978).
     8.  Chronic Toxicity
         The only  chronic  study performed  was  an embryo-larval  test of the
freshwater  fish,  the fathead minnow  (Pimeohales  promelas),  that  produced a
chronic value of 1,000 ug/1.  No other chronic studies were available.
     C.  Plant Effects
         The freshwater  algae Selenastrum capricfarnutum, when tested for the
effects of dichlorobenzenes  on  chlorophyll  a and  cell numbers, had effective
concentrations ranging from  91,500  to 98,000;  149,000 to 179,000; and 96,700
to  98,100  ug/1  for  1,2-,  1,3-,   and  1,4-dichlorobenzene,  respectively.
Similar studies  in the marine  algae  Skeletonema  costatum revealed effective
concentrations of  44,100 to 44,200;  49,500  to  52,300;  and  54,300  tc 59,ICQ
for 1,2-,  1,3-, and 1,4-dichlorobenzenes.
     0.  Residues
         Bioconcentraticn  factors of  89,  66, and £0  were  obtained for 1,2-,
1,3-,  and 1,4-dichlorobenzenes  in  the   bluegill.   Data  on  marine  biccon-
centration factors are not available.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.  Human
         The Occupational  Safety  and Health  Administration,  (OSHA, 1976),
and  the  American  Conference of Governmental  Industrial  Hygienists  (ACGIH,
1977)  threshold  limit  value is 300  mg/m   for  1,2-dichlorobenzene  and  450
mg/m   for 1,4-dichlorobenzene.   The  acceptable  daily intake  (ADI)  of  1,2-
                                                                      »
or 1,4-dichlorobenzene  is  1.316 mg/day (Natl. Acad.  Sci.,  1977).   There are

-------
no  standards  for  1,3-dichlorobenzene.   The  U.S.  EPA  (1979)  draft  water
quality criterion for total dichlorobenzene (all three isomers) is 0.16 mg/1.
     B.  Aquatic
         The draft  criteria for  the  protection of  freshwater  organisms  are
44 pg/1 not  to exceed 99 pg/1  for  1,2-dichlorobenzene;  310 pg/1 not  to  ex-
ceed 700  ug/1  for  1,3-dichlorobenzene; and  190 pg/1 not to  exceed  440 pg/1
for 1,4-dichlorobenzene.  For marine  organisms  criteria  have  been  drafted as
15 pg/1 not  to exceed  34  pg/1  for 1,2-dichlorobenzene;  22 pg/1 not to exceed
49  ug/1  for  1,3-dichlorobenzene;  and  15 pg/1  '"not  to  exceed  34 pg/1  for
1,4-dichlorobenzene.

-------
                               DICHLOROBENZENE5

                                  References
American  Conference  of Governmental  Industrial  Hygienists.   1977.   Docu-
mentation of the threshold  limit  values  for substances in workroom air (with
supplements  for those  substances  added  or  changed  since  1971).   3rd  ed.
Cincinnati, Ohio.

Anderson, K.J.,  et al.  1972.   Evaluation  of herbicides  for possible muta-
genic properties.  Jour. Agric. Food Chem. 20: 649.

Azouz, W.M., et al.   1955.   Studies in detoxication,  62:  The metabolism of
halogenobenzenes.  Orthoand paradichlorobenzenes.  Biochem. Jour.  59: 410.

Balba,  M.H. and  J.G.  Sana.   1974.   Metabolism'• of  lindane-1^ by  wheat
plants frown from treated seed.  Environ. Latt.  7: 181 (Abstract).

Campbell,  O.M;  and  R.J.L.  Davidson.    1970.    Toxic  haemolytic  anaemia in
pregnancy due  to a pica for paradichlorcfcenzene.   Jour.  Obstet. Gynaec.  3r.
Cmnwlth.  77: 657.

Carey, M.A.  and E.S. McDonougn.   1S43.   On the production  of polyploicly in
Allium with paradichlorobenzene.

Qav.'son,  G.W.,   et  al.  1977.   The  toxicity of 47 industrial  chemicals to
fresh and saltwater fishes.   Jour. Hazard. Mater.  1:  3C3.
"rank,  S.S.  and  H.J.   Cchsn.   1961.   Fixed  drug  eruption  due  to  pars-
c'ichiorobenzene.  N.Y. Jour. Wed.  61: 4075.

Gaffney,  P.E.    1976.   Carpet  and  rug  industry  case  study.  I.  Water and
wastewater  treatment plant  operation.   Jour.  Water  Poliut.  Control  Fed.
48: 2590.

Glaze,  W.H.,  et al.  1976.   Analysis of  new chlorinated  organic compounas
formed  by  chlorination   of  municipal  wastewater.   In:  ?roc.  Con.f.  Environ.
Impact Water Chlorination.  Iss. Conf.-751096, pages~l53-75.  (Abstract).

Hallowell,  M.   1959.  Acute  haemolytic anemia  following  the ingestion  of
paradichlorobenzene.  Arch. Dis. Child.  34: 74.

Hollingsworth, R.L., et  al.   1956.  Toxicity  of  paradichlorobenzene.  Deter-
minations  on  experimental  animals  and  human  subjects.    AMA   Arch.  Ind.
Health  14: 133.
                                                     «•

Hollingsworth, R.L.,  et  al.  1958.  Toxicity  of o-dichlorobenzene.   Studies
on animals and industrial experience.   AMA Arch.  Ind. Health  17:  180.
                                                                       »
Jacobs, S.  1957.   The handbook of  solvents.   0.  Van Nostrand Co., Inc., New
York.

-------
Jacobs, A.,  et al.   1974a.   Accumulation of  noxious  chlorinated substances
from Rhine  River  water in  the  fatty tissue of  rats.   Vom  Wasser (German)
43: 259.  (Abstract).

Jacobs, A., et al.   1974b.   Accumulation  of organic compounds, identified as
harmful  substances   in  Rhine  water,   in  the   fatty   tissues  of  rats.
Kernfcrschungszsntrum Karlsruhe (Ser.)  KFK 1969 UF, pp. 1 (Abstract).

Jordan, I.E.,   1954.   Vapor pressure  of  organic  compounds.    Interscience
Publishers, Inc.,  New York.

Kirk,  R.E.  and  D.E.  Othmer.   1963.   Kirk-Othmer encyclopedia  of  chemical
technology.  8th ed.  John Wiley and Sons, Inc. New York.

Morita, M.,  et al.   1975.   A  systematic determination of  chlorinated ben-
zenes in human adipose tissue.  Environ. Pollut. 9:.175.   (Abstract).

Morita, M.  and  G.  Ohi.   1975.   Para-dichlorobenzene in human  tissue  and
atmosphere in Tokyo metropolitan area.  Environ. Pollut.   8: 269.

Mostafa,   I.Y.   and  P.M.   Moza.    1973.    Degradation   of   camma-oenta-
chloro-1-cyclohexane  (garnma-PCCH)  in corn  and pea  seedlings.   Egypt.  Jour.
Cnem. Iss. Spec.:   235.  (Abstract).

National Academy  of Sciences.  1977.   Drinking  water and health.   U.S.  EPA
Contract No. 68-01-3169.  Washington, O.C.

Occupational  Safety  and  Health  Administration.    1576.    General  industry
standards.  19 CFR 1=10.  July 1. 1975; OSEA  22Cc",  revised  Jan.  1976.   U.S.
Dep. Labor. Washington, D.C.

Pagn.otto,  L.D. and J.E.  Walkley.   1966.  Urinary  dichlcrcpher.ol  as  an index
of paradichlorobenzene  exposure.   Ind.  Eyg. Assoc.  Jour.  26:  137.   (Rev.  in
Food Cosmet. Toxicol.  4: 109.  (Abstract)".

Parke,   D.V.  and  R.T.  Williams.   1955.   Studies  in  detoxication:   The
metabolism of  halogenobenzenes.   (a) Metadichlorobenzene  (b) Further obser-
vation on the metabolism of chlorobsnzene.  Biochem. Jour.   59: '415.

Prasad, I.   1970.   Mutagenic effects of  the  herbicide 3',4'-dichlorcpropio-
nanilide and its degradation products.  Can. Jour. Microbiol.  16: 369.

Schmidt,  G.E.   1971.   Abnormal  odor  and  taste  due  to  p-dichlorobenzene.
Arch. Lebensmittelhyg.  (German)  22: 43.   (Abstract).

Snarma, A.K.>and  S.K. Sarkar.   1957.   A  study on  the  comparative effect of
chemicals on  chromosomes of  roots,  pollen mother  cells  and  pollen  grains.
Proc. Indian Acad. Sci. Sect. B.  45: 288.

Srivastava,  L.M.    1966.    Induction of  mitotic   abnormalities  in  certain
genera of tribe Vicieae by paradichlorobenzene.  Cytologia  31: 166.

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

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

Varshavskaya,  S.P.   1967.   Comparative  toxicological  characteristics  of
chlorobenzene and dichlorabenzene  (orthoand para-isomers)  in relation to the
sanitary protection of water bodies.   Gig. Sanit. (Russian)  33: 17.

Ware, S.A. and  W.L.  West.   1977.  Investigation of selected potential envi-
ronmmental contaminants:   halogenated  benzenes.   U.S.  Environ. Prot. Agency,
Washington, O.C.

Weast,  R.C.,  et  al.   1975.  Handbook of chemistry  and physics.   56th ed.
CRC Press, Cleveland, Ohio.

-------
                                      No. 68
       3,3'-Dichlorobenzidine


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

           APRIL 30, 1980

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

-------
                       SPECIAL NOTATION










U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated



3,3'-dichlorobenzidine and has found sufficient evidence to



indicate that this compound is carcinogenic.

-------
                   3,3'-PICHLOROBEN 2IDINE



                           SUMMARY



     The adverse health effects associated with  3 ,3'-dichloro-



benzidine include the elevated risk of carcinogenicity  based



upon data from several experimental bioassays.   Animals ex-



posed to dust containing dichlorobenzidine were  found to have



a slight to moderate pulmonary congestion.



    • One aquatic toxicity test has been performed  for di-
                                    /•


chlorobenzidine, yielding results indicating that  concentra-



tions of 0.5 ug/1 were acutely toxic to a freshwater fish



species.

-------
                    3,3'-DICHLOROBEN ZIDINE

I.   INTRODUCTION

     This profile  is  based  primarily  on the  Ambient Water

Quality Criteria Document for  Dichlorobenzidine  (U.S.  EPA,

1979).  The molecular formula  of  3,3'-dichlorobenzidine

(4,4'-diamino-3,3'-dichlorobiphenyl)  is C^H^gC^^/

and has a molecular weight  of  253.13.  The chemical is spar-

ingly soluble  in water (0.7 g/1 at  15°C), but  readily  soluble

in organic solvents.  Because  of  the  fact that 3,3'-dichloro-

benzidine is an organic base,  it  may  be fairly tightly bound

to humic materials, causing long-term  storage  in  soils.

     3,3'-Dichlorobenzidine has been  demonstrated to be a

carcinogen in  experimental  animals.  Various types  of  sar-

comas and adenocarcinomas have been  induced  at injection

sites, and in  specific organ systems  upon dosage  by gavage.

No evidence is available implicating  3,3'-dichlorobenzidine

as a human carcinogen.

II.  EXPOSURE

     A.   Water

          3,3'-Dichlorodibenzidine  has been  detected in water

near a waste disposal lagoon ranging  from 0.13 to 0.27 mg/1,

as have benzidine  concentrations  up  to 2.5 mg/1  (Sikka, et

al. 1978).  In water  of the Sumida  River in  Tokyo receiving

effluents of dye and  pigment factories (Takemura, et al.
                                           »•
1965) total aromatic  amines including  3,3'-dichlorobenzidine

were reported  as high as 0.562 mg/1.   The literature tends, to

support the possibility that the  use of storage lagoons to

handle 3,3'-dichlorobenzidine  wastes may pose  a threat to

persons relying on nearby wells for drinking water.

-------
     B.   Food



          Data quantifying  levels  of  3,3'-dichlorobenzidine



in foods have not been  reported.   It  was  suggested  that con-



sumption 'Of fish would  serve  as  the major dietary intake of



3,3'-dichlorobenzidine.  No measurable  levels  of 3,3'-dichloro-



benzidine were detected  (<10  ug/D  in fish sampled  near a



contaminated waste-lagoon (Diachenko, 1978).



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


average bioconcentration factor  to  be 1,150 for  3,3'-dichloro-



benzidine for the edible portions  of  fish and  shellfish con-



sumed by Americans.  This estimate  is based on the octanol/



water partition coefficient.



     C.   Inhalation



          The low volatility  and large  crystal structure of



3,3'-d ichlorobenzidine would  tend  to  minimize  the risk  of .ex-



posure to the chemical  Ln ambient  air.  However,  inhalation



may be a major source of exposure  to  those individuals  occu-



pationally exposed to 3,3'-dichlorobenzidine.  Concentrations



as high as 2.5 mg/100 m-^ have been  reported in one Japanese



pigment factory (Akiyama, 1970).



     D.   Dermal



          Under specific conditions of  moist skin and high



atmospheric humidity and temperature  dermal absorption  of



3,3'-dichlorobenzidine may be possible.
                                           ••


III.  PHARMACOKINETICS



     A.   Absorption                                      .



          Data concerning the rates and degree of absorption



of dichlorobenzidine have not be quantitated.

-------
     B.   Distribution




          One study administering  (14C}-3,3'-dichloroben-



zidine at doses of 0.2 mg/kg  intravenously  in  rats,  monkeys,



and dogs revealed a general distribution  of  radioactivity




after 14 days.  The highest (14c)-3,3'-dichlorobenzidine



levels were found in the livers of all  three species,  in  the



bile of monkeys and in lungs  of dogs  (Kellner,  et  al.  1973).



     C.   Metabolism



          Following the intravenous injection  of 0.2 mg/kg



(^*c)-3,3'-dichlorobenzidine, the  total urinary radioac-



tivity was recovered as one-third  unchanged  (^C)-3,3'-



dichlorobenzidine, one-third  as the mono-N-acetyl  derivative



of the parent compound, and the remainder not  recoverable



(Kellner, et al., 1973).  Chronic  ingestion of  small doses  of



3 , 3'-dichlorobenzidine lead to the appearance  of four  meta-



bolic products including benzidine  (U.S. EPA,  1979), however,



the results may be questionable due to  the analytical  methods



employed in the study.  No metabolites of 3,3'-dichlorobenzi-



dine have been detected in the excreta of dogs  experimentally



administered the parent compound (U.S. EPA, 1979), nor the



urine of human subjects experimentally administered  the chem-



ical (Gerarde and Gerarde, 1974).



     E.   Excretion



          Several studies have indicated that  fecal  elimina-



tion may be a major route of excretion  in animals  and  humans



(U.S. EPA,  1979).  One study  (Meigs, et al. 1954)  detected'



unspecified amounts of 3,3'-dichlorobenzidine  in the urine  of



occupationally exposed workers.

-------
IV.  EFFECTS ON MAMMALS
     A.   Carcinogenicity
          A number of  investigations  have  reported  the car-
cinogenic potential of 3,3'-dichlorobenzidine.   Dietary 3,3'-
dichlorobenzidine at 1,000 mg/kg have been associated  with
the significant occurrence of mammary adenocarcinomas, granu-
locytic leukemia, and  zymbal gland  carcinomas  in male  rats
and mammary adenocarcinomas in  female  ra-ts (Stula,  et  al.
1975). In dogs, oral doses of 100 mg/kg were associated with
the significant occurrence of hepatic  and  urinary bladder
carcinomas (Stula, et  al. 1975).  Levels of 0.5  and 1.0 mis
of a 4.4 percent suspension of  3,3'-dichlorobenzidine  in rat
feed, resulting in a 4.53 g total dose of  the  chemical,  pro-
duced an increase of cancers of  the mammary gland,  Zymbal
gland, urinary bladder, skin, sraall intestine, liver,  thyroid
gland, kidney, hematopoietic system and salivary glands
(Pliss, 1959).  Hepatic tumors  and  sebaceous gland  carcinoma
were observed in mice exposed to a  total dose  of 127.5 to 135
mg over a ten month period of time  (Pliss, 1959).   3,3'-Di-
chlorobenzidine was administered at levels of  30 mg  every 3
days for 30 days by gavage.  Observations  over nine  months
demonstrated that DCB  is ineffective  as a  mammary carcinogen
(Griswold, et al.  1968).  A diet of  0.3 percent 3,3'-dichloro-
benzidine was marginally carcinogenetic and tumorigenic  to
hamsters (U.S. EPA, 1979).  3,3'-Dichlorobenzidine  has also
found to produce transformation  in cultured rat  embryo celis
(Freeman, et al. 1973).  Epidemiology  studies  in  the United
States, Great Britian,  and Japan have  not  provided  evidence

-------
that 3,3'-dichlorobenzidine by  itself  induces  bladder  cancer


in  workers occupationally exposed  to  the  chemical.   For some


studies, though, the latent period  for  tumor  formation might


not have elapsed.


     B.   Mutagenicity


          3,3'-Dichlorobenzidine has been  shown  to  induce


frame shift mutations in Salmonella typhimurium  tester strain


TA1598 in the presence of the S9 NADPH-fortified  rat  liver

enzyme preparation  (Garner, et  al.  1975).   Similar  results


with tester strain TA98 indicating  frame shift mutations and


tester strain 1000  indicating base-pair substitutions  were


observed by prior metabolic activation with a  male  mouse


enzyme system (Lazear and Louis, 1977).


     C.   Teratogenicity


          Information relative  to the  teratogenic effects of


3,3'-dichlorobenzidine was not  found in the available


literature.  Document (U.S. EPA, 1979).  The  chemical  has


been shown to cross the placental barrier  and  increase the


incidence of leukemia in the offspring of  pregnant  mice  given


doses of 8-10 mg of 3 , 3'-dichlorobenzidine  subcutaneously


during the last week of pregnancy, but these  results may


represent toxic effects on neonates through suckling milk


from dosed mothers  (Golub, et al. 1969, 1974).  Altered


growth and morphology of cultured kidney tissue obtained  from


prenatally exposed mouse embryos has been  observed  (Shabad,
                                                           »

et al. 1972;  Golub, et al.  1969).

-------
     D.   Toxicity
          An acute oral LD^Q for DCS  in mice,  given  to
mice for seven consecutive days was 352 mg/kg/day  for  females
and 386 mgAg/day for males.  Single-dose LD50 values
were reported as 488 and 676 mg/kg for female  and  male  mice,
respectively.  Rats exposed to atmospheric dust containing
unspecified amounts of 3,3'-dichlorobenzidine  for  14 days
showed no increased mortalities.  Upon autopsy slight  to*
moderate pulmonary congestion and one pulmonary abcess  were
observed.
V.   AQUATIC TOXICITY
     The only aquatic species tested  for the toxic effects of
3,3'-dichlorobenzidine was the bluegill, Lepomis macrochirus.
It was found to be acutely toxic at concentrations of 0.5
mg/1 or greater (Sikka, et al. 1978).
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 possibil-
ity that these criteria will be changed.
     A.   Human
          The American Conference of Governmental  Industrial
Hygienists has recommended that exposure to 3,3'-dichloroben-
zidine be reduced to zero, based on the demonstrated carcino-
genicity of the chemical in experimental animals.  Occupa-
tional standards have not been placed on 3,3'-dichlorobenzl-
dine and standards regulating levels of the chemical in the
environment or in food have not been proposed.

-------
     A recommended draft criterion of  1.69 x  10~2  ug/i



has been established, corresponding  to a  lifetime  cancer risk



of lO""^.  This value was derived  from  data relating  3,3'-



dichlorobenzidine to the daily consumption of  two  liters of



water and 18.7 g of fish and shellfish.



     B.   Aquatic



          Data were insufficient  to  draft criteria for  either



freshwater or marine life.

-------
                   3,3'-DICHLOROBEN ZIDINE

                         REFERENCES

Akiyama, T.  1970.  The investigation on the manufacturing
plant of organic pigment.  Jikei. Med. Jour.  17:  1.

Diachenko, G.  1978.  Personal communication, U.S.  Food  and
Drug Administration.

Freeman, A.E., et al.  1973.  Transformation of cell  cultures
as an indication of the carcinogenic potential of  chemicals.
Jour. Natl. Cancer Inst.  51: 799.

Garner, R.C., et al.  1975.  Testing of some benzidine ana-
logues for raicrosomal activation to bacterial mutagens.
Cancer Lett.  1: 39.

Gerarde, H.W., and D.F. Gerarde.  1974.  Industrial experi-
ence with 3,3'-dichlorobenzidine: an epidemiological  study of
a chemical manufacturing plant.  Jour. Occup. Med.  16:  322.

Golub, N.I.  1969.  Transplacental action of 3,3'-dichloro-
benzidine and orthotolidine on organ cultures of embryonic
mouse kidney tissue.  Bull. Exp. BipJL. Med.  (U.S.S.R.) 68:
1280.

Golub, N.I., et al.  1974.  Oncogenic action of some  nitrogen
compounds on the progeny of experimental mice.  Bull.  Exp. •
Biol. Med.  (U.S.S.R.)  78: 62.

Griswold, D.P., et al.  1968.  The carcincgenicity of  multi-
ple intragastric doses of aromatic and heterocyclic nitro or
amino derivatives in young female Sprague-Dawley rats.
Cancer Res.  28: 924.

Kellner, H.M., et al.  1973.  Animal studies on the kinetics
of bensidine and 3 , 3'-dichlorobenzidine.  Arch. Toxicol.  31:
61.

Lazear, E.J., and S.C. Louis.  1977.  Mutagenicity of  some
congeners of benzidine in the Salmonella typhimurium  assay
system.  Cancer Lett.  4: 21.

Meigs, J.W., et al.  1954.  Skin penetration by diamines of
the benzidine group.  Arch. Ind. Hyg. Occup. Med.  9:  122.

Pliss, G.B.  1959.  Dichlorobenzidine as a blastomogenic
agent.  Vopr. Onkol.  5: 524.
                            6 ?--

-------
Shabad, L.M., et al.  1972.  Transplacental effects of some
chemical compounds on organ cultures of embryonic kidney
tissue.  Cancer Res.  32: 617.

Sikka, H.C., et al.  1978.  Fate of 3,3'-dichlorobenzidine  in
aquatic environments.  U.S.-•"Environ. Prot. Agency 600/3-8-
068.

Stula, E.F., et al.  1975.  Experimental neoplasia in rats
from oral administration of 3,3'-dichlorobenzidine , 4,4'-
methylene-bis(2-chloroaniline), and 4,4'-methylene-bis(2-
methylaniline).  Toxicol. Appl. Pharmacol.  31: 159.

Takemura, N., et al.  1965.  A  survey of the pollution of the
Sumida River, especially on the aromatic, amines in the water.
Internat. Jour. Air Water Pollut.  9: 665.

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


-------
                                      No. 69
         1,1-Dichloroethane
  Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENC7
       WASHINGTON, D.C.  20460

           APRIL 30, 1980

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

-------
                              1.1-OICHLDROETHANE
                                   Summary
     There i's no available evidence to indicate that 1,1-dichloroethane pro-
duces carcinogenic or mutagenic effects.  A  single  study in rats  failed  to
show teratogenic effects  following  inhalation exposure.
     Symptoms produced by human poisoning include respiratory  tract  irrita-
tion, central nervous system depression,  and  marked  cardiac excitation.  An-
imal studies indicate that  1,1-dichloroethane may produce liver damage.
     Sufficient toxicological data  are not  available to  calculate  aquatic
exposure criteria.
                                 £7-3

-------
                              1,1-OICHLOROETHANE
I.   INTRODUCTION
     This  profile  is based  on  the Ambient  Water Quality  Criteria  Document
for Chlorinated Ethanes (U.S. EPA, 1979a).
     The chloroethanes are hydrocarbons in which  one  or more of the  hydrogen
atoms  have been  replaced by  chlorine atoms.   Water  solubility  and  vapor
pressure decrease  with increasing  chlorination,  while  density and  melting
point   increase.    1,1-Oichloroethane  (ethylidene   dichloride;   ethylidene
chloride;  molecular  weight  98.96)  is a  liquid  at  room temperature with  a
boiling  point  of  57.3°C,  a  melting  point  of -98°C,  a specific gravity  of
1.1776, and a solubility in water of 5 g/liter (U.S.  EPA, 1979a).
     The chloroethanes are used as  solvents,  cleaning and degreasing agents,
and in  the chemical  synthesis of  a number of compounds.  No commercial pro-
duction of 1,1-dichloroethane has been reported in the  United States (NIOSH,
1973).
     The chlorinated ethanes form  azeotropes with  water (Kirk and  Othmer,
1963).  All  are  very soluble in  organic  solvents (Lange,  1936).  Microbial
degradation of the chlorinated  ethanes  has  not been  demonstrated  (U.S.  EPA,
1979a).
     The reader is referred  to  the Chlorinated Ethanes  Hazard  Profile  for  a
more general discussion of chlorinated ethanes (U.S.  EPA, 1979b).
II.  EXPOSURE
     The chloroethanes are present  in raw and finished  waters  due primarily
to industrial discharges.  Small  amounts  of  the chlqxoethanes  may be  formed
by chlorination  of  drinking  water or  treatment  of  sewage.   Air  levels of
these volatile compounds  are  produced by  evaporation during  use as  degreas-
ing agents  and in dry-cleaning operations  (U.S.  EPA,  1979a).
                                 t-f-1

-------
     Sources of  human  exposure  to chloroethanes include water, air,  contami-
nated  foods  and  fish,  and dermal  absorption.   Fish and shellfish have  shown
levels of chloroethanes in the nanogram range  (Dickson  and Riley, 1976).
     No  information on levels  of 1,1-dichloroethane  in foods was  found  in
the  available  literature.  Sufficient  data is  not available  to  estimate  a
steady-state bioconcentration factor for 1,1-dichloroethane.
III. PHARMACOKINETICS
     Pertinent  data could  not  be located  in  the available  literature  on
1,1-dichloroethane  for absorption,  distribution,   metabolism  and excretion.
However, the reader is referred  to a more general  treatment of chloroethanes
(U.S.  EPA,  1979b)  which indicates rapid absorption of chloroethanes  follow-
ing  oral or inhalation exposure; widespread  distribution  of the chloroeth-
anes throughout  the body; enzymatic dechlorination and oxidation  to  the al-
cohol  and  ester  forms; and excretion  of the  chloroethanes  primarily in the
urine  and in expired air.
     Additionally,  it  has been  indicated  that  the  absorption of 1,1-dichlcr-
oethane  is  most similar  to  that  of  the 1,2-isomer (indicating  significant
dermal absorption as well as rapid oral or inhalation absorption).
IV.  EFFECTS
     A.  Carcinogsnicity and Mutagenicity
         Pertinent data could not be located in the available literature.
     8.  Teratogenicity
         An inhalation  study  in  rats has indicated no  major teratogenic ef-
fects of 1,1-dichloroethane (Schwetz, et al. 1974).
     C.  Other Reproductive Effects
         Inhalation  of  1,1-dichloroethane  by  pregnant  rats  produced  delayed
ossification of  sternebrae in  fetuses,  indicating  an effect  of the compound
in retarding fetal development (Schwetz, et al. 1974).

-------
     D.  Chronic Toxicity
         Use of  1,1-dichloroethane  as  an anesthetic was discontinued because
of marked  excitation of  the heart  (Browning,  1965).  Poisoning  cases have
shown  respiratory tract  irritation and central  nervous  system  depression
(U.S. EPA, 1979a).  Animal  studies  indicate  that inhalation of 1,1-dichloro-
ethane may produce liver damage (Sax, 1975).
V:   AQUATIC TOXICITY
     Pertinent aquatic  toxicity  data could  not be located  in the available
literature.
VI.  EXISTING GUIDELINES AND STANDARDS
     A.  Human
         The current  promulgated  Occupational Safety  and  Health Administra-
tion  exposure standard  for  1,1-dichloroethane  is  100  ppm,  time-weighted
average for up to a 10-hour work day, 40-hcur work week.
         Sufficient data are  not  available to derive  a criterion  to protect
human health from exposure to 1,1-dichloroethane from ambient water.
     8.  Aquatic
         Sufficient toxicologic data are not available to  calculate aquatic
exposure criteria.

-------
                              1,1-OICHLQROETHANE

                                  REFERENCES
Browning,  E.    1965.   Toxicity  and  metabolism   of   industrial   solvents.
Elsevier Publishing Co., Amsterdam.

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  D. Othmer.  1963.  Encyclopedia  of  Chemical Technology.   2nd
ed. John Wiley and Sons Inc.   New  York.

Lange, N., ed.   1956.  Handbook of Chemistry.   9th  ed.   Handbook Publishers,
Inc.  Sandusky, Ohio.

National  Institute  for  Occupational  Safety and  Health.   1978.    Ethylene
dichloride  (1,2-dichloroethane).   Current  Intelligence  Bull.   25.    OHEVJ
(NIOSH) Publ. NO. 78-149.

Sax,  N.I.,  ed.   1975.   Dangerous  properties of  industrial materials.   4th
ed.  Reinhold Publishing Corp.   New York.

Schv/etz,  3.A.,   at al.   1974.  Embryo  and  fetotoxicity of  inhaled carbon
tetrachloride,    1,1-dichloroethane,   and   methyl  ethyl  ketone   in   rats.
Toxicolo. Appl. Pharrnacol.   28:  452.

U.S.  EPA.   1979a.    Chlorinated  Ethanes  Ambient  Water  Quality  Criteria.
(Draft).

U.S.   EPA.    1979b.    Environmental   Criteria   and.   Assessment    Office.
Chlorinated Ethanes:   Hazard  Profile.   (Draft).
                                 61-7

-------
                                      No. 70
         I,2-Dichloroethane
  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.
                         70-1

-------
                      SPECIAL NOTATION










U.S. EPA1s Carcinogen Assessment Group (GAG)  has  evaluated



1,2-dichioroethane  and has found sufficient evidence  to



indicate that this  compound is carcinogenic.
                      70-3

-------
                              1,2-OICHLOROETHANE
                                   Summary

     Results of  an  NCI carcinogenesis bioassay  in rats and mice  have  shown
that  1,2-dichloroethane  may  produce  a  wide  variety of  tumors,   including
squamous  cell  carcinomas,  hemangiosarcomas,  mammary  adenocarcincmas,  and
hepatocellular carcinomas.  Mutagenic effects have  been shown  in the  Ames
Salmonella  system  and  in E.  coli;   metabolites  of  1,2-dichloroethane  have
also shown rnutagenic effects in the Ames assay.   v
     One study  has  failed to  indicate teratogenic effects  following  inhala-
tion  exposure  to  1,2-dichloroethane  although  reproductive   toxicity  was
demonstrated.   Chronic human  exposure  to  1,2-dichloroethane  has produced
neurological symptoms  and liver and  kidney  damage.   Poisoning victims  have
shown diffuse dystrcphic changes in the brain and spinal cord.
     Acute  toxicity  values  for freshwater organisms  ranged  from  431,QCO  to
530,GOO jjg/1.  • Marine invertebrates  appeared  to be  somewhat more sensitive
to 1,2-dichlorcethane  with an LC^  value of 113,GCC jjg/1 reported.
                                     70-1
                                     Oi; /^
                                   ~ 0 i u ~

-------
                              1,2-OICHLOROETHANE



I.   INTRODUCTION



     This profile is based on the draft  Ambient Water  Quality  Criteria Docu-



ment for Chlorinated Ethanes (U.S.  EPA,  1979a).



     The chloroethanes are hydrocarbons  in which one or  more of the hydrogen



atoms of ethane are  replaced  by  chlorine atoms.  Water  solubility  and vapor



pressure decrease  with  increasing  chlorination,  while  density and  melting



point increase.  1,2-Dichloroethane  (molecular  weight  98.96)  is a  liquid  at



room  temperature  with  a  boiling   point  of   83.4 C,  a  melting  point  of



-35.4°C, a  specific  gravity of 1.253, and a  solubility  of 8.1 g/1  in water



(U.S. EPA,  1979a).



     The chloroethanes are used as  solvents, cleaning  and  degreasing agents,



and in  the  chemical  synthesis of a  number  of  compounds.   A large portion  of



1,2-dichloroethane is  used  in the  production of vinyl chloride and  chlori-



nated chemicals, and 33  an  ingredient,  along  with tetraethyl  lead,  in anti-



knock mixtures (U.S.  EPA, 1979a).



     1,2-Oichloroethane production  in  1976 was 4.000  x  103 tons (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 teen demonstrated (U.S.  E?a,



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
                                 •70-r

-------
by  chlorination of  drinking  water  or  treatment  of sewage.   Of  80  water
samples tested, 27 contained  1,2-dichloroethane at concentrations  of  0.2 to
3pg/l (U.S. EPA,  1974).
     Sources of human  exposure to chloroethanes not  only  include water,  but
also air, contaminated  foods  and fish, and dermal  absorption.   For example,
1,2-dichloroethane has  been detected  in  11 of 17 spices  in concentrations
ranging from 2 to  23 jug/g  of spice  (Page  and  Kennedy,  1975).   In fish  and
shellfish,  levels  of  chloroethanes  in the nanogram  range have  been  found
(Oickson and Riley,  1576).
     The  U.S.   EPA  (1979a)  has  estimated  the  weighted  average bioconcen-
tration factor  for 1,2-dichloroethane to  be 4.6  for the  edible  portions of
fish  and  shellfish  consumed  by Americans.   This  estimate was based  on  the
measured steady-state bioconcentration studies in bluegills.
III. PHARMACQKINETICS
     A.  Absorption
         The chloroethanes  are acsorbed rapidly following  oral or inhalation
routes of exposure (U.S.  EPA,  1979a).  Animal  studies indicate  that signif-
icant  absorption  of  1,2-dichloroethane  may  occur  following dermal  apcli-
cation (Smyth,  et al. 1969).
     3.  Cistrioution
         Pertinent information could  not  be located in the available litera-
ture on  1,2-dichloroethane.  The reader  is referred to more  general  treat-
ment  of  the chloroethanes  (U.S. EPA,  1979b)   which  indicates a widespread
distribution of chloroethanes  through the  body.

-------
     C.  Metabolism
         In general, the metabolism of chloroethanes involves both enzymatic
dechlorination  and  hydroxylation  to  corresponding   alcohols  (U.S.   EPA,
1979a).  Metabolism of  1,2-dichloroethane  produces  a  variety of metabolites
in the  urine.   The main two are:   s-carboxymethylcysteine  and thiodiacetic
acid  (Yllner, 1971a,b,c,d).    Yllner   (1971a,b,c,d)  also  stated  that  the
percentage  of  1,  2-dichloroethane  metabolized  decreased  with  increasing
dose, suggesting saturation of  metabolic pathways.
     D.  Excretion
         The  chloroethanes are  excreted  primarily in  the  urine and in  ex-
pired air  (U.S.  EPA,  1979a).   Animal studies conducted  by  Yllner (1971a,b,
c,d) indicate that large amounts of chlorinated ethanes administered by i.p.
injection  are excreted  in the urine,  with  very  little  excretion in  the
feces.   Excretion appears  tc be rapid,  since  90 percent of an i.p.  adminis-
tered dose o:~ 1,2-dichlcrosthane was  eliminated in  the  first  24 hours  (U.S.
EPA,  1979a).
IV.  EFFECTS
     A.  Carcinogenicity
         Results of  the NCI bioassay for carcinogenicity (NCI,  1978)  have
indicated  that  1,2-dichloroethane  e.c~inistratiQn  produced  an incrsase  in
several types of tumors.   Squamous cell carcinomas and hemangiosarcomas were
produced in male rats, and mammary adenocarcinomas in  female rats,  following
feeding of  1,2-dichloroethane.   In  mice,  hepatocellular carcinomas  in  males
and mammary adenocarcinomas in  females were both increased after oral treat-
ment with 1,2-dichloroethane.
                                70-7
                                 -&H-

-------
     8.  Mutagenicity
         Testing of  1,2-dichloroethane  in the  Ames "Salmonella assay and  an
E.  coli  assay  system have  indicated mutagenic  activity of  this  compound
(8rem,  et  al.  1974).   Metabolites  of  1,2-dichloroethane  (S-chloroethyl
cysteine, chloroethanol,  and chloroacetaldehyde) have  shown positive  muta-
genic effects  in the  Ames system (U.S. EPA, 1979a).  1,2-Oichloroethane  has
also  been   reported   to  increase  mutation   frequencies   in  pea  plants
(Kiricheck,  1974)  and Drosophila (Nylander,  et  al.  1978).
     C.  Teratogenicity                         "
         Inhalation studies  with 1,2-dichloroethane in  pregnant  rats  did  not
indicate teratogenic effects (Vozovaya,  1974).
     0.  Other Reproductive Effects
         Rats  exposed' to  1,2-dichloroethane  by  inhalation  showed  reduced
litter sizes,  decreased  live births,  and decreased fatal weights  (Vczovaya,
1974).
     E.  Chronic Toxicity
         Patients  suffering  from   1,2-dichlorcethane  poisoning  have  shown
diffuse  dystrophic  changes  in  the brain  and   spinal  cord  (Akimov,  et  al.
1973).   Chronic exposures  have produced  neurologic  changes  and  liver  and
kidney impairment (NIOSH, 197Sa).
         Animal studies  with  1,2-dichloroethane  toxicity have  shown  liver
and kidney damage and  fatty  infiltration, and  some bone marrow effects  (U.S.
EPA, 1979a).
     F.  Acute Toxicity
         Oral  human  LD.   (lowest dose  which has caused  death)  values have
                                                                      »
been estimated  at  500 and  810  mg/kg  in two studies  (NIOSH, 1978b).   Other
species  show a  similar  sensitivity  to 1,2-dichloroethane,  except   for  the
                                    70-%

-------
rat.   An  LD^-  value for  this species  has  been  estimated  to be  12 jjg/kg



(NIOSH, 1978b).



V.   AQUATIC TOXICITY



     A.  Acute Toxicity



         Acute  96-hour  static LC5Q  values  ranged from 431,000  to 550,000



ug/1 for the bluegill (Lepomis macrochirus), while a  single  48- hour static



LC5Q  value  of  218,000  ug/1  was obtained  for  the   freshwater  cladoceran



Daphnia magna  (U.S.  EPA,  1978).   A  single  acute  marine  invertebrate study



was  available,  reporting  a  96-hour  static  LCco  value of 113,000  jjg/1 for



the mysid shrimp (Mysidopsis  bahia)  (U.S.  EPA,  1978).



B.   Chronic Toxicity and Plant Effects



         Pertinent information could not be  located in the available litera-



ture on chronic toxicity and  plant effects.



     C.  Residues



         A bicconcentraticn  factor of  2 has been  reported  fcr the bluecill



(U.S. EPA,  1979a).



VI.  EXISTING GUIDELINES AND  STANDARDS



     Neither the human  health nor the  aquatic  criteria  derived by U.S. EPA



(1979a), which are summarized below,  have gone through the process of public



review;  therefore,   there  is  a  possibility that  these  criteria  will  be



changed.



     A.  Human



         Based on the NCI  carcinogenesis  bioassay  data,  and  using a linear,



nonthreshold  model,  the  'U.S.   EPA   (1979a)   has' estimated   a  level  of



1,2-dichloroethane in ambient water that will result in an additional cancer
                                                                     »


risk of 10"5 to be 7 ug/1.
                                   70-7

-------
         The  8-hour   TV/A  exposure   standard   developed  by   QSHA  for
1,2-dichloroethane is 5Q ppm.
     3.   Aquatic
         In  freshwater  environment   a   criterion  has  been  drafted  for
1,2-dichloroethane as  3,900 jug/1 as a 24-hour average,  not  to exceed 8800
jug/1.  For marine life, the criterion has been drafted as 880 ug/1, not to
exceed 2000 >jg/l.
                                  70-10

-------
                     1,2-DICHLOROETHAHE

                         REFERENCES

Akimov, G.A., et al.  1978.  Neurologic disorders  in acute
dichloroethane poisoning.  Zh. Nerropatol. Psikhiatr.  78:
687.

Brem, S.L., et al.  1974.  The mutagenicity and DNA-tMod ifying
effect of haloalkanes.  Cancer Res.  34: 2576.

Dickson, A.G., and J.P. Riley.  1976.  The distribution of
short-chain halogenated aliphatic hydrocarbons in  some marine
organisms.  Mar. Pollut. Bull.  79: 157.

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.

Lange, N. (ed.)  1956.  Handbook of chemistry.  9th ed.
Handbook Publishers, Inc., Sandusky, Ohio.

National Cancer Institute.  1978.  Bioassay of 1,2-dichloro-
ethane for possible carcinogenicity.  Natl. Inst.  Health,
Ilatl. Cancer Ins-. Carcinogenesis Testing -Program.  DHEW
Publ. Ho. (NIH) 75-1205.  Pub. Health Sec". U.S. Dep.  Health
Sdu. Welfare.

National Institute for Occupational Safety and Health.  I973a.
Ethylene dichloride (1,2-dichloroethane).  Current Intelli-
gence Bull.  25.  DHEW (NIOSH) Publ. No. 78-149.

National Institute for Occupational Safety and Health.  1978b.
Registry of toxic effects of chemical substances,  DHEW (NIOSH)
Publ. No. 79-100.

Nylander, P.O.., et al.  1978.  Mutagenic effects  of petrol in
Drosophila melanoaaster.  I. Effects of benzene of and 1,2-
dichloroethane.  Mutat. Res.  57: 163.

Page, B.D., and B.P.C. Kennedy.  1975.  Determination  of
methylene chloride, ethylene dichloride, and  trichloroethy-
lene as solvent residues in spice oleoresins, using vacuum
distillation and electron-capture gas chromatography.  Jour.
Assoc. Off. Anal. Chem.  58: 1062.

Smyth, H.F. Jr., et al.  1969.  Range-finding toxicity data:
List VII.  Am. Ind. Hyg. Assoc. Jour.  30: 470.

U.S. EPA.  1974.  "Draft analytical report-Mew Orleans area
water supply study," EPA 906/10-74-002.  Lower Mississippi
River Facility, Slidell, La., Surveill. Anal. Div. Region VI,
Dallas, Tex.
                           70-11

-------
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.  1979a.  Chlorinated Ethanes: Ambient Water Quality
Criteria. (Draft) .

U.S. EPA.  1979b.  Environmental Criteria and Assessment Of-
fice.  Chlorinated Ethanes: Hazard Profile (Draft).

Van Dyke, R.A., and C.G. Wineman.  1971.  Enzymatic
dechlorination: Dechlorination of chloroethanes and propanes
in vitro.  Biochem. Pharmacol.  20: 463.

Vozovaya, M.A.  1974.  Development of progeny of two genera-
tions obtained from female rats subjected to the action of
dichloroe thane. , Gig. Sanit.  7: 25.

Yllner, S.  1971a.  Metabolism of 1 ,2-dichloroethane -14c
in the mouse.  Acta. Pharmacol. Toxicol.  30: 257.

Yllner, S.  1971b.  Metabolism of 1, 1, 2-trichloroethane-l-2-
       the mouse. ' Acta. Pharmacol. Toxicol.  30: 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-tetrachloroethar.e-
-•^C in the mouse.  Acta. Pharmacol. Toxicol.  29: 499.
                         70 -

-------