CHLORINATED BENZENES
Ambient Water Quality Criteria
              Criteria and Standards Division
              Office  of Water Planning and Standards
              U.S.  Environmental Protection Agency
              Washington,  D.C.

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                        CRITERION DOCUMENT



                       CHLORINATED BENZENES



CRITERIA



                           Aquatic Life



     Chlorobenzene



          The data base for freshwater aquatic life is insuffi-



cient to allow use of the Guidelines.  The following recommenda-



tion is inferred from toxicity data on 1,2,4,5-tetrachlorobenzene



and saltwater organisms and 1,2-dichlorobenzene and freshwater



organisms.



          For chlorobenzene the criterion to protect freshwater



aquatic life as derived using procedures other than the Guidelines



is 1,500 ug/1 as a 24-hour average and the concentration  should



not exceed 3,500 ug/1 at any time.



          The data base for saltwater aquatic life  is  insufficient



to allow use of the Guidelines.  The following recommendation  is



inferred from toxicity data on 1,2,4,5-tetrachlorobenzene and



saltwater organisms and 1,2-dichlorobenzene and freshwater
                *


organisms.



          For chlorobenzene the criterion to protect saltwater



aquatic life as derived using procedures other than the Guidelines



is 120 ug/1 as a 24-hour average and the concentration should  not



exceed 280 ug/1 at any time.



     1,2,4-trichlorobenzene



          The data base for freshwater aquatic life  is insuffi-



cient to allow use of the Guidelines.  The following recommenda-



tion is inferred from toxicity data on 1,2,4,5-tetrachlorobenzene



and saltwater organisms and 1,2-dichlorobenzene and  freshwater



organisms.

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          For 1,2,4-trichlorobenzene  the  criterion to protect



freshwater aquatic  life  as derived  using  procedures other than the



Guidelines is 210 ug/1 as a  24-hour average ano  the concentration



should not exceed 470 ug/1 at  any  t nec



          The data  base  for  saltwatt-c aquatic life is insufficient



to allow use of  the Guidelines.  Tht  following  recommendation is



inferred from toxicity data  on 1, 2, •' , 5-tetrachlorobenzene and



saltwater organisms and  1,2-dichlorcbenzene and  freshwater



organisms.



          For 1,2,4-trichlorobenzene  the  criterion to protect



saltwater aquatic life as derived  using procedures other than the



Guidelines is 3.4 ug/1 as a  24-hour average and  the concentration



should not exceed 7.8 ug/1 at  any  time.



     1/2,3 t5-tetrachlorobenzene



          The data  base  for  freshwater aquatic life is insuffi-



cient to allow  use  of the Guidelines.  The following recommenda-



tion is  inferred from toxicity data on 1,2,4,5-tetrachlorobenzene



and saltwater organisms  and  1,2-dichlorobenzene  and freshwater



organisms.



          For 1,2,3,5-tetrachlorobenzene  the criterion to protect



freshwater aquatic  life  as derived  using  procedures other than the



Guidelines is 170 ug/1 as a  24-hour average and  the concentration



should not exceed 390 ug/1 at  any  time.



          The data  base  for  saltwater aquatic life is insufficient



to allow use of  the Guidelines. The  following recommendation is



inferred from  toxicity data  on 1,2,4,5-tetrachlorobenzene and



saltwater organisms and  1,2-dichlorobenzene and  freshwater



organisms.

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          For 1,2,3,5-tetrachlorobenzene the criterion to protect


saltwater aquatic life as derived using procedures other than  the


Guidelines is 2.6 ug/1 as a 24-hour average and the concentration


should not exceed 5.9 ug/1 at any time.


     1,2,4,5-tetrachlorobenzene


          The data base for freshwater aquatic life is insuffi-


cient to allow use of the Guidelines.  The following  recommenda-


tion is inferred from toxicity data on 1,2,4,5-tetrachlorobenzene


and saltwater organisms and 1,2-dichlorobenzene and freshwater


organisms.


          For 1,2,4,5-tetrachlorobenzene the criterion to protect


freshwater aquatic life as derived using procedures other than the


Guidelines is 97 ug/1 as a 24-hour average and the concentration


should not exceed 220 ug/1 at any time.


          For 1,2,4,5-tetrachlorobenzene the criterion to protect


saltwater aquatic life as derived using the Guidelines is 9.6  ug/1


as a 24-hour average and the concentration should  not exceed 26


ug/1 at any time.


     pentachlorobenzene


          The data base for freshwater aquatic life  is  insuffi-


cient to allow use of the Guidelines.  The following  recommenda-


tion is inferred from toxicity data on 1,2,4,5-tetrachlorobenzene


and saltwater organisms and 1,2-dichlorobenzene and  freshwater
                       :

organisms.


          For pentachlorobenzene the criterion to  protect  fresh-


water aquatic life as derived using procedures other  than  the


Guidelines is 16 'ug/1 as a 24-hour average and the concentration


should not exceed 36 ug/1 at any time.

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          The data base  for saltwater  aquatic  life  is  insufficient

to allow use of the Guidelines.  The following  recommendation  is

inferred from toxicity data on  1,2,4,5-tetrachlorobenzene  and

saltwater organisms and  1,2-dichlorobenzene  and  freshwater

organisms.

          For pentachlorobenzene the criterion  to protect  salt-

water aquatic life as derived using procedures  other  than  the

Guidelines  is 1.3 ug/1 as  a 24-hour average  and  the concentration

should not  exceed 2.9 ug/1 at any  time.

                           Human Health

     For the prevention  of adverse  organoleptic  or  toxicological

effects, the recommended criteria  for  chlorinated benzenes are  as

follows:

    Substance             Criterion        Basis  for  Criterion

Monochlorobenzenel        20 ug/1          Organoleptic  effects

Trichlorobenzene          13 ug/1          Organoleptic  effects

Tetrachlorobenzene        17 ug/1          Toxicity studies

Pentachlorobenzene        .5 ug/1          Toxicity study


IA toxicological evaluation of  monochlorobenzene resulted  in
a level of  450  ug/1;  however, organoleptic effects  have  been
reported at 20  ug/1.

     For the maximum  protection of  human  health  from  the potential

carcinogenic effects  of  exposure to hexachlorobenzene  (HCB)

through  ingestion of  water and  contaminated  aquatic organisms,  the

ambient water  concentration  is  zero.   Concentrations  of  HCB  esti-

mated  to  result in  additional  lifetime cancer  risks ranging  from

no additional  risk  to an additional risk  of  1  in 100,000 are pre-

sented in  the  Criterion  Formulation section  of  this document.   The

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Agency is considering setting criteria at an interim  target



risk level in the range of 10~5/ 10~6, or 10~? with corres-



ponding criteria of 1.25 ng/1, 0.125 ng/1, and 0.0125 ng/1,



respectively.

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Introduction



     The chlorinated benzenes,  excluding dichlorobenzenes,



are monochlorobenzene (CgHcCl) ,  1, 2, 3-tr ichlorobenzene (CgH-,



Clo), 1,2,4-trichlorobenzene (CgHoClo),  1,3,5-trichlorobenzene



(CgH3Cl3),  1,2,3,4-tetrachlorobenzene (CgH2Cl4),  1,2,3,5-



tetrachlorobenzene (CgH3Cl4),  1,2,4,5-tetrachlorobenzene



(CgH2Cl4),  pentachlorobenzene  (CgHCl,-),  and hexachlorobenzene



(CgClg).  Based on annual production in the U.S., 139,105



kkg of monochlorobenzene was produced in 1975, 12,849 kkg



of 1,2,4-trichlorobenzene, 8,182 kkg of 1,2,4,5-tetrachloroben-



zene and 318 kkg of hexachlorobenzene were produced in 1973



(West and Ware, 1977; U.S.I.T.C., 1975;  EPA,  1975a).



     The remaining chlorinated benzenes are produced mainly



as by-products from the production processes  for the above



four chemicals.  Production and use of chlorinated benzenes



results in 34,278 kkg of monochlorobenzene, 8,182 kkg of



trichlorobenzenes and about 1,500 kkg of tetra-, penta-,



and hexa-chlorinated benzenes  entering the aquatic environment



yearly.   Annual amounts on monochlorobenzene  (690 kkg) and



hexachlorobenzene (1,628 kkg)  contaminate solid wastes.



Yearly estimates of atmospheric contamination of monochloro-



benzene and tetrachlorobenzenes are 362.and 909 kkg, respec-



tively (West and Ware, 1977).



     Monochlorobenzene is used for the synthesis of ortho



and para nitrochlorobenzenes (50 percent),  solvent uses



(20 percent), phenol manufacturing (10 percent) and DDT



manufacturing (7.5 percent). 1,2,4-trichlorobenzene is used



as a dye carrier (46 percent), herbicide intermediate  (28



percent), a heat transfer medium, a dielectric fluid  in
                              A-l

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transformers, a degreaser, a  lubrica  ;  aad  a  _ .-. antial ir.--.cr.i-




cide against termites.  The other  tr  h]or^V   ;•-..-  I'fjort:.  -



are not used in any quantity.   1,2,4  -; .-.'        _,^e. j;ene



is the only tetrachloro-isomer  used     . id.  '„      qu-.ntities.



Fifty-six percent of  the  annual con?  .?  .: .       2,4  S-tetjd-



chlorobenzene is used  in  the  product! n "•£  t'~ -   'foliant,



2 , 4 , 5-trichlorophenoxy acetic acid,  .   p^rcenc   a  the synthe-



sis of 2,4,5-trichlorophenol  and 11  > rcsnt  e~  a fungicide.
                                         *


Pentachlorobenzene  is  used in small  c ar.ti  iea  as  a captive



intermediate in the synthesis of specialty  chemicals  (West



and Ware, 1977). Hexachlorobenzene in 1972  was  used as a



fungicide (23 percent)  to control  wheat bunt  and smut on



seed grains.  Other industrial  uses  (77 percent)  included



dye manufacturing,  an  intermediate in organic synthesis,



porosity controller in the manufacturing of  electrodes,



a wood preservative and an additive  in  pyrotechnic composi-



tions for the military (EPA,  1975a).



     In recent  years,  hexachlorobenzene has  become of concern



because of  its  widespread distribution  as an environmental



contaminant  and a contaminant of food products  used for



human consumption  (Grant, et  al. 1974). Hexachlorobenzene



has been  found  in adipose tissue and milk of cattle being



raised  in the  vicinity of an  industrialized region bordering



the Mississippi River between Baton  Rouge and New Orleans,



Louisiana.   Hexachlorobenzene residues  have been found in



adipose  tissue  of  sheep in western Texas and eastern California



 (EPA,  1975b).   The  occurrence and effects of hexachlorobenzene



have  been  reported  in many organisms,  e.g.  birds (Vos, et



al.  1971;  Cromartie,  et al.  1975), rats (Medline,  et al.






                               A-2

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1973),  man (Cam and Nigogosyan, 1963) and fishes  (Holden,
1970; Johnson, et al. 1974, ,Zi.tko, 1971) . .'Magnification
in the natural food.chain .is indicated by Gilbert-son and
Reynolds (1972) observation of hexachlorobenzene  in the
eggs of common terns, which had apparently eaten  contaminated
fish.  This compound has also been found -in samples of ocean
water and its persistence in the environment has  been acknowl-
edged (Seltzer, 1975).
     Specimens of levee soil taken from along the Mississippi
River,  known to be contaminated with hexachlorobenzene waste,
had levels of the compound ranging from 107.0 to  .874.. 0 /jg/kg
(wet weight)   (EPA, 1976a).
     Among seven samples of sediments taken from  the lower
Mississippi River, only one had detectable amounts of hexa-
chlorobenzene.  The concentration found was .231,jug/L.  This
site was known to be contaminated ,by hexachloroben'zene in
the past (Laska., et al. 1976) .
     The National Organics Reconnaissance Survey  tested
ten water supplies for a variety of organic chemicals.  Mono1-
chlorpbenzene was detected but not quantified in  three of
the ten .drinking water supplies.  Drinking water  supplies
from 83 locations in Region V, EPA were analyzed  for various
pesticides and organic chemicals. Hexachlorobenz-ene was
detected in three locations with concentrations  ranging
from 6 to 10 ng/1.
     The National Organics Reconnaissance Survey  tested
ten finished drinking waters fcr a variety of organic  chemi-
cals (EPA, 1975c).
                               A-3

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      Some physical properties  of  the  chlorinated  benzenes

 are given below in Table 1 (Weast,  1975.



                             TABLE  1
Compound
MW
mp(°C)  bp(°C)
density  logoctanol
           water
         partition
monochlorobenzene
tr ichlorobenzene
1,2,3-
1,2,4-
1,3,5-
tetrachlorobenzene
1,2,3,4-
1,2,3,5-
1,2,4,5-
pentachlorobenzene
hexachlorobenzene
112.56

181.45
—
—

215.90
—
—
250.34
284.79
-45.6

52.6
17
63.4

47.5
54.5
138-140
86'
230
131-132

218-219
213.5
208

254
246
243-246
277
322
1.107

143
1.454
145

146
--
1.858
1.834
2.044
2.83

—
4.23
—

—
—
4.93
5.63
6.43
      Monochlorobenzene,  which is the most polar compound,

 is soluble in water to the extent of 488 mg/1 at 25° (Mellan,

 1970; Mardsen and Marr,  1963).   Solubilities of the other

 chlorobenzenes in water  were not available.  The chlorinated

 benzenes are generally good solvent for fats, waxes, oils

 and greases.  The lipid  solubility of these compounds is

 high and are expected to accumulate in ecosystems  (Mardsen

 and Marr, 1963;  Mellan,  1970).
                               A-5

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                          REFERENCES







Cam, C. , and G. Nigogosyan.  1963. Aoqu'.red  toxic  porphyria



cutanea tarda due  to  hexachlorobenzrne. Jour. Am. Med. Assoc.



183: 88.







Cromartie, E.W. 1975.  Residues  of organochlorine  pesticides



and polychlorinated biphenyls and autopsy data  for  bald



eagles, 1971-1972. Pestic. Monit. Jour. 9:  11.






Gilbertson, M., and L.M.  Reynolds.  1972. Hexachlorobenzene



(HCB)  in the eggs  of  common  terns in  Hamilton Harbour, Ontario.



Bull.  Environ. Contain.  Toxicol.  7:  371.






Grant, D.L., et al. 1975a. Hexachlorobenzene  accumulation



and decline of tissue residues  and  relationship to  some



toxicity criteria  in  rats. Environ. Qual. Safety  Suppl.



3:  562.






Grant, D.L., et al. 1975b. Effect of  hexachlorobenzene on



rat reproduction.  Toxicol. Appl. Pharmacol. 33: 167.  (Author



abstract.)







Hampel, C., and G. Hawley. 1973. The  Encyclopedia of  Chemistry,



3rd ed. Van Nostrand  Reinhold Co.,  N.Y.







Holden, A.V.  1967. International co-operative study of organo-



chlorine  pesticide residues  in  terrestrial  and  aquatic wild-



life,  1967, 1968,  1970. Pestic. Monit.  Jour.  4: 117.
                               A-6

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 Johnson,  J.L.,  et  al.  1975.  Hexachlorobenzene  (HCB)  residues



 in fish.  Bull.  Environ.  Contam.  Toxicol.  11: 393.







 Kirk,  R.E.,  and D.F. Othmer.  1963.  Kirk-Othmer  Encyclopedia



 of Chemical  Technology,  2nd  ed.  Vol.  4, and Vol.  5.  John



 Wiley  and Sons,  New York.







 Laska, A.L.,  et al. 1976. Distribution of  hexachlorobenzene



 and hexachlorobutadiene  in water soil and  selected aquatic



 organisms along  the lower Mississippi River, Louisiana.



 Bull.  Environ.  Contam. Toxicol. 15: 535.







 Mardsen,  C.,  and S. Marr, 1963.  Solvents Guide. Cleaver-Hume



 Press Ltd.,  London.







 Medline,  A.,  et  al. 1973. Hexachlorobenzene and rat  liver.



 Arch. Pathol. 96: 61.







 Mellan, I. 1970. Industrial Solvents. Noyes Data Corp. Park



 Ridge, N.J.







 Seltzer, R.J. 1975. Ocean pollutants  pose potential  danger



 to man. Chem. Engr. News 53: 19.







Snell,  D., et al. 1969. Encyclopedia  of Industrial Chemical



Analysis.  Vol. 9. Interscience Publishers, N.Y.
                              A-7

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Stecher, P.G.,  ed.  1968. The Merck Index. An  encyclopedia



of chemicals and drugs. 9th ed. Merck and Co.,  Inc., Rahway,



N.J.







U.S. EPA. 1975a. Survey of Industrial Processing Data: Task



I, Hexachlorobenzene and hexachlorobutadiene  pollution from



chlorocarbon processes. Mid. Res. Inst. EPA,  Off. Toxic



Subs. Washington, D.C.







U.S. EPA. 1975b. HCB review report: Fifth 90-day HCB meeting



and status of HCB studies.







U.S. EPA. 1976a. An ecological study of hexachlorobenzene.



EPA-560/6-76-009.







Varshavskaya, S.P. 1967. The hygienic standardization of



mono- and dichlorobenzenes in reservoir waters. Nov. Tr.



Aspir. Ordina. Pervyi Moskov. Medit.  Instit. 175.







Vos, J.G., et al. 1971. Toxicity of hexachlorobenzene in



Japanese quail with special reference to porphyria,  liver



damage, reproduction, and tissue residues.  Toxicol.  and



Applied Pharmacol. 18: 944.







Weast, R.C., ed. 1975. Handbook of Chemistry and Physics.



The Chemical Rubber Co., Cleveland,  Ohio.
                              A-8

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West, W.L., and S.A. Ware, 1977. Preliminary Report,  Investiga-

tion of Selected Potential Environmental Contaminants: Halo-

genated Benzenes. Environ. Prot. Agency, Washington,  D.C.


                                       r
Zitko, V. 1971. Polychlorinated biphenyls and organochlorine

pesticides in some freshwater and marine fishes. Bull. Environ.

Contain.  Toxicol. 6: 464.
                             A-9

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AQUATIC LIFE TOXICOLOGY*



                       FRESHWATER ORGANISMS



Introduction



     This discussion does not include the dichlorobenzenes which



are treated in a separate criterion document.  Toxicity of the



remaining compounds in this class have been determined with



several fish species, Daphnia magna and Selenastrum capricornutum.



No chronic effects data are available.



Acute Toxicity



     All data reported for freshwater fish are 96-hour, static



toxicity tests with unmeasured concentrations.  Pickering  and



Henderson (1966) reported unadjusted 96-hour LC50 values  for



goldfish, guppy, and bluegill to be 51,620, 45,530, and 24,000



ug/1, respectively, for chlorobenzene (Table 1).  Two 96-hour LC50



values for chlorobenzene and fathead minnows were 33,930  ug/1 in



soft water (20 mg/1) and 29,120 ug/1 in hard water  (360 mg/1)



(Table 1).  This indicates that hardness does not significantly
*The reader is referred to the Guidelines for Deriving Water



Quality Criteria for the Protection of Aquatic Life  [43  FR  21506



(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in  order'to  better



understand the following discussion and recommendation.   The



following tables contain the appropriate data that were  found  in



the literature, and at the bottom of each table  are  the  calcula-



tions for deriving various measures of toxicity  as described  in



the Guidelines.
                               B-l

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affect the toxicity of chlorobenzene.  U.S.  EPA  (1978)  reported



96-hour LC50 values for  bluegill exposed  to  chlorobenzene,  1,2,4-



trichlorobenzene, 1,2,3,5-tetrachlorobenzenef  1,2,4,5-tetrachloro-



benzene and pentachlorobenzene  to be be 15,900,  3,360,  6,420,



1,550 and 250 ug/1/ respectively.  Comparable  tests  (U.S.  EPA,



1978) were conducted with  three dichlorobenzenes  and  the  96-hour



LC50 values ranged from  4,280 to 5,590 ug/1.   Only 1,2,3,5-tetra-



chlorobenzene is an apparent anomaly in the  trend to  increasing



toxicity with chlorination.



     Unadjusted 48-hour  EC50 values reported for  Daphnia  magna



(U.S. EPA, 1978) are:  chlorobenzene - 86,000  ug/1;  1,2,4-tri-



chlorobenzene - 50,200 ug/1; 1,2,3,5-tetrachlorobenzene - 9,710



ug/1; and pentachlorobenzene -  5,280 ug/1  (Table  2).  The 48-hour



EC50 value for 1,2,4,5-tetrachlorobenzene  was  greater than  the



highest exposure concentration, 530,000 ug/1 (Table  5).   The



48-hour EC50 for three dichlorobenzenes and  Daphnia magna ranged



from 2,440 to 28,100  ug/1.  For Daphnia magna  the toxicity  of



chlorinated benzenes  generally  tended  to  increase as  the  degree  of



chlorination increased.



     No marked difference  in sensitivity  between  fish and inverte-



brate species is evident from the available  data.  The  Final Acute



Values for the chlorinated benzenes are:   chlorobenzene - 3,500



ug/1; 1,2,4-trichlorobenzene -  470 ug/1;  1,2,3,5-tetrachloro-



benzene -  390 ug/1; 1,2/4,5-tetrachlorobenzene -  220  ug/1;  and



pentachlorobenzene -  36  ug/l«   The Final  Acute Values for chloro-



benzene and  1,2,3,5-tetrachlorobenzene are based  on  Daphnia magna



data whereas  all  others  are based on  fish data.

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 Chronic  Toxicity



      No  chronic  toxicity data  are  available for fish or inverte-



 brate species.



 Plant Effects



      Ninety-six-hour  EC50 tests, using  chlorophyll  a^ inhibition



 and  cell number production  as  measured  responses, were  conducted



 with  the green alga,  Selenastrum capricornuturn (Table 3).   The



 effects of chlorinated benzenes on  this  alga  generally  increased



 as chlorination increased,  but the  trend was  not smooth.   The alga



 was considerably less sensitive than  fish  and Daphnia magna.   The



 Final  Plant Values are 220,000 ug/1 for  chlorobenzene,  35,000 y.g/1



 for 1,2,4-trichlorobenzene, 17,000 ug/1  for 1, 2, 3,5-tetrachloro-



 benzene, 47,000 ug/1  for  1,2,4,5-tetrachlorobenzene  and 6,600 ug/1



 for pentachlorobenzene.



 Residues



     Data which are adequate for computing  acceptable bioconcen-



 tration factors are available  for two chlorinated benzenes.   After



 28-day exposures, the steady-state bioconcentration  factors  for



bluegill for pentachlorobenzene and 1,2,3,5-tetrachlorobenzene are



3,400 and 1,800,  respectively  (Table 4).  The half-lives for  these



compounds were between 2 and 4 days for  1,2,3,5-tetrachlorobenzene



and greater than  7 days for pentachlorobenzene  (U.S.  EPA,  1978).



For three dichlorobenzenes the bioconcentration  factors obtained



using the same procedures (U.S. EPA, 1978)  ranged from  60  to  89.
                              B-3

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     No measured  steady-state  bioconcentration factors (BCF)  are



available  for  other  chlorinated  benzenes.   However,  BCFs  can  be



estimated  using the  octanol-water  partition coefficients  of 290,



18,000, 93,000, and  2,500,000  for  chlorobenzene,  1,2,4-trichloro-



benzene, 1,2,4,5-tetrachlorobenzene,  and hexachlorobenzene,



respectively.  These  coefficients  are  used  to  derive  estimated



BCFs of 44, 1,000,' 3,500,  and  42,000  for chlorobenzene, 1,2,4-tri-



chlorobenzene, 1,2,4,5-tetrachlorobenzene,  and  hexachlorobenzene,



respectively,  for aquatic  organisms that contain  about 8  percent



lipids.  If it is known that the diet  of the wildlife of  concern



contains a significantly different lipid content, appropriate



adjustments in the estimated BCFs  should be made.



     Bioconcentration  factors  correlate well with an  increase in



chlorine content.  The sequence of measured and estimated biocon-



centration factors are 44  (chlorobenzene),  72  (mean of dichloro-



benzene data), 1,000  (1,2,4-trichlorobenzene),  1,800  (1,2,3,5-



tetrachlorobenzene),  3,500  (1,2,4,5-tetrachlorobenzene),  3,400



(pentachlorobenzene), and  42,000 (hexachlorobenzene).



Miscellaneous



     A variety of data on  other adverse effects is presented in



Table 5.  Bioconcentration  factors derived from a model ecosystem



(Isensee, et al.  1976) ranged  from 730 to 9,870 but it could not



be determined whether these were steady-state results.

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CRITERION FORMULATION
                     Freshwater-Aquatic Life
Summary of Available Data
     The concentrations below have been rounded to two significant
figures.
chlorobenzene
     Final Fish Acute Value = 4,900 u_g/l
     Final Invertebrate Acute Value = 3,500 ug/1
          Final Acute Value = 3,500 ug/1
     Final Fish Chronic Value = not available
     Final Invertebrate Chronic Value = not available
     Final Plant Value = 220,000 ug/1
     Residue Limited Toxicant Concentration = not available
          Final Chronic Value•= 220,000 ug/1
          0.44 x Final Acute Value = 1,500 ug/1
1,2,4-trichlorobenzene
     Final Fish Acute Value = 470 ug/1
     Final Invertebrate Acute Value = 2,000 ug/1
          Final Acute Value = 470 ug/1
     Final Fish Chronic Value = not available
     Final Invertebrate Chronic Value = not available
     Final Plant Value = 35,000 ug/1
     Residue Limited Toxicant Concentration = not available
          Final Chronic Value = 35,000 ug/1
          0.44 x Final Acute Value = 210 ug/1
1,2,3, 5-tetrachlorobenzene
     Final Fish Acute Value = 900 ug/1
   -  Final Invertebrate Acute Value = 390 ug/1

                              B-5

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          Final Acute Value = 390 ug/1



     Final -Fish Chronic Value = not available



     Final Invertebrate Chronic Vajue - not  available



     Final Plant Value = 17,000 ug/-1



     Residue Limited Toxicant Concentration  -  not  available



          Final Chronic Value = 17,',00 ug/1



          0.44 x Final Acute Value   170  ug/1



1,2,4,5-tetrachlorobenzene



     Final Fi-sh Acute Value = 220 yx;/l



     Final Invertebrate Acute Value = not  available



          Final Acute Value = 220 ug/1



     Final Fish Chronic Value = not available



     Final Invertebrate Chronic Value = not  available



     Final Pla'nt Value = 47,000 ug/1



     Residue Limited Toxicant Concentration  =  not  available



          Final Chronic Value = 47,000 ug/1



          0.44 x Final Acute Value  = 97 ug/1



pentachlorobenzene



     Final Fish Acute Value = 36 ug/1



     Final Invertebrate Acute Value = 210  ug/1



          Final Acute Value = 36 ug/1



     Final Fish Chronic Value = not available



     Final Invertebrate Chronic Value = not  available



     Final Plant Value = 6,600 ug/1



     Residue Limited Toxicant Concentration  =  not  available



          Final Chronic Value = 6,600 ug/1



          0.44 x Final Acute Value  = 16 ug/1
                               B-6

-------
      No freshwater criterion can be derived for any chlorinated



 benzene using the Guidelines because no Final Chronic Value for



 either fish or invertebrate species or a good substitute for



 either value is available,  and there are insufficient data to



 estimate a criterion using  other procedures.



      However, data for 1,2,4,5-tetrachlorobenzene and saltwater



 organisms and 1,2-dichlorobenzene and freshwater organisms can be



 used  as the basis for estimating criteria.



      For 1,2,4,5-tetrachlorobenzene and saltwater organisms 0.44



 times the Final Acute Value is 11 ug/1. This concentration is



 close to the Final Chronic  Value of 9.6 ug/1 derived from an



 embryo-larval test with  the sheepshead minnow.   Also, for 1,2-



 dichlorobenzene and freshwater organisms 0.44 times the Final



 Acute Value is less than the Final Chronic  Value based on an



 embryo-larval test with  the fathead minnow.   Therefore, a reason-



 able  estimate of  criteria for  chlorinated benzenes and freshwater



 organisms  would be 0.44  times  the Final Acute Value.



 chlorobenzene



      The  maximum  concentration of chlorobenzene is the Final Acute



 Value  of  3,500  ug/1  and  the  estimated 24-hour average concentra-



 tion  is  0.44  times  the Final Acute Value.   No important adverse



 effects  on  freshwater aquatic  organisms have been reported to be



 caused  by  concentrations lower than the 24-hour average concentra-



 tion.







     CRITERION:   For chlorobenzene  the  criterion to protect fresh-



water  aquatic  life as derived  using  procedures  other than the
                              B-7

-------
Guidelines  is  1,500  ug/1  as  a  24-hour average and the



concentration  should  not  exceed  3/500 ug/1  at any time.



1,2,4-trichlorobenzene



     The maximum  concentration of  1,2,4-trichlorobenzene is the



Final Acute Value of  470  U9/1 and  the estimated 24-hour  average



concentration  is  0.44 times  the  Final Acute Value.   No important



adverse effects on freshwater aquatic organisms have been reported



to be caused by concentrations lower  than  the 24-hour average



concentration.



     CRITERION:   For  1,2,4-trichlorobenzene the criterion to



protect freshwater aquatic life  as derived  using  procedures other



than the Guidelines  is 210 ug/1  as a  24-hour average and the



concentration  should  not  exceed  470 ug/1 at any time.



1,2,3,5-tetrachlorobenzene



     The maximum  concentration of  1,2,3,5-tetrachlorobenzene is



the Final Acute Value of  390 ug/1  and  the estimated  24-hour



average concentration is  0.44 times the Final  Acute  Value.   No



important adverse effects on freshwater aquatic organisms  have



been reported  to  be  caused by concentrations  lower than  the



24-hour average concentration.



     CRITERION:   For  1,2,3,5-tetrachlorobenzene the  criterion to



protect freshwater aquatic life  as derived  using  procedures  other



than the Guidelines  is 170 ug/1  as a  24-hour  average  and  the



concentration  should not exceed  390 ug/1 at  any time.
                              B-8

-------
1,2,4 ,5-tetrachlorobenzene
     The maximum concentration of 1,2,4,5-tetrachlorobenzene  is
the Final Acute Value of 220 ug/1 and the estimated 24-hour
average concentration is 0.44 times the Final Acute Value.  No
important adverse effects on freshwater aquatic organisms have
been reported to be caused by concentrations lower than  the
24-hour average concentration.
     CRITERION:  For 1,2,4,5-tetrachlorobenzene the criterion to
protect freshwater aquatic life as derived using procedures other
than the Guidelines is 97 ug/1 as a 24-hour average and  the con-
centration should not exceed 220 ug/1 at any time.
pentachlorobenzene
     The maximum concentration of pentachlorobenzene  is  the Final
Acute Value of 36 ug/1 and the estimated 24-hour average concen-
tration is 0.44 times the Final Acute Value.  No important  adverse
effects on freshwater aquatic organisms have been  reported  to be
caused by concentrations lower than the 24-hour average  concentra-
tion.
     CRITERION:  For pentachlorobenzene the criterion to protect
freshwater aquatic life as derived  using procedures other than the
Guidelines is 16 ug/1 as a 24-hour  average and  the concentration
should not exceed 36 ug/1 at any time.
                               .-9

-------
Table  1.  Freshwater fish acute values for chlorinated benzenes
Dioucsay Test
' Giaauisffl . Method* cone
Goldfish. S U
Carassius aurotus
Fathead minnow, S U
Pimcphales promelas
Fathead minnow, S U
Pimcphales pronielas
Fathead minnow, S • U
Pimcphales promelas
Guppy. S U
Poeciila retlculatus
0, Bluegill. S U
i l.epomis macrochirns
0 Bluegill, S U
Lcpomis macrochirus
Bluegill, S U
Lcpomis macrochirus
Blue gill, S U
l.epomis macrochirus
Bluegill. ' . S U
l.epomis macrochiijus
Bluegill. S U
l.epomis macrochirus

" S = static
** U - unmeasured
Geometric mean of adjusted values:
Chemical Time
.** Peace i lotion (tire)
Chlorobenzene 96
Chlorobenzenc 96
Chlorobenzene 96
Chlorobenzene 96
Chlorobenzenc 96
Chlorobenzene 96
Chlorobenzene 96
1,2.4-trichloro- 96
benzene
1.2.3.5-tetra- 96
Chlorobenzenc
1.2.4,5-tetra- 96
Chlorobenzene
Pcntachloro- 96
benzene


Chlorobcnzune - 19,100 ng/l
IXbo
51.620
33.930
29.120
33.930
45.530
24.000
15.900
3.360
6.420
1.550
250


19JOO
~3^9^-
Adjusted
LCbO
(u<|/l( Ketoienct
28.220
18.550
15,920
18.550
24.890
13.120
8.690
1.837
3.510
847
140


- 4.900
1 , 2 ,4-trichlorobenzene = 1,837 Mg/l —\ -n— •



1 , 2, 3, 5-tetrachlorobenzene =
1 ,2.4,5-tetrachlorobenzene =
Pentachlorobenzene •» 140 Mg/l
3,510 Mg/
847 ,,g/l
i-S =
Pickering &
Henderson, 1966
Pickering &
Henderson . 1966
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
Pickering &
Henderson, 1966
U.S. EPA. 1978
U.S. EPA, 1978
U.S. EPA. 1978
U.S. EPA, 1978
U.S. EPA, 1978


Mg/l
470 Mg/l
3 510
847'
379 =
• 36 ,,g/l
220 Mg/l


-------
Table  2.   KrcuhwaLcr invertebrate acute values for chlorinated benzenes  (U.S. El'A,  1978)
Cladoceran,
Oaphnia magna
Cladoceran,
Daplinla magna
Cladoceran,
Oaphnia magna
Cladoceran,
Daphnia magna
* S •= static
** u . unmeasured
03 Geometric mean of
1
bioabtiay Tett cheinicdi Time
Method* Cone .** Description (Ilia)
S U Chlorobenzene 48
S U 1.2.4-trichloro- 48
benzene
S U 1.2,3.5-tetra- 48
Chlorobenzene
S U fentachloro- 48
benzene


Adjusted values: Chlorobenzene - 73,000 pg/1
Adjusted
LC'j(J LCbU
(IKI/1I (uq/1)
86.000 73,000
50.200 42,500
9.710 8.220
5.280 4.470


2^- - 3.500 ig/1
                      1,2.4-trlchlorobenzene  -  42.500  Mg/l     A2^°° -  2.000 Mg/l
1.2,3,5-tetrachlorobenzene •= 8.220 ng/1
                                                                       - 390 ng/1
Pentachlorobenzene =• 4.470
                                                         -W    - 210 pg/1

-------
               Table  3.   Freshwater plant effects for chlorinated benzenes  (U.S. EPA.  1978)
Organism
Alga.
Selenastrum
capricornutum

.Alga.
Sclenaatrum
capricornucuin
Alga.
Sglcnastrum
capricornutum

Alga.
Selenastrum
capricornutum
 Alga.
 Selenastrum
 capricornutum

 Alga.
 Selcnastrum
 capricornutum
                         Effect
               Concentration
               (yy/11	
    Chlorobenzene

EC50 96-hr        232.000
chlorophyll a
EC50 96-hr        224.000
cell numbers
                        1.2,A-trtchlorobenzene
EC50 96-hr
chlorophyll a


EC50 96-hr
cell numbers
35.300
36.700
                      1,2,3,S-tctrachloroben2ene
EC50 96-hr
chlorophyll a


EC50 96-hr
cell numbers
17.200
17,700
                      1,2 ,4.5-tctrachlprobenzenc
 Alga.
 Selenastruiii
 £ifli£i£P.- ""turn

 Alga.
 Selenasirurn
 capricornutuiii
 Alga.
 So It: pas I. rum
 £ H R r I £.
EC50 96- hr         52.900
chlorophyll a


EC50 96- hr         /t6.800
cull numbers
 Puntachlorohenzcno

EC50 96-hr          6.780
chlorophyll a

-------
                       Table  3.  (Continued)
         Organism
         Alga.
         Selenastrum
         caprlcornutum
EC50 96-hr
cell numbers
                                                Concentration
6.630
CD
 I
M
Ul
         Lowest plant value:  Chlorobenzene -  22A.OOOiig/l

                              l.2.4-trichlorobenzene= 35.300 ug/1

                              1.2.3.5-tetrachlorobenzene = 17.200 vgfl

                              1,2.4.5-tetrachlorobenzene = A6.800 jig/1

                              Pentachloroben^ene =• 6.630 Mg/1

-------
en
 i
           Bluegill.

           l.eppnila macrochirua
           UlueRill.

           Lcnomis macrochlrua
    I'entaclilorobenzene


          3.AGO
28
1.2,3, S-Tetracjylorobenzene


          1.800                   23

-------
                               Table 5.  Other freshwater data  for chlorinated  benzenes
03
 I

Ul
           Organism
           Ri-d  uwump  crayfish,
           Procambarus  clurki
l.art'emouth bass,
Mjcropcurua salmoides
Alga.
Chlorella pyrenoidosa

Alga.
Ocdogpnluin cardiacum

Snail,
He]isnma sp.

Cladoceran,
Daphnia niaRna

.Atlantic salmon,
Salmo salar

Channel catfish,
Tctalurug punctatus
                                    Test
                                                                       Result
            Mosqui tofish,
            Gamhuuia af finis
            ClaJoceran.
            Daphnia inugna
                             '
                        unknown
                                    10 days
                                       6,
                                    15 days
                          3 mo a


                         33 days


                         33 days


                         30 days


                          2 days


                          8 days


                          3 days




                         48 hrs
  Mexachlorobenzene

 Mortality



 Mortality





 Growth
I.C50 not  La ska. et al. 1978
reached
at 27.3 iig/l

No        l.aska. et al. 1978
difference
from controls
at 25.8 ,,g/l
and 10 iig/1
                                                                       1 to
                                                                       10,000
 Bioconcentration
 factor = 730

 Bioconcentration
 factor = 1,500

 Bioconcentration
 factor - 910

 Uloconcentratlon•
 factor = 690

 Bioconcentratlon
 factor = 9.870

 Bioconcentration
 factor = 1.580

1,2.4,5-Tetraghlorobenze n e

 1.050
          Ceike 6. Parasher, 1976b
          l

          Iscnsee, et al. 1976


          Isensee, et al . 1976


          Isensee, et al. 1976


          Zitko & llutzinger. 1976


          Isensee, et al. 1976


          Isensee. et al. 1976
>530,000  U.S. EPA. 1978

-------
                        SALTWATER ORGANISMS



Introduction



     The data  base  for chlorinated benzenes (not including the di-



chlorobenzenes discussed  in  another document)  and saltwater or-



ganisms is  limited  to  chlorobenzene,  1,2,4-trichlorobenzene, 1,2,



3,5-tetrachlorobenzene , 1,2,4,5-tetrachlorobenzene,  pentachloro-



benzene, and hexachlorobenzene.   The  effects  of salinity,  tempera-



ture, or other water quality factors  on  toxicity of  the  chlori-



nated benzenes are  unknown.   Separate criteria are necessary for



each chlorinated  benzene  because toxicity  generally  increases  with



increas.ed chlorination and toxicity may  vary  depending on  the



positions of chlorine  in  the compounds.



Acute Toxicity



     Toxicity  tests with  the sheepshead  minnow have  been conducted



(U.S. EPA,  1978)  with  five chlorinated benzenes (Table 6).   All



tests were  conducted under static  conditions  and concentrations  in



water were  not measured.  Concentrations acutely toxic to  this



saltwater fish were relatively high for  the lower  chlorinated  ben-



zenes and toxicity generally increased with increasing chlorina-



tion; unadjusted  96-hour  LC50 values  for dichlorobenzenes  (7,440



to 9,660 ug/D to sheepshead minnows  were  slightly lower than  that



for chlorobenzene.  The sheepshead minnow  was  generally  more



acutely sensitive to the  chlorinated  benzenes,  except for  1,2,4-



trichlorobenzene  and pentachlorobenzene, than  were four  freshwater



fish species (Table 1); 96-hour  LC50  values of  sheepshead minnows



and bluegills differed by factors of  1.5 to 6.4.  The unadjusted



96-hour LC50 values for sheepshead minnows ranged from 21,400 ug



1,2,4-trichlorobenzene/l  to  830  ug pentachlorobenzene/1.   Since
                              B-16

-------
Since only one test was completed with each chemical, when the ad-
justed LC50 values are divided by the sensitivity factor  (3.7),
the following Final Fish Acute Values are obtained:  chloroben-
zene, 1,600 ug/1; 1,2,4-trichlorobenzene, 3,200 ug/1; 1,2,3,5-
tetrachlorobenzene, 540 ug/1; 1,2,4,5-tetrachlorobenzene, 120
ug/1; and pentachlorobenzene, 120 ug/1-
     Mysidopsis bahia, the only invertebrate species tested, was
more sensitive to three of five chlorinated benzenes than the
sheepshead minnow and more sensitive to  all chlorinated  benzenes
tested than the freshwater cladoceran, Daphnia magna (Tables 6,7,
and 2).  Chlorobenzene (96-hour LC50 = 16,400 ug/D was  the  least
toxic, while pentachlorobenzene was the  most acutely toxic  (96-
hour LC50 = 160 ug/1).  As with sheepshead minnows,  sensitivity  to
the chlorinated benzenes (including the  dichlorobenzenes) general-
ly increased as chlorination  increased.  When the  adjusted  LC50
values for each of the five  compounds tested with  Mysidopsis bahia
are divided by the species sensitivity factor  (49),  the  Final  In-
vertebrate Acute Values are:  280 ug chlorobenzene/1;  7.8 ug 1/2,
4-trichlorobenzene/l; 5.9 ug  1,2,3,5-tetrachlorobenzene/l;  26  ug
1,2,4,5-tetrachlorobenzene/l; and 2.9 ug pentachlorobenzene/1.
Chronic Toxicity
     Only one study has been  c inducted to determine  the  chronic
toxicity of chlorinated benzer >s  to saltwater organisms  (Table 8).
In an embryo-larval study vv>tr. the sheepshead minnow in  which
survival of hatched fi.sh wa--  effected, the limits  for  1,2,4,5-
tetrachlorobenzene ::c*e .2   o 80 ug/1 (U.S. EPA,  1978).  Since
data on only one test are a/aiiable, when the chronic  value of
64.5 ug/1 is divided by the  species sensitivity  factor (6.7),  th'e
                               B-17

-------
Fish Chronic Value  is  9.6  ug/1/  a  value  lower  than the Final Acute

Value of 26 ug/1 for this  chlorinated  benzene.

Plant Effects

     The saltwater  alga, Skeletonema costatum,  was less sensitive

to the chlorinated  benzenes  than the mysid  shrimp or sheepshead

minnow (Table 9).   Ninety-six-hour EC50  values  for growth,  based

on concentrations of chlorophyll a_ in  culture,  were comparable to

96-hour EC50 values calculated  from cell numbers and,  except for

chlorobenzene,  EC50 values for  Skeletonema  costatum were 3  to 25

times lower than EC50  values for the freshwater alga.   Those EC50

values for the  saltwater alga based on chlorophyll a^ and cell num-

bers, respectively, are:   343,000  ug and 341,000 ug chloroben-

zene/1; 8,750 ug and 8,930 ug 1,2,4-trichlorobenzene/l; 830 ug and
                     •>
700 ug If2,3,5-tetrachlorobenzene/l; 7,100  ug  and 7,320 ug  1,2,4,

5-tetrachlorobenzene/l;  and  2,230  ug and 1,980  ug pentachloroben-

zene/1.  There  are  no  data reported on effects  of chlorinated ben-

zenes on saltwater  vascular  plants.

Residues

     Hexachlorobenzene (HCB) is bioconcentrated from water  into

tissues of saltwater organisms  (Tables 10 and  11).  Bioconcentra-

tion factors  (BCF,  concentration in tissue  divided by concentra-

tion in water)  range from  1,964 to 23,000 for  fish and shellfish

 (Parrish,  et  al.  1974).   However,  the  BCF's for fishes and  inver-

tebrate-species exposed- for  96-hours probably  underestimate

steady-state  BCF's  for organisms chronically exposed to hexa-

chlorobenzene.   Bioconcentration factors for grass shrimp,  pink

 shrimp,  and  sheepshead minnows  exposed for  96-hpurs ranged  from

 1,964  to  4,116  while the BCF for pinfish was 15,203 (Table  11).
                                -I a

-------
 Concentrations of HCB in these whole-body samples were probably



 not at equilibrium due to the short exposure period; highly



 chlorinated  compounds generally do not reach chemical equilibrium



 in  exposed animals in short  exposure periods.



      The  BCF in the flesh of pinfish, Lagodon rhomboides, chronic-



 ally exposed for 42 days to  HCB was 23,000 (Table 10) for the five



 exposure  concentrations  tested (0.06 to 5.2 ug/1).  Analysis of



 the concentrations of HCB in pinfish indicate  that HCB concentra-



 tions after  7  days of exposure were approximately one-quarter of



 the total concentration  after 42 days of exposure; concentrations



 after 42 days  of exposure appear to be near chemical equilibrium.



 Concentrations  of  HCB in pinfish muscle were reduced only 16 per-



 cent  after 28  days of depuration and this slow rate is similar to



 that  for DDT in  fish  (Parrish,  et  al.  1974).   Since HCB bioconcen-



 trated  to high  concentrations in all tissues of pinfish and de-



 puration was slow  as  compared to several other organochlorine pes-



 ticides (Parrish,  et  al.  1974),  HCB has a high potential to trans-



 fer  through  and  be  retained  in  aquatic food webs.



      Additional  BCFs  for other  chlorinated benzenes are discussed



 in  the freshwater  section of  this  document.



Miscellaneous



     Data on other  toxicological effects (Table 11)  indicate that



adverse growth effects on one species  of protozoa,  Tetrahymena



pyriformis,  result  from  10-day  exposure  to 1 ug hexachloro-



benzene/1.
                              B-19

-------
CRITERION FORMULATION



                       Saltwater-Aquatic  Life



Summary of Available Data



     The concentrations  below  have  been  rounded  to  two  significant



figures.



Chlorobenzene



     Final Fish Acute  Value =  1,600 ug/1



     Final Invertebrate  Acute  Value = 280 ug/1



          Final Acute  Value =  280 ug/1



     Final Fish Chronic  Value  = not available



     Final Invertebrate  Chronic Value = not available



     Final Plant Value = 340,000 ug/1



     Residue Limited Toxicant  Concentration = not available



          Final Chronic  Value  = 340,000 ug/1



          0.44 x Final Acute Value = 120 ug/1



1,2,4-trichlorobenzene



     Final Fish Acute Value =  3,200 ug/1



     Final Invertebrate Acute Value = 7.8 ug/1



          Final Acute Value =  7.8 ug/1



     Final Fish Chronic Value  = not available



     Final Invertebrate Chronic Value = not available



     Final Plant Value = 8,800 ug/1



     Residue Limited Toxicant Concentration = not available



          Final Chronic Value = 8,800 ug/1



          0.44 x Final Acute Value =3.4 ug/1

-------
 1,2/3,5-tetrachlorobenzene



      Final  Fish Acute Value =  540 ug/1



      Final  Invertebrate Acute  Value = 5.9  ug/1



          Final Acute Value =  5.9 ug/1



      Final  Fish Chronic Value  = not available



      Final  Invertebrate Chronic Value =  not  available



      Final  Plant Value =  700 ug/1



   /  Residue Limited Toxicant  Concentration  = not  available



          Final Chronic Value  = 700 ug/1



          0.44 x Final Acute Value = 2.6 ug/1



 1,2 , 4,5-tetrachlorobenzene



      Final  Fish Acute Value =  120 ug/1



      Final  Invertebrate Acute  Value = 26 ug/1



          Final Acute Value =  26 ug/1



      Final  Fish Chronic Value  =9.6 ug/1



      Final  Invertebrate Chronic Value = not  available



      Final  Plant Value =  7,100 ug/1



      Residue Limited Toxicant  Concentration  = not.  available



          Final Chronic Value  = 9.6 ug/1



          0.44 x Final Acute Value = 11 ug/1



pentachlorobenzene



     Final Fish Acute Value =  120 ug/1



     Final Invertebrate Acute Value = 2.9 ug/1



          Final Acute Value =2.9 ug/1



     Final Fish Chronic Value = not available



     Final Invertebrate Chronic Value = not  available



     Final Plant  Value = 2,000  ug/1
                              B-21

-------
     Residue  Limited Toxicant Concentration = not available



           Final  Chronic Value = 2,000 ug/1



           0.44 x Final Acute Value =1.3 ug/1



1,2,4/5-tetrachlorobenzene



     The maximum concentration of 1,2,4,5-tetrachlorobenzene is



the Final  Acute  Value of 26  ug/1  and  the 24-hour average concen-



tration is  the Final Chronic Value of 9.6 ug/1.   No important



adverse effects  on  saltwater aquatic  organisms have been reported



to be caused  by  concentrations lower  than the 24-hour average



concentration.



     CRITERION:   For 1, 2,4,5-tetrachlorobenzene  the criterion to



protect saltwater aquatic  life as  derived using  the Guidelines  is



9.6 ug/1 as a 24-hour average and  the concentration should not



exceed 26  ug/1 at any time.



     No saltwater criterion  can be derived for any other chlori-



nated benzene using  the  Guidelines because no Final Chronic Value



for either  fish  or  invertebrate species  or a  good  substitute for



either value  is  available.



     However, data  for 1,2,4,5-tetrachlorobenzene  and  saltwater



organisms and 1,2-dichlorobenzene  and freshwater organisms  can be



used as the basis for estimating criteria.



     For 1,2,4,5-tetrachlorobenzene and  saltwater  organisms  0.44



times the Final  Acute Value  is  11  ug/1 and  this concentration is



close to the  Final Chronic Value of 9.6  ug/1  derived from  an



embryo-larval test with  the  sheepshead minnow.  Also,  for



.1,2-dichlorobenzene  and  freshwater organisms  0.44  times  the  Final



Acute Value is less  than the  Final Chronic Value based on  an



embryo-larval test with  the  fathead minnow.   Therefore,  a
                              B-22

-------
reasonable estimate for other.chlorinated benzenes and  saltwater



organisms would be 0.44 times the Final Acute Value.



chlorobenzene



     The maximum concentration of chlorobenzene  is the  Final  Acute



Value of 280 ug/1 and the estimated 24-hour average  concentration



is 0.44 times the Final Acute Value.  No important adverse  effects



on saltwater aquatic organisms have been reported to be caused  by



concentrations lower than the 24-hour average concentration.



     CRITERION:  For chlorobenzene the criterion to  protect



saltwater aquatic life as derived using procedures other than the



Guidelines is 120 ug/1 as a 24-hour average and  the  concentration



should not exceed 280 ug/1 at any time.



1 / 2,4-trichlorobenzene



     The maximum concentration of 1,2,4-trichlorobenzene is the



Final Acute Value of 7.8 ug/1 and the estimated  24-hour average



concentration is 0.44 times the Final Acute Value.   No  important



adverse effects on saltwater aquatic organisms have  been reported



to be caused by concentrations lower than the 24-hour average



concentration.



     CRITERION:  For 1,2,4-trichlorobenzene the  criterion to



protect saltwater aquatic life as derived using  procedures  other



than the Guidelines is 3.4 ug/1 as a 24-hour average and the



concentration should not exceed 7.8 ug/1 at any  time.



1,2/3,5-tetrachlorobenzene



     The maximum concentration of 1,2,3,5-tetrachlorobenzene  is



the Final Acute Value of 5.9 ug/1 and the estimated  24-hour



average concentration is 0.44 times the Final Acute  Value.   No



important adverse effects on saltwater aquatic organisms have been
                               B-23

-------
reported to be caused  by  concentrations  Icver than the 24-hour
   7'
average concentration.

     CRITERION:   For 1, 2, 3, 5-tetraci-  ' robenzens the criterion to

protect saltwater  aquatic  life  as  a.. •.v  d  ,i3ir;_ procedures oLher

than the Guidelines  is  2.6 ug/1 as e  24  hour a  • ^ge and the

concentration should not  exceed 5.9  j/'  ac any time

pentachlorobenzene

     The maximum  concentration  of  pe  tachlorobenzene is the Final

Acute Value of 2.9 ug/1  and  the estimated  24-hour average concen-

tration is 0.44 times  the  Final Acute Value.  No important adverse

effects on saltwater aquatic organisms have been reported to be

caused by concentrations  lower  than the  24-hour average concentra-

tion.

     CRITERION:   For pentachlorobenzene  the criterion to protect

saltwater aquatic life as  derived  using  procedures other than the

Guidelines  is  1.3 ug/1 as  a 24-hour average and the concentration

should not exceed 2.9  ug/1 at any  time.
                               B-24

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               Table   6. Marine  fish  acute values  for  chlorinated benzenes  (U.S.  EPA.  1978)
                                                                           Adjusted



03
NJ
cn
Sheepshead minnow,
Cyprinodon varlcgatus
Shcepshead minnow,
Cyprinodon varie^atus
Sheep sheud. minnow,
Cyprinodon varlcgatus
Sheepshead minnow,
Cyprinodon variegatus
Slieupshuad minnow.
Cypvi nuilon vjriegacus


UiOatieay
Mtt]iod*_
S
S
S
S
S

Test
U
U
I)
U
U

Description
Chlorobenzene
1.2.4-
trichloro-
benzene
1.2.3.5-
tetrachloro-
bunzene
1.2.4.5-
tetrachloro-
benzene
Pentachloro-
benzcne

Time LCbo l.c5o
96 10.500 5,740
96 21.400 11.699
96 3.670 2.010
96 840 460
96 830 450

S = static

U = unmeasured

Geometric mean of adjusted  values:  chlorobenzene = 5,740
                                     1.2,4-trlchlorobenzene = 11.699 ng/1
                                     1.2.3,5-tetrachlorobenzene = 2,010

                                     1.2,4.5-tetrachlorobenzene = 460 |ig/l
                                                                      450
~rrr~" 1-600 "B/1
                   3.200
                   » 540 pg/1

               = 120 ng/1
                                     pentachlorobenzene = 450 |ig/l    3-7 = 120 |ig/l

-------
Table  /.
Bioassay Tost
StililQiSH! Hgthpd* cousi*
Mysid shrimp. S U
Mysidopsts bahia
Mysid shrimp, S U
Mystdopsis bahia
Mysid shrimp. S U
Myaldopsiji bahia
Mystd shrimp, S U
My_sidop_ais bahia
Mysid shrimp. S U
Mysidopsia bahta
* S « static
*••'• U = unmeasured
Geometric mean of adjusted values:



Chemical Time LC'jU
Description |jt»a) ("'!/*>
Chlorobcnzene 96 16.400
1.2.4- 96 450
trichlorobenzene
1.2.3.5- 96 340
tetrachloro-
bcnzenu
1.2.4.5- 96 1,480
tetrachloro-
bcnzene
Pentachloro- 96 160
benzene


chlorobenzene » 13.890 iig/1 — £g —
1,2.4-trichlorobenzene = 381 yg/1
1,2 ,3.5-tetrachlorobenzene » 290 yg/1

Adlusted
LC5o
13.890
381
290
1,250
140


- 280 Mg/1
Hl - 7.8 Mg/1
I?- 5.9 ,g/l
1,250
1,2,4.5-tetrachlorobenzene  °  1,250  iig/i


pentachlorobenzene = 140 iig/1
                                                         140
                                                         jfg— a 2.9 ng/1

-------
03
I
                                                            Chronic
                                                  Limits    Value
           Organism                     Test*     lmi/i>     (ug/1)
           Sheepshead minnow.            E-L      92-180**     64.5
           Cyprinodon vartegatus                     -••
           * E-L ~ embryo-larval

           **1.2.A.5-tetrachlorobenzene

             Geometric mean of chronic values •»  6A.5 Mg/1     ~~STJ

             Lowest chronic value •> 6A.5 iig/1

-------
                                   Marine  plant  effects  for  chlorinated benzenes (U.S.  EPA.  1978)
                                                 Concentration
tt
I
         Oiganlam
         Alga.
         Skeletonema coscatum

         Alga.
         Skeletonema costatum
         Alga.
         Skeletonema costatum

         Alga.
         Skeletonema costatum
Alga.
Skeletonema costatum

Alga.
Skeletonema costatum
         Alga,
         Skeletonema costatum

         Alga.
         Skeletonema costatum
         Alga.
         Skeletonema  costatum

         Alga.
         Skelbtonema  costatum
                                  Effect
                        EC50 96-hr
                        cell numbers

                        EC50 96-hr
                        chlorophyll a
               Chlorobenzcne

                 341.000
                 343.000
                        EC50 96-hr
                        cell numbers

                        EC50 96-hr
                        chlorophyll a
          1,2,4-trlchlorobenaene

                   8.930
                   8.750
EC50 96-hr
cell numbers

EC50 96-hr
chlorophyll a
1,2,3,5-tetrachlorobenaene

             700
                                                      830
                        EC50 96-hr
                        cell numbers

                        EC50 96-hr
                        chlorophyll a
        1.2,4,5-tetrachlorobenzene

                   7.320
                        EC50 96-hr
                        cell numbers

                        EC50 96-hr
                        chlorophyll a
                   7.100


             Pcntaclilorobenzene

                   1.980


                   2,230
          Final  plant  value:
                    Chlorobenzene = 341.000 pg/1
                    1.2,4-trichlorolienzene - 8,750 |ig/l
                    1.2,3,5-tetrachlorobeni:ene = 700 ng/1
                    1,2,4,5-tetrachlorobeni:ciie = 7,100 Mg/1
                    Pentachloiobenzene - 1.9UO Mg/1

-------
00
 I
M
VO
                       Table  10. Marine residues for chlorinated benzenes  (Parrish, ec al.  1974)

                                                                         Time
         Organism                          cioconcentratioii  Factor      (days)



         Pinflsh.                                   23,000*               42
         I.agocJon rhomboides




         * Mean concencracion factor in 25 muscle samples for hexachlorobenzene.

-------
                               Table   11. Other marine JuLu  chlorinated benzenes*
            Organism

            Protozoan,
            Tetrahymena pyritortnis

            Grass shrimp.
            Paliiemonctcs puglo

            Pink shrimp,
            1'enaeus dnorarum

            Pink shrimp,
            Pcnacus duorarum
                         Test
                         puratjpn   Ettect

                         10 Jays    Decreaued growth
                        96 hrs    Mean  bioconccntration
                                  factor •= ft .116

                        96 hrs    Mean  bioconcentration
                                  factor = 1,964

                        96 hrs    33% mortality during
                                  exposure to  25 pg/1;
                          Result
                          Jug/1}     pet eteijCg
                                    Gelke & Praslier, 197S
                                    Parrish, et al.  1974
                                    Parrlsh, et al.  1974
                                    Parrish. et  Hl.  1974
03
 I
U)
o
            Shcepshcad minnow,      96 hrs
            Cyprlnodon vartegatus
Pinfish,
La^odon rhonibotdos
                                    96 hrs
Mean bioconcentration
factor = 2.254

Mean bioconcentration
factor = 15,203
           '•'•' All  data  are  for hexachlorobenzene (I1CU)
                                                                                   .1   \<)
I'  ' •  »'. ri  /il .  1974

-------
                     CHLORINATED BENZENES


                          REFERENCES





 Geike,  F.,  and  C.D.  Parasher.   1976a.   Effect  of  hexachloro-


 benzene (HCB) on  growth  of  Tetrahymena  pyriformis.   Bull.


 Environ.  Contam.  Toxicol.   16:  347.





 Geike,  F.,  and  C.D.  Parasher.   1976b.   Effect  of  hexachloro-


 benzene on  some growth parameters of Chlorella pyrenoidosa.


 Bull. Environ.  Contam. Toxicol.  15: 670.





 Isensee,  A.R.,  et al.  1976.  Soil persistence and  aquatic
                                        r

 bioaccumulation potential of hexachlorobenzene (HCB).  Jour.


 Agric.  Food Chem.  24: 1210.





 Laska,  A.L., et al.  1978.  Acute and chronic  effects  of


 hexachlorobenzene and hexachlorobutadiene in Red  Swamp Cray-


 fish  (Procambarus clarki) and selected  fish species.   Toxicol,


 Appl. Pharmacol.  43: 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.





Pickering, Q.H., and C. Henderson.   1966.  Acute  toxicity


of some important petrochemicals to fish.  Jour.  Water Pollut.


Control Fed.  38:  1419.
                               B-31

-------
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.







Zitko, V., and 0. Hutzinger.  1976.  Uptake of chloro- and



bromobiphenyls, hexachloro- and hexabromobenzene by fish.



Bull. Environ. Contam. Toxicol.  16: 665.
                               B-32

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                      MONOCHLOROBENZENE



Mammalian Toxicology and Human Health Effects



                               EXPOSURE



Introduction



     Monochlorobenzene (MCB) is used industrially both as a



synthetic intermediate and as a solvent.  As a synthetic  in-



termediate, it is primarily used in the production of phenol,



DDT and aniline.  Because it is a solvent for a  large variety



of compounds and is noncorrosive, it finds  technological  use



as a solvent in the manufacture of adhesives, paints, pol-



ishes, waxes, diisocyanates, Pharmaceuticals and natural



rubber.



     Data derived from U.S. International Trade  Commission



reports show that between 1969 and 1975, the U.S. annual  pro-



duction of MCB decreased by 50 percent  from approximately 600



million pounds to approximately 300 million pounds  (U.S.



EPA, 1977).  It is, as expected from its structure,  highly



lipophilic and hydrophobic, its solubility  in water  being



about 100 parts per million.  The octanol to water  partition



coefficient for MCB is 2.83.  Monochlorobenzene  also has  a



relatively high vapor pressure (9 torr  at 20°C). As will be



seen from the next section, this is an  important considera-



tion in estimating the: likely retention of  MCB  in surface



waters.
                             C-l

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Ingestion from Water



     Based on the vapor  pressure,  water  solubility and molec-



ular weight of chlorobenzene,  Mackay  and Leinonen (1975)  esti-



mated the half-life of evaporation from  water  for MCB to  be



5.8 hours.  This is compared  to  4.8 hours for  benzene and



73.9 hours for DDT.



     MCB has been detected  in ground  water,  "uncontaminated"



upland water and in waters  contaminated  either by industrial,



municipal or agricultural waste.   It  has been  identified  in



textile plant effluents  (Erisman  and  Goldman,  1975).   Table 1



consists of a compilation of  data from other EPA reports  and



shows the results of  various  water surveys  as  related to  MCB.



Considering the volatile nature  of MCB,.  these  data should be



considered from a point  of  view  of gross estimate of  expo-



sure.  For example, in the  analysis of the  water for  Lawson's



Fork Creek, South Carolina, the  range indicated is the result



of two analyses four  days apart  (U.S. EPA,  1977). The pre-



sence .of MCB at other sites has  been  demonstrated qualita-



tively by volatile organic  analysis.   It has been detected in



"uncontaminated" upland  water in Seattle, Wash., (Erisman and



Goldman, 1975) and  in raw water  contaminated with agricultur-



al runoff in Ottumwa, Iowa  and Grand  Falls,  North Dakota



(U.S. EPA, 1977).   Some  information is available which might



give  insight as to  the source of contamination.  For  example,



it has been estimated that  during the manufacture of  MCB, 800



mg escapes  into column water  streams  for every kg manufactur-



ed.   Another  4 g  of MCB  per kg manufactured is recovered  from



fractionating  columns for land disposal  (U.S.   EPA, 1977).
                              C-2

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                              TABLE 1
            Examples of Occurrence of Monochlorobenzene
                   Source:  EPA, 1975; EPA, 1977
Location
Source
Concentration
   (ug/D
Miami, FL

Philadelphia, PA


Cincinnati, OH


New York, NY
             • i

Lawrence, MA


Terrebone Parish, LA


Lawsons Fork Creek, SC

Coosa River, GA
Ground water

Raw water contaminated
with municipal waste

Raw water contaminated
with industrial discharge

"Uncontaminated" upland
water

Raw water contaminated
with industrial discharge

Raw water contaminated
with municipal waste

Industrial discharge

Municipal
     1.0

     0.1


  0.1 - 0.5


     4.7


     0.12


     5.6


  8.0 - 17.0

    27.0
   Ingestion from Food

        There are data which imply and demonstrate that MCB in

   water can bioaccumulate in the food chain (Neely, et al. 1974,

   Lu and Metcalf,  1975).   MCB is stable in water and, thus,

   that  which does  not evaporate is available for bioconcentra-

   tion,  the amount of accumulation depending upon the physical

   nature of the  substance.   Neely, et al.  (1974) determined the

   bioconcentration factor for MCB based on the partition coef-

   ficient and  assigned  it a value of  46.   For comparison, ben-

   zene  was  19  and  DDT was 650.   Lu and Metcalf (1975) deter-
                                C-3

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mined the ecological  magnification  of  MCB  in  various  aquatic

species.  Their data  are shown  in Table  2.  For  purposes  of

comparison, the ecological magnification of aldrin  and  DDT in

mosquito fish was 1,312 and 16,960,  respectively.

     Further data by  Lu and Metcalf  (1975) indicate that  MCB

resists biodegradation.  They determine  the biodegradability

index (BI) which was  defined as the  ratio of polar products

of degradation to the nonpolar products.  For MCB, BI ranges

from 0.014 to 0.063 in the organisms shown in Table 2.  The

low value for BI was  similar to that seen for DDT and aldrin.

For example, in mosquito fish the BI for MCB was 0.014, for

DDT it was 0.012 and  for aldrin it was 0.015.
                           TABLE 2

        Ecological Magnification of Monochlorobenzene
                 in Various Aquatic Organisms
         (From Lu and Metcalf, 1975; U.S. EPA, 1977)
        Species
Ecological Magnification
   (corganisms/c H2°)
      Mosquito fish
    (Gambusia affinis)

     Mosquito larvae
 (Culex quinquifasciatus]

         Snails
         (Physa)

        Daphnia
    (Daphnia magna)

         Algae
 (Oedogonium cardiacum)
           645


          1292


          1313


          2789


          4185

-------
     A bioconcentration factor (BCF) relates the concentra-

tion of chemical in water to the concentration in aquatic or-

ganisms, but BCF's are not available for the edible portions

of all four major groups of aquatic organisms consumed in the

United States.  Since data indicate that the BCF for lipid-

soluble compounds is proportional to percent lipids, BCF's

can be adjusted to edible portions using data on percent

lipids and the amounts of various species consumed by Ameri-

cans.  A recent survey on fish and shellfish consumption  in

the United States (Cordle, et al. 1978) found that the per

capita consumption is 18.7 g/day.  From the data on the nine-

teen major species identified in the survey and data on the

fat content of the edible portion of these species  (Sidwell,

et al. 1974), the relative consumption of the four major

groups and the weighted average percent lipids for each group

can be calculated:

                              Consumption    Weighted Average
         Group                 (Percent)      Percent Lipids

Freshwater fishes                 12                4.8

Saltwater fishes                  61                2.3

Saltwater molluscs                 9                1.2

Saltwater decapods                18                1.2

Using the percentages for consumption and lipids for each of

these groups, the weighted average percent lipids  is 2.3  for

consumed fish and shellfish.
                             C-5

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     No measured steady-state  bioconcentration  factor (BCF)



is available for chlorobenzene, but  tha equation  "Log BCF =



0.76 Log P - 0.23" can  be  used  (Vei^h, et  al. Manuscript)  to



estimate the BCF for aquatic organ.'  ms that  contain  about



eight percent lipids from  the  octanol-water  partition coef-



ficient (P).  An adjustment factor -.f  2.3/8.0 = 0.2875 can be



used to adjust  the estimated BCF  from  the  8;0 percent lipids



on which the equation  is based  to the  2.3  percent  lipids  that



is the weighted average for consumed fish  and shellfish.



Thus, the weighted average bioconcentration  factor for the



edible portion  of all  aquatic  organisms consumed  by  Americans



can be calculated.







Compound                       P       BCF     Weighted  BCF







Chlorobenzene                288        44           13







Inhalation



     No data have been found which deal with exposure to  MCB



by air outside  of the  industrial  working  environment.  The



information concerning the industrial  exposure  of  workers has



come primarily  from  eastern  European sources and  is  tabulated



in Table  3.   In addition to  that  information, Girard, et  al.



 (1969)  reported on a case  of  an elderly female  who was ex-



posed  to  a  glue/  containing  0.07  percent  MCB,  for  a  period of



six  years (See  Special Groups  at  Risk).   Chopra,  et  al.



 (1978)  predicted a  mathematical chance for MCB  to  be in smoke



 from endosulfan treated tobacco.
                              C-6

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                               TABLE 3

          Recorded Industrial Exposures to Monochlorobenzene


Plant Activity            Concentration of           Reference
                             MCB (mg/1)


Manufacture of DDT        0.020 - average      Gabor and Raucher, 1960
                          0.300 - highest

Manufacture of monuron    0.001 .- 0.01         Levina, et al. 1966

                          0.004 - 0.01         Stepangan, 1966
    Dermal

         No reports were available concerning the dermal exposure

    of MCB.

    Summary and Conclusions

         Environmental exposure to MCB must be considered to be

    primarily via  water.   Because  of the short half-life of MCB

    in water,  it would be relatively difficult to monitor likely

    human exposure unless multiple sampling were done.  Compared

    to substances  such as DDT,  the accumulation of MCB  within the

    food  chain  is  limited;  however,  even this accumulation tends

    to magnify  the possible human  exposure  to MCB via discharge

    into  water.

                          PHARMACOKINETICS

   Absorption

         There  is  little  question,  based on human effects and

   mammalian toxicity  studies,  that  MCB is absorbed  through the

   lungs  and from the  gastrointestinal  tract (c.f.  U.S. EPA,

   1977).  Based  on what  is known  about congeners,  it  is also

   probably absorbed  from  the  surface of the skin.



                                C-7

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Distribution



     Because MCB  is  highly  lipophilic and hydrophobia, it



would be expected  that  it would  be  distributed throughout



total body water  space,  with  body  lipid providing a deposi-



tion site.  The data available on  the related halobenzene,



bromobenzene,  show this  to  be the  case (Reid, et al.  1971).



Barring some abnormal kinetic pattern, it would  also  be



expected that  redistribution  from  tissue sites would  reflect



plasma decay rates.   Again, with bromobenzene this was the



case, the plasma  tl/2 being 5.8  hours and the tl/2 for fat



being 6.2 hours.



Metabolism



     Metabolism of MCB has  been  studied in a  number of labor-



atories..  Hydroxylation  occurs para  to the chloride via an



NADPH-cytochrome P-448 dependent microsomal enzyme system.



Further hydroxylation then occurs to  form the corresponding



catechol compound.   The  diphenolic derivative is  a predomi-



nant form, quantitatively,  in comparison  to the monophenolic



compounds.  Various  conjugates of these  phenolic  derivatives



are the primary excretory products  (Lu,  et al. 1974).  ,The



conjugates are formed by microsomal enzymes,  in  this  case  the



NADPH-cytochrome P-450 dependent system.   However,  it  would



appear that the rate  limiting step in  metabolism  of MCB  is



original hydroxylation of the ring.   There  are some differ-



ences in the nature  of the conjugates, depending  upon  the



species studied.  Williams, et al. (1975)  found that among



thirteen species of  non-human mammals, 21  to  65 percent of



excreted radioactivity from the administration of  14C-MCB  is
                             C-8

-------
present in the urine as p-chlorophenylmercapturic  acid.   The



output of this conjugate in man was only 16 percent  of  the



administered dose.  Williams (1959) also reported  that  about



27 percent of MCB administered to the rabbit was expired  un-



changed in the air over a one to two day period; 47  percent



of the dose was excreted as glucuronic acid or  sulfate  con-



jugate, and 25 percent as mercapturic acid conjugate.   This



accounts for the total dose and would imply that very  little



is excreted unchanged.  This would be expected.  The lipo-



philic nature of MCB would predict that it would be  almost



totally reabsorbed by the renal tubules such  that  its  decay



from the plasma would rely totally on metabolism and on



ventilatory excretion.



     The ease with which MCB is metabolized or  eliminated via



the lungs would predict that its bioaccumulation potential  is



somewhat limited.   Varshavskaya (Iroc) found  that when MCB



were administered to rats at a dose of 0.001  mg/day for nine



months, the coefficient of accumulate .  -,  7 1.25.   This would



mean that accumulation is somewhat 1: ~. i. :• "  if  the  exposure



level is kept constant.  For example, ::  a  single  dose were



taken every 24 hours and this resulted  in a total  body accu-



mulation of 1.25 x the dcse, t>a tl/2 would be  calculated to



be approximately eleven hours.  This wcu.'1'"  suggest that in



the rat, upon exposure tc c cr ^tant dose, maximum body con-



centration is reachc-d in abuu<: two days.  The  same numbers



cannot be applied to man be .at "•: of  differences in organ



clearance, but relatively s^ei .ing it would be  expected that
                             C-9

-------
equilibrium would -be  reached  in  a  short  time from an environ-



mental point of view  and  that  prolonged  exposure to constant



levels in the environment would  not  be expected to result in



continuous accumulation.



     Evidence has  been  building  which  implies that the meta-



bolism of halogenated benzene  compounds  results in the forma-



tion of toxic intermediates.   Brodie,  et al.  (1971) pre-



treated animals with  phenobarbital to  stimulate the activity



of drug metabolizing  enzymes  in  the  liver.   This treatment



potentiated liver  necrosis induced "by  halogenated aromatic



compounds (of which monobromobenzene was the primary ex-



ample) .  This is apparently related  to the  formation of metab-



olites capable of  forming complexes  with, cellular ligands.



The covalent binding  of the metabolites  of  halogenated ben-



zene derivatives with protein  has  been correlated with the



ability of these compounds to  induce hepatic necrosis (Reid,



et al. 1971, 1973; Reid and Krishna, 1973).   Oesch, et al.



(1973) -has reported that  rats  pretreated with 3-methylcholan-



threne are protected  from MCB  evoked hepatotoxicity.   This



was ascribed to the modification of  a  coupled monooxygenase



epoxidehydrase system (Oesch,  et al. 1973).   Carlson and



Tardiff  (1976) reported that  the oral  administration of 10 to



40 mg/day of MCB to rats  for  14  days induced a variety of



microsomal enzymes which  metabolize  foreign  organic compounds



including benzpyrenehydroxylase.  Cellular  toxicity,  includ-



ing carcinogenic and  mutagenic activity, may be related to



the formation of highly active metabolic intermediates such



as epoxides.  In this connection,  Kohli, et  al. (1976) have




                              C-10

-------
 suggested that the metabolism of MCB occurs through arene



 oxide intermediates as shown in Figure 1.



                            EFFECTS



 Acute,  Sub-acute and Chronic Toxicity



      The acute toxic effects of MCB were qualitatively similar



 in some cases  to chlorinated hydrocarbons such as carbon



 tetrachloride.   The oral  LDso of monochlorobenzene in the rat



 is approximately 3 g/kg.   When administered by subcutaneous



 injection,  the LD5Q increases by about 25 percent  Von



 Oettingen (1955)  found that large doses of MCB (7 to 8 g/kg



 subcutaneously)  were fatal  in a few hours as a result of CNS



 depression.  When the dose  utilized was 4 to 5 g/kg, death



 occurred  after  a  few days  and resulted from hepatic and/or



 renal necrosis.   Vecerek,  et al.  (1976) found the oral LD5Q



 of MCB  in rats  to be 3.4 g/kg.   At  this dose,  the animals



 died after about  seven days  and showed signs of a number of



 metabolic disturbances  including  elevated levels  of SGOT,



 lactate dehydrogenase,  alkaline phosphatase, blood urea ni-



 trogen and decreased  levels  of  glycogen phosphorylase and



 blood sugars.  Yang  and Peterson  (1977)  administered MCB 5



 mmol/kg intraperitoneally to  male rats  and  found  an increase



 in bile duct pancreatic fluid  flow.



     Data on the  subchronic  and chronic toxicity  of MCB are



sparse and somewhat  contradictory.   Lecca-Radu (1959)  admin-



 istered MCB by inhalation to  rats and  guinea pigs for periods
                             C-ll

-------
  SR
                             1
                                                     OH
                                   .OH
Figure 1:  Proposed routes for the biotransformation of
monochlorobenzene via arene oxides (Kohli, et al. 1976),

-------
up to one year in doses which did not affect the liver or the

kidney but did find modification of erythrocyte carbonic an-

hydrase activity and leukocyte indolephenol oxidase activity.

Knapp, et al. (1971) administered MCB orally by capsule to

dogs in doses of 27.25, 54.5 and 272.5 mg/kg/day five days.a

week over a 90-day period.  Four out of eight of the animals

in the high dose group died after 14 to 21 daily doses.

Clinical studies prior to death revealed an increase in im-

mature leukocytes, low blood sugar, elevated SGPT and alka-

line phosphatase and in some dogs increases in  total biliru-

bin and total cholesterol.  "Gross and/or microscopic patho-

logical changes" were seen in the liver, kidneys, gastroin-

testinal mucosa and hematopoietic tissue of the dogs which
          r
died and, less extensively, in the dogs which, were  sacrificed

after 65 or 66 daily doses.  No consistent signs of MCB tox-

icity were seen in dogs in the intermediate and low levels.

MCB was given by diet for a period of 93 to 99  days to  rats

at doses of 12.5, 50 and 250 mg/kg/day.  Growth was retarded

in male rats in the high dose group.  There was an  increase

in liver and kidney weight for rats in the high and intermed-

iate levels.  This was not accompanied by any "histopatho-

logical" findings (Knapp, et al. 1971).

     The toxicity of MCB following exposure by  inhalation  and

by oral administration has been studied at the  Dow  Chemical

Company (Irish, 1963).  Rats, rabbits and guinea pigs were

exposed seven hours a day, five days a week, for a  total of

32 exposures over a period of 44 days at concentrations of

200, 475, and 1,000 ppm.  The response of the animals  in  the
                             C-13

-------
high dose group was  characterized  by  "histopathological



changes" in the lungs,  liver  and kidneys.   In  the  middle dose



group, there was  an  increase  in  liver weight  and a slight



liver "histopathology".   In  the  low dose group,  no apparent



effects were observed.   In none  of 'he groups  was  a hemato-



logical change seen.   MCB was administered  orally  to rats



five days a week  for a total  of  137 doses'  over 192 days, in



dose groups of 14.4,  144  and  228 mg/kg.  In the  middle and



high dose groups  there were  significant  increases  in liver



and kidney weight and some "histopathological  changes" in the



liver.  Blood and bone marrow were normal  in  all animals



(Irish, 1963).



     Rimington and Ziegler  (1963), citing  the  widespread out-



break of human cutaneous  porphyria in Turkey  in  1959 appar-



ently caused by wheat treated with hexachlorobenzene fungi-



cide, examined a  series of chlorinated benzene compounds in



rats with regard  to experimental porphyria.  MCB at an oral



dose of 1140 mg/kg for five  days increased  the excretion of



urinary coproporphyrin, porphorobilinogen  and  delta-aminole-



vulinic acid.  Some hair loss was  also observed  due to fol-



licular hyperkeratosis.



     A  study by Varshavskaya (1968) describes  the  CNS, liver



and  hematopoietic system changes in seven  male rats per group



which received oral doses of 0.1 mg/kg to  0.001  mg/kg MCB for



a  period of  nine  months.   This report indicates  that doses of



0.001 mg/kg  MCB  for seven months affected  the  CNS  of rats,



and  that  similar  effects resulted  from similar o-dichloroben-



zene dosages.   However, these results are  somewhat unexpected






                              C-14

-------
 in  light of other  studies  in  the  literature.   For  example,



 Hollingsworth, et  al.  (1956)  reported  results  from an  experi-



 ment with o-dichlorobenzene which differed  by  over three



 orders of magnitude  from those of the  Varshavskaya (1968)



 study.  This discrepancy in o-dichlorobenzene  results  leaves



 the MCB results of the Varshavskaya study open to  question.



 Synergism and/or Antagonism



     In general, the halogenated benzenes appear to increase



 the activity of microsomal NADPH-cytochrome P-450  dependent



 enzyme systems.  Induction of microsomal enzyme activity  has



 been shown to enhance the metabolism of a wide variety of



 drugs, pes.ticides  and other xenobiotics.  Exposure to  mono-



 chlorobenzene could  therefore result in decreased  pharmaco-



 logic and/or toxicologic activity of numerous  compounds.



 Frequently, chemical agents are metabolized to more active or



 toxic "reactive" intermediates.  In this event, exposure  to



monochlorobenzene would result in enhanced activity and/or



 toxicity of these agents.



Teratogenicity, Mutagenicity and Carcinogenicity



     There  have been no studies conducted to evaluate  the



 teratogenic,  mutagenic or carcinogenic potential of MCB.
                             C-15

-------
                     CRITERION FORMULATION

Existing  Guidelines and Standards

     The  Threshold Limit Value (TLV)  for MCB as adopted by

the American  Conference of Governmental Industrial Hygienists

(1971)  is 75  ppro  (350  mg/m^).   The  American Industrial Hygiene

Association Guide  (1964)  considered 75  ppm to be too high.

The recommended maximal allowable concentrations in air in

other countries are:   Soviet  Union/ 10  ppm;  Czechoslovakia,,

43 ppm; Romania, 0.05  mg/1.   The  latter value for Romania was

reported  by Gabor  and  Raucher  (1960)  and  is  equivalent to 10

ppm.

Current Levels of  Exposure

     MCB  has  been  detected in  water monitoring surveys of

various U.S.  cities (U.S.  EPA,  1975;  1977)  as was presented

in Table  1.   Levels reported  were:  ground  water - 1.0 ug/1;

raw water  contaminated  by  various discharges  - 0.1 to  5.6

ug/1; upland  water - 4.7 ug/1;  industrial  discharge -  8.0 to

17.0 ug/1; and municipal water  -  27 ug/1.   These data  show a

gross estimate of  possible human  exposure  to  MCB through  the

water route.

     Evidence of possible  exposure  from food  ingestion is  in-

direct.  MCB  is stable  in  water and thus could  be  bioaccumu-

lated by edible fish species.

     The only data  concerning exposure to MCB  via  air  are

from the  industrial working environment.  Reported  industrial

exposures  to MCB are 0.02  mg/1  (average value)  and  0.3 mg/1

(highest value) (Gabor  and Raucher,  1960); 0.001  to  0.01  mg/1

(Levina, et al. 1966);  and 0.004 to 0.01 mg/1  (Stepangen,

1966).
                             C-16

-------
Special Groups at Risk



     The major group at risk of MCB intoxication are  individ-



uals exposed to MCB in the workplace.  Table 3 shows  recorded



industrial exposures to MCB.  Girard, et al. (1969) reported



the case of an elderly female exposed to a glue containing



0.07 percent MCB for a period of six years.  She had  symptoms



of headache, irritation of the eyes and the upper  respiratory



tract, and was diagnosed to have medullary aplasia.   Smirnova



and Granik (1970) reported on three adults who developed



numbness, loss of consciousness, hyperemia of  the  conjunctiva



and the pharynx following exposure to "high" levels of  MCB.



Information concerning the ultimate course of  these  indivi-



duals is not available.  Gabor, et al.  (1962)  reported  on  in-



dividuals who were exposed to benzene, chlorobenzene  and



vinyl chloride.  Eighty-two workers examined for certain  bio-



chemical indices showed a decreased catalase activity in  the



blood and an increase in peroxidase, indophenol oxidase and



glutathione noted levels.  Dunaeveskii  (1972)  reported  on  the



occupational exposure of workers exposed to the chemicals  in-



volved in the manufacture of chlorobenzene at  limits  below



the allowable levels.  After over 3 years cardiovascular  ef-



fects were noted as pain in the area of the heart, bradycar-



dia, irregular variations in electrocardiogram, decreased



contractile function of myocardium and disorders  in  adapta-



tion to physical loading.  ?ij -itova, et al.  (1973) reported



on the prolonged exposure of individuals  involved  in  the  pro-



duction of diisocyanates to the factory air which  contained



MCB as well as other chemicals.  Diseases noted  include bron-
                             C-17

-------
chitis, sinus arrhythmia,  tachycardia,  arterial  dystrophy and
anemic tendencies.  Petrova and Vishnevskii  (1972)  studied
the course of pregnancy  and deliveries  in  women  exposed  to
air in a varnish manufacturing factory  where  the air  contain-
ed three times the maximum permissible  level  of  MCB but  also
included toluene, ethyl  chloride, butanol, ethyl bromide and
orthosilisic acid ester.   The only  reported  significant  ad-
verse effect of this mixed exposure was toxemia  of  pregnancy.
Basis and Derivation of  Criterion
     There is no information  in the literature which  indi-
cates that monochlorobenzene  is, or is  not,  carcinogenic.
There is enough evidence to suggest that MCB  does cause  dose
related target organ toxicity, though  the  data still  want
for an acceptable chronic  toxicity  study.  There is little,
if any, usable human exposure data  primarily  because  the
exposure was not only  to MCB  but to other  compounds of known
toxicity.
     The no-observable-adverse effect  level  (NOAEL) for  deri-
vation of the water quality criterion  is derived from the
information  in the studies by Knapp, et al.  (1971)  and Irish
(1963).  These are 27.25 mg/kg/day  for  the dog  (the next
highest dose was 54.5  mg/kg and showed  an  effect);  12.5
mg/kg/rat from the Knapp study  (the next highest dose was 50
mg/kg  arid showed an effect);  and 14.5  mg/kg/rat  from  the
Irish  study  (the next  highest dose  was  144 mg/kg and  showed
an effect).  When  toxic effects were observed at higher
doses,  the dog was  judged .to  be somewhat more sensitive  than

-------
 rats.   The Irish study ran over a period of six months which

 was twice as long as the Knapp study of both species.  Since

 the Knapp and Irish studies appear to give similar results

 and since there are no chronic toxicities to rely on, it was

 decided to take the NOAEL level from the longest term study,

 that is,  14.4 mg/kg for six months.

      Considering that there are relatively little human expo-

 sure data,  that there is no long-term animal data, and that

 some theoretical questions, at least, can be raised on the

 possible  effects of chlorobenzene on blood-forming tissue, it

 was decided to use  an uncertainty factor of 1,000.  From this

 the acceptable daily intake (ADI) can be calculated as

 follows:
           ADI  =  7° k?  f  ^A4        = 1.008 mg/day
     The average daily  consumption of water was taken to be

two liters and  the consumption  of  fish to be 0.0187 kg daily.

A bioconcentration factor  of  13 was utilized.   This is the

value reported  by the Duluth  EPA Laboratories  (see Ingestion

from Foods section) .  The  following calculation results in an

acceptable criterion based on the  available toxicologic data:

                   _ 1.008 _   ...   ..
                   2 +  (13 x  0.0187)  = 45° ^g/1

     Varshavskya (1968) has reported  the  threshold concentra-

tion for odor and tas.te of MCB  in  reservoir water as being 20

u.g/1 which is the only report available.   This  value is about

4.5 percent of  the possible standard  calculated above.  It
                              C-19

-------
is, however, approximately 17  times greater  than  the  highest
concentration of MCB measured  in survey  sites  (see  Table  1).
Since water of disagreeable  taste and odor is  of  significant
influence on the quality of  life, and thus,  related to
health, it would appear that the organoleptic  level of 20
ug/1 should be the recommended criterion.
                              -20

-------
                         REFERENCES







American Conference of Governmental Industrial Hygienists.



1971.  Documentation of the threshold limit values for



substances in workroom air.  3rd Ed.







American Industrial Hygiene Association. 1964.  Chloroben-*



zene.  Am. Ind. Hyg. Assoc. Jour. 25: 97.







Brodie, B.B., et al. 1971.  Possible mechanism of  liver



necrosis caused by aromatic organic compounds.  Proc. Natl.



Acad. Sci. 68: 160.







Carlson, G.P., and R.G. Tardiff. 1976.  Effect of  chlorinated



benzenes on the metabolism of foreign organic compounds.



Toxicol. Appl. Pharmacol. 36: 383.







Chopra, N.M., et al. 1978.  Systematic studies on  the break-



down of endosulfan in tobacco smokes:  Isolation and  identi-



fication of the degradation products from the pyrolysis of



endosulfan in a nitrogen atmosphere.  Jour. Agric. Food Chem.



26: 255.







Cordle, F., et al. 1978.  Human exposure to polychlorinated



biphenyls and polybrominated biphenyls.  Environ.  Health



Perspect. 24: 157.
                             C-21

-------
Djinaeveskii, G.A. 1972.   Functional condition  of  circulatory



organs in workers employed  in the production of organic



compounds.  Gig« Tr. Prof.  Zabol. 1«;  ^8.








Erisman, H., and M. Goldman. 1975.  Identification of  organic



compounds in textile plant  effluents.   Presented  at  the  First



Chemical Congress of the  North American Continent, Mexico



City/ Mexico, November  30 - December  5, as  cited  in  EPA



(1977).








Filatova, V.S., et  al.  1973.  Industrial  hygiene  and pathol-



ogy  in production and use of diisocyanates.  Profil.



Trarmatizma Prof. Zabol., Lech.  Traum,  219.








Gabor, S., and  K. Raucher.  1960.  Studies on the  determina-



tion of  the maximum permissible  concentrations of benzene  and



monochlorobenzene.  Jour. Hyg. Epidemiol.  Microbiol. Immunol.



4:  223.







Gabor,  S., et  al. 1962.  Certain biochemical indexes of  the



blood in workers  exposed  to toxic substances  (benzene,



chlorobenzene,  vinyl  chloride).   Prom.  Toxikol.   i Klin.



Prof. Zabol. Khim.  Etiol. SB  221.








Girard,  R.,  et  al.  1969.  Serious blood disorders and  expo-



sure to chlorine  derivatives  of  benzene.   (A report  of 7



cases).   Jour.  Med. Lyon  50:  771.
                              C-22

-------
 Hollingsworth,  R.L.,  et al.  1956.   Toxicity of paradichloro-



 benzene:   Determination on  experimental animals and human



 subjects.  AMA Arc.  Ind. Health.  14:  138.







 Irish,  D.D.  1963.   Halogenated  hydrocarbons:   II.  Cyclic. In



 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.   Toxicol.  Appl.



 Pharmacol.  19:  393.







 Kohli,  I.,  et al. 1976.  The metabolism of  higher  chlorinated



 benzene isomers.  Can. Jour. Biochem.  54:  203.







 Lecca-Radu, M.  1959.  Modifications of  blood  carbonic an-



 hydrase and  indophenol  oxidase  in chronic benzene  and mono-



 chlorobenzene intoxication.  Igiena 8:  231.







 Levina, M.M., et al.  1966.  Issues concerning  sanitary work-



 ing conditions  and  the  state of  health  of those workers in



 the field of monuron production.  Gig.  Tr.  Prog. Zabol. 11:



 54.







Lu, A.Y.H., et  al. 1974.  Liver  microsomal  electron transport



systems.  III.  Involvement of cytochrome b5  in the NADH-



supported cytochrome P^-450 dependent hydroxylation of



chlorobenzene.  Biochem. Biphys. Res. Comm. 61:  1348.






                             C-23

-------
Lu, P.Y. ,  and  R.L.  Metcalf.  1975.   Environmental fate and



biodegradability of  benzene  derivatives  as  studied in a model



aquatic  ecosystem.   Environ.  Health  Perspect.  10:  269.








Mackay,.  D., and P.J.  Leinonen.  1975.   Rate  of  evaporation of



low-solubility contaminants  from water bodies  to atmosphere.



Environ. Sci.  Technol.  9:  1178.








Neely, W.B., et al.  1974.  Partition  coefficient to  measure



bioconcentration potential of organic  chemicals  in fish.



Environ. Sci.  Technol.  8:  1113.








Oesch, F.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.








Petrova, N.L., and A.A. Vishnevskii. 1972.  Course of preg-



nancy and deliveries  in women working  in the organosilicon



varnish  and enamel industries.  Nauch Jr. Inrutsk. Med. Inst.



115: 102.








Reid, W.D., and G. Krishna. 1973.  Centrolobular hepatic



necrosis related to covalent binding of aromatic hydrocar-



bons.  Exp. Molec. Pathol.  18: 80.
                             C-24

-------
Reid, W.D., et al. 1971. Bromobenzene metabolism and hepatic



necrosis. Pharmacology 6: 41.








Reid, W.D., et al. 1973.  Metabolism and binding of aromatic



hydrocarbons in the lung; relationship to experimental bron-



chiolar necrosis.  Am. Rev. Resp. Dis. 107: 539.








Rimington, C., and G. Ziegler. 1963.  Experimental porphyria



in rats induced by chlorinated benzenes.  Biochem. Pharmacol.



12: 1387.








Sidwell, V.D., et al. 1974.  Composition of the edible por-



tion of raw (fresh or frozen) crustaceans, finfish, and mol-



lusks.  I.  Protein, fat, moisture, ash, carbohydrate, energy



value, and cholestrol.  Mar. Fish. Rev. 36: 21.








Smirnova, N.A., and N.P. Granik. 1970.  Remote  consequences



of acute occupational poisoning by some hydrocarbons  and



their derivatives.  Gig. Truda. Prof. Zabol. 5: 50.








Stepanyan, L.K., 1966.  Combin3d effect of chlorobenzene



ethyl cellosolve and high temperature on workers.  Mater.



Itogovoi. Nauch. Konf. Vop. Gi3. Tr. Prof. Khim. Gornorud.



Prom., 3rd. 47.








U.S. EPA. 1977. " Investigation of selected potential  environ-



mental contaminants:  Halogenated benzenes.  EPA 560/2-77-004,
                             C-25

-------
U.S. International Trade Commission. 1966. Synthetic organic



chemicals: U.S. production and sales. U.S. Government  Print-



ing Office, Washington, D.C.







U.S. International Trade Commission. 1975. Synthetic organic



chemicals: U.S. production and sales. U.S. Government  Print-



ing Office, Washington, D.C.







Varshavskaya, S.P. 1968.  Comparative toxicological charac-



teristics of chlorobenzene and dichlorobenzene  (ortho-and-



para-isomers) in  relation to  the  sanitary protection of water



bodies.  (Russian  translation.)    Hyg. San. 33:  10.







Vecerek,  B., et al.  1976.  Xenobiochemical characteristics of



chlorobenzene.  Bratisl. Lek. Listy  65:  9.







Veith,.G.D., et al.  An  evaluation of using partition coeffi-



cients and water  solubility to estimate  bioconcentration  fac-



tors for  organic  chemicals in fish.  (Manuscript.)







Von Oettingen, W.F.  1955.  The halogenated aromatic hydrocar-



bons.  In  The halogenated aliphatic, olefinic,  cyclic, aro-



matic  and aliphatic  aromatic  hydrocarbons, including the



halogenated  insecticides,  their  toxicity and  potential dan-



gers.  U.S.  Dep.  Health Edu.  Welfare. No. 414:  283. Cited ini



U.S.  EPA. 1977.

-------
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 metab-

olism of some organic halogen compounds. Page. 91 in A.D.

Mclntyre and C.F. Mills, eds. Ecological and toxicological

research. Plenum Press, New York.


          «
Yang, K.H.,  and R.E. Peterson. 1977.  Differential  effects of

halogenated  aromatic hydrocarbons on pancreatic excretory

function in  rats.  Fed. Proc. 36: 356. l/
                             C-27

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                       TRICHLOROBENZ ENES


Mammalian. Toxicology and Human Health Effects
        -  •• • /'.'- v
           -'.-•••           EXPOSURE


Introduction


     There are  three isomers of trichlorobenzene (TCB):  1,

                                                         t
2,3-trichlorobenzene,  1,2,4-trichlorobenzene and 1,3,,5-tri-


chlorobenzene.   Of  the three,  1,2,4-TCB is the most economi-


cally important (U.S.  EPA,  1977).   It is  used as a dye car-


rier in the application of  dyes to  polyester materials, as  an

intermediate  in the  synthesis  of  herbicides,  as a flame re-


tardant and for other  functional  uses.  The  U.S.  production


of 1,2,4-trichlorobenzene in 1973 was over 28 million  pounds


(Synthetic Organic Chemicals.   U.S.  Production and Sales.


U.S. International Trade Commission,  1975).   A mixture of the


three isomers is  used  as a  solvent,  a lubricant and as a

dielectric fluid.  The 1,2,3  and 1,3,5-TCB isomers  as  indi-


vidual compounds  are primarily used  as  intermediates in chem-


ical synthesis.   TCB's are  most probably  intermediates in the

mammalian metabolism of lindane  (Kujawa,  et  al.  1977).
                               28

-------
Ingestion from Water



     Table 1 shows data from monitoring the various water



sites.  These data suggest the possibility of TCB contamina-



tion of the drinking water.  In a report  (U.S. EPA, 1975)  in



which the sample site was not identified, the highest  re-



ported concentration of trichlorobenzene  in drinking water



was 1.0 ug/1.



Ingestion from Foods



     Whereas the bioaccumulation of  some  of the  other  members



of the chlorinated benzene series has been studied with  re-



gard to model aquatic ecological systems, such has not appar-



ently been the case with the TCB's.  The  accumulation  of



TCB's in the food chain depends upon their concentration in



aquatic organisms.  Haas, et -al. (1974) has found  that 40



percent of the remaining 1,2,4-TCB in wastewater was absorbed



by microorganisms and the suggestion has  been made by  EPA



that the material concentrates in the cell wall.   This type



of information indicates that TCB's will  persist in a  water



environment and are available for incorporation  into  fish.



TCB has been detected in trout taken from Lake Superior  and



turbot taken from Lake Huron (U.S. EPA, 1977).



     Bioconcentration factors are not available  for the



edible portions of all four major groups  of aquatic organisms



consumed in the United States.  Since data indicate that the



BCF for lipid-soluble compounds is proportional  to percent



lipids, BCF's can be adjusted to edible portions using data



on percent lipids and the amounts of various  species  consumed
                             C-29

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                                     occurrence or TLts-s in water
                                      (Source:  U.S.  EPA, 1977)
      Compound
         Location
                  Source
Concentration'
   (ug/D
o
i
CO
o
      1,2,3-TCB
      1,2,4-TCB
      1,3,5-TCB
  Catawba Creek, NC
  Catawba Creek, NC
  Chattanooga Creek, TN
  Joint Water Pollution
  Control Plant (JWPCP)
  Hyperion Sewage Treatment
  Works, LA (HSTW)
  HSTW

  Orange County Sewage
  Department (OCSD)
  Port Loma Sewage Treat-
  ment Plant (PLSTP)
  Oxnard, CA Sewage
  Treatment Plant (OSTP)
  Los Angeles River
  Holston River, TN
  JWPCP
  HSTW

  HSTW

  OCSD
  PLSTP
  OSTP
  Los Angeles River
            Municipal discharge
            Industrial discharge
            Industrial discharge
            Municipal waste water

            5 mile effluent, municipal
            waste water
            7 mile effluent, municipal
            waste water
            Municipal waste water

            Municipal waste water

            Municipal waste water

            Surface run off
            Industrial discharge
            Municipal waste water
            5 mile effluent, municipal
            waste water
            7 mile effluent, municipal
            waste water
            Municipal waste water
            Municipal waste water
            Municipal waste water
            Surface run off
  21-46a
  12a
  500b
  6.0; 1.8a

  6.7; 3.1C

  275; 130C

  0.30a

  0.23; <0.01C

  0.9; 0.25C

  0.007d
  26
  0.2; 0.8C
  <0.0-1;  <0.01C

  0.9; <0.2C

  0.2
  0.02; <0.01C
  0.4; <0.01C
  0.006d
      aSummer
      bSpring
GSummer; Fall
dWinter
epall

-------
 by Americans.   A recent survey on fish and shellfish consump-

 tion in the United States (Cordle,  et al. 1978) found that

 the per capita consumption is 18.7  g/day.  From the data on

 the nineteen major species identified in the survey and data

 on the fat content of the edible portion of these species

 (Sidwell,  et al.  1974), the relative consumption of the four

 major groups and  the weighted average percent lipids for each

 group can  be calculated:

                              Consumption    Weighted Average
         Group                (Percent)       Percent Lipids

 Freshwater fishes                 12                4.8

 Saltwater  fishes                  61                2.3

 Saltwater  molluscs               9                1.2

 Saltwater  decapods               18                1.2

 Using  the  percentages  for consumption and lipids for each of

 these  groups,  the  weighted average  percent lipids is 2.3 for

 consumed fish  and  shellfish.

     No measured steady-state  bioconcentration  factor (BCF)

 is available for 1,2,4-trichlorobenzene  but the equation "Log

 BCF =  0.76 Log P -  0.23"  can  be  used  (Veith,  et al.   Manu-

 script) to estimate  the BCF for  aquatic,  organisms  that con-

 tain about eight percent  lipids  from  the octanol-water parti-

 tion coefficient (P).   An  adjustment  factor of  2.3/8.0 =

 0.2875 can be used  to adjust  the  estimated  BCF  from  the 8.0

percent lipids on which the equation  is  based to the 2.3 per-

cent lipids that is the weighted  average for  consumed fish

and shellfish.  Thus, the weighted average  bioconcentration

factor for the edible portion of  all  aquatic  organisms con-

sumed by Americans can be calculated.


                             C-31

-------
 Compound
                 BCF
         Weighted BCF
 1/2,4-trichlorobenzene
     18,000
1,000
290
      There  is  some  information  on  studies  of  biochemical  oxy-

gen demand  (BOD)  in  waste  water  containing  microorganisms  from

treatment plants.  This  information has  been compiled  previously

(U.S. EPA, 1977)  and is  reproduced  in Table 2.   This  table sum-

marizes the  20-day BOD for 1,2,4-TCB.  As can  be  seen,  the re-

sults vary from no biodegradation to complete  biodegradation of

the 1,2,4-TCB.
                             TABLE  2
            Effects of  1,2,4-Trichlorobenzene on BOD
                       (From U.S. EPA, 1977)
Source of Organisms
BOD20 (percent of
theoretical value)
       References
Microorganisms from             78
industrial waste treat-
ment plant

Microorganisms from            100
industrial waste treat-
ment plant

Mixture of microorganisms       50
from 4 different textile
treatment plants

Microorganisms from "typi-       0
cal" treatment plant         (2 days)
                       Hintz,  1962
                       Alexander,  1972
                       Porter  and  Snider,
                       1974
                       Haas,  et  al.  1974
                              C-32

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     Simmons, et al.  (1976) also noted a lack of degradation



of 1,2,4-TCB based on BOD determinations.  However, direct



chemical analysis indicated a 14 percent reduction in the



compound in industrial wastewater after 24 hours, a 36 per-



cent reduction in 72 hours and 43 percent reduction at 7



days.-  This would indicate that the limitation in change of



BOD is due primarily to incompletely oxidized metabolites.



Inhalation and Dermal



     Vapor pressures for TCB's are:  1,2,3-TCB, 0.07 mm Hg



(25°C), 1.0 mm Hg (40°C); 1,2,4-TCB, 0.29 mm Hg  (25°C); 1.0



mm Hg  (38.4°C); 1,3,5-TCB, 0.15 mm Hg  (25°C), 10 mm Hg  (78°C)



(U.S. EPA, 1977; Sax, 1975).  This is  relatively low compared



to mono- and dichlorobenzenes.  Nevertheless, TCB's have been



detected in particulates from aerial fallout.  In a study of



aerial fallout in southern California  (spring, 1976), five



sampling sites showed median levels of "less than 11 ng/m2/



day" for 1,2,4-TCB and "less than 6 ng/m2/day" for 1,3,5-TCB



(U.S. EPA, 1977).



     There have been no direct reports of exposure of humans



to TCB via inhalation resulting in toxicity.  A  recent  study



by Coate, et al. (1977) has demonstrated that inhalation ex-



posure of rats, rabbits and monkeys will result  in a toxic



effect (vide infra).  The amount of TCB  necessary  to induce  a



toxic reaction via application to the  skin  is quite high and



thus exposure to TCB via water on the  skin  is not  considered



to be a significant factor in tne determination  of criteria



standards (Brown, et al. 1969).
                             C-33

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                      PHARMACOKINETICS



Absorption



     All three  isomers  of  TCB  are  absorbed  from the  gastroin-



testinal tract,  intact  skin  and  lungs.   However,  the absorp-



tion is somewhat  less than that  seen  for the  monochlorinated



and dichlorinated  benzenes (U.S. EPA, 1977)



Metabolism



     The primary  route  of  metabolism  of  TCB's is  through the



formation of monophenols with  very little,  if any, formation



of mercapturic  acid  or  catechols (Williams, 1959;  Parke  and



Williams, 1960;  Kohli,  et  al.  1976).  Kphli,  et al.  (1976)



reported that the  major metabolite in the rabbit  for 1,2,3-



TCB was 2,3,4-trichlorophenol  (2,3,4-TCP)  (11 percent of the



dose) with minor  metabolites being 2,3,6-TCP  (1 percent) and



3,4,5-TCP  (2 percent).   For  1,2,4-TCP,  the  monophenols were



in the  form of  2,4,5-TCP and 2,3,5-TCP  both present  in ap-



proximately the  same percentage  of the  original dose (five



and six percent,  respectively).   In the  case  of 1,3,5-TCB,



the two metabolites  were 2,3,4-TCP and  2,4,6-TCP (1.5 and 3.0



percents,  respectively).   These  authors  proposed  a pathway



for metabolism  which goes  through  arene  oxide steps  as shown



in Figure  1.  Parke  and Williams (1960)  have  also described



small quantitites of monochlorobenzene  and  parachlorophenol



in the  urine  of rabbits following  the administration of



1,3,5-TCB.   It  can be  assumed  that the  TCB  is transformed by



the NADPH-cytochrome P-450 microsomal enzyme  system.  The



overwhelming  evidence  points towards  this direction, but in



actuality  the experiments  designed to demonstrate this point





                              C-34

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                                Cl
                                      Cl
                                       Cl
Cl
                                                                                    Cl
                                                                                          Cl
                                                               Cl
o
I
to
                 Figure 1:   Proposed pathways for the biotransformation of trichlorobenzene

                       isomers through arene oxide intermediates (Kohli, et al.  1976)

-------
specifically  have  not been done.   Egyankor and Franklin, et



al.  (1977)  incubated TCB isomers  with rat hepatic microsomal



cytochrome  P-450.   He found that  the  order of affinity of the



isomers for cytochrome P-450 was  1,2,3-TCB greater than 1,2,



4-TCB greater  than 1,3,5-TCB.   Interestingly, this is the



same order  which has been  found for the  metabolism of TCB



isomers to  phenol.   They also noted that 1,3,5-TCB inhibits



hepatic microsomal  mixed function  oxidase system while the



1,2,3-TCB and  the  1,2,4-TCB enhanced  it.   Ariyoshi,  et al.



(1975a,b,c) reported on  the microsomal enzyme systems in in-



tact rats.  They found that 1,3,5-TCB increased  the  amount  of



microsomal  protein,  phospholipids  and cytochrome P-450 as



well as stimulating the  activities of aminopyrine demethy-



lase, aniline  hydroxylase,  and delta  aminolevulinic  acid syn-



thesis (Ariyoshi,  et al. 1975a).   Similar results were ob-



tained for  1,2,4-trichlorobenzene.  Increases  were observed



in cytochrome  P-450  content of the liver,  enhanced delta ami-



nolevulinic acid synthetase  activity,  aminopyrine demethylase



activity, microsomal  protein, microsomal  phosphate,  liver



weight and  aniline  hydroxylase (Ariyoshi,  et  al.  1975).



     Carlson and Tardiff (1976) reported  that  1,2,4-TCB



caused a decrease  in  hexobarbital sleeping time  and  an  in-



crease in the  activities of  cytochrome-c  reductase,  cyto-



chrome P-450 glucuronyl  transferase,  benzpyrene  hydroxylase



and azoreductase.   Carlson  (1978)  investigating  the  effect of



1,2,4-TCB on metabolism  systems in the liver,  concluded  that



the compound induces  xenobiotic metabolism of  the phenobar-



bital type  rather than the  3-methylcholanthrene  type.

-------
     There is a paucity of kinetic data concerning TCB's.
However, based on data from Williams (1959) and Parke and
Williams (1960) some estimates can be made as to the biologi-
cal half-life of the isqmers.  From these data, it was esti-
mated that the approximate half-lives of the isomers are:
1,2,3-TCB, 2 days; 1,2,4-TCB, 5.5 days; 1,3,5-TCB, 8.5 days.
This is a consideration in the evaluation of toxicity studies
for all species, especially those which are considered sub-
chronic.
Excretion
     Williams  (1959) reported that five days after oral
administration of the compound to the rabbit, 78 percent of
the administered 1,2,3-TCB was excreted as monophenols;  five
days after the administration of 1,2,4-TCB, 42  percent was
excreted as monophenols; five days after administration, 9
percent of administered 1,3,5-TCB was excreted  as mono-
phenols.  There was no evidence for the existence of  signifi-
cant alternative metabolic pathways implying that the elimi-
nation of 1,3,5-TCB is significantly slower than  the  other
two isomers.  This is related to the ease of oxidation of  the
various isomers and reflected in the monophenol metabolites
excreted.
                           EFFECTS
Acute, Sub-acute, and Chronic Toxicity
     There is  a limited amount of relevant data on  the  toxi-
                    0
city of 1,2,4-TCB and essentially no data  on  the  toxicity  of
the other two  isomers.  Cameron, et al.  (1937)  first  de-
scribed hepatotoxic effects of trichlorobenzene,  finding it
                              C-37

-------
to be less than that of monochlorobenzene or  orthodichloro-
benzene.  Brown, et al.  (1969) reported  the single  dose  acute
oral LDso in rats to be 756 mg/kg  (556 to 939 mgAg*  95  per-
cent confidence limits).   In mice,  the single dose  acute oral
LDs0 was 766 mg/kg  (601 to 979 mg/kg, 95 percent  confidence
limits).  With the  rats, deaths occurred within five  days of
exposure and in mice within three  days of exposure.   For both
species, intoxication was  manifested  as  depression  of activ-
ity at  low doses and predeath extensor convulsions  at lethal
doses.  They also determined a single dose  acute  percutaneous
toxicity in rats.   This was 6139 mg/kg  (4299  to 9056  mg/kg,
95 percent confidence limits).  From  the same study,  data on
skin irritation were reported.  The authors concluded that
1,2,4-TCB was  not very  irritating,  although fissuring typical
of a decreasing action  was observed after prolonged contact
in rabbits and guinea pigs.  Spongiosis, acanthosis and  para-
keratosis were noted  in  both species  along  with some  inflam-
mation  of the  superficial  dermis  in rabbits exposed daily for
three weeks.   Some  guinea  pigs exposed to 0.5 ml/day  for five
days/week for  three weeks  died  following extensor convul-
sions.  The livers  of  these animals were found to have necro-
tic  lesions.
     Coate, et al.  (1977)  reported on a  chronic  inhalation
exposure of rats  (30  animals per  group), rabbits  (16  animals
per  group)  and monkeys  (9  animals  per group)  to 0.25, 50 and
100  ppm of  1,2,4-TCB  for periods  up to  26 weeks.   No  exposure
                              C-38

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 related  ophthalmologic  changes  were detected in. rabbits and



 monkeys  after  26  weeks  of  exposure  (rats  were not examined),



 and  similarly,  no exposure-related  changes were detected in



 BUN,  total  bilirubin, SCOT,  SGPT, alkaline phosphatase and



 LDH  when determined  at  4,  13 and  26 weeks of exposure.  Hema-



 tological values  were also normal when  examined at 4,  13 and



 26 weeks.   Pulmonary function tests were  carried out on the



 monkeys.  No treatment  associated changes were noted in



 static compliance, carbon  monoxide  diffusion capacity, dis-



 tribution of ventilation,  transpulmonary  pressure or a bat-



 tery  of  lung volume  determinations.   Histological changes



 were  noted  in  the  livers and kidneys of rats necropsied after



 4 and 13 weeks  of  exposure.   These  changes were noted  in



 animals  from all  treatment  groups and were manifested  as an



 increase  in size  and vacuolation of hepatocytes.   However,



 after 26 weeks, no compound  related  histopathological  changes



 were  noted  in  rabbits or monkeys.



      Rowe (written communication, April,  1975)  reported that



persons exposed to 1,2,4-TCB vapor  at 3 to 5 ppm experienced



minor eye and  respiratory  irritation.   The odor was  described



as easily noticeable at these concentrations.   There was a



detectable odor at concentrations up  to 2.4 ppm,  but no eye



 irritation was evident.   No  odor was  noted at  concentrations



up to 0.88 ppm.



     Smith,  et al. (1978) conducted  a 90  day,  daily  oral dose



study of 1,2,4-TCB in rhesus monkeys  (four animals per group)



for concentrations of 1, 5,  25, 90,  125 and 174 mg/kg.   Their



report,  which is an abstract, states  that  single  oral  daily





                             C-39

-------
doses of  25  mg/kg  or less were nontoxic whereas doses of 90



mg/kg or  higher  were toxic and doses  of 173.6 mg/kg were



lethal within  20 to 30  days.   There were no deaths observed



in the 1,  5  and  25 mg/kg group and one  death occurred in each



of the 90  mg/kg  and 125 mg/kg  groups  and two deaths occurred



in the 174 mg/kg group.   Animals  on the highest dose exhi-



bited severe weight loss and predeath fine  tremors.  All of



the animals  in the highest dose group had elevated BUN,  Na,



K, CPK, SCOT,  SGPT/  LDH and alkaline  phosphatase as well as



hypercalcemia  and  hyperphosphatemia from 30 days on.   Smith,



et al. (1978)  have been using  the urinary pattern of chlor-



guanide metabolites  as  an  indication  of cytochrome P-450 de-



pendent drug metabolism.   The  abstract  states  that at the



high doses monkeys  showed  evidence of the hepatic induction



as well as an  increased  clearance of  intravenous doses of



labeled TCB.   Further information on  the study (Smith, per-



sonal communication) gave  evidence of liver enzyme induction



in the 90, 125 and  174  mg/kg animals.    There were  some patho-



logical changes  noted in  the livers of  the  high  dose  groups,



primarily a fatty  infiltration.  The point  at  which  there was



absolutely no effect related to the compound was  at  the  5



mg/kg level.  Since  further detailed  information  on  the



results of this  study are  lacking no estimation  of  a NOAEL



can be made.



     Rimington and  Ziegler  (1963)  were  able  to  induce an  ex-



perimental porphyria in rats with 1,2,4-TCB which was marked



by an increased  urinary coproporphyrin  excretion  and an  in-



creased porphorobilinogen excretion in  urine.  This porphyria
                             C-40

-------
could be reversed by glutathione.  They also noted a hair
loss due to hyperkeratosis.
Synergism and/or Antagonism
     In general/ the halogenated benzenes appear to increase
the activity of microsomal NADPH-cytochrome P-450 dependent
enzyme systems.  Induction of microsomal enzyme activity has
been shown to enhance the metabolism of a wide variety of
drugs/ pesticides and other xenobiotics.  Exposure to TCB
could, therefore, result in decreased pharmacologic and/or
toxicologic activity of numerous compounds.  Frequently,
chemical agents are metabolized  to more active or toxic
"reactive" intermediates.  In this event exposure to TCB
would result in enhanced activity and/or toxicity of these
agents.
Teratogenicity, Mutagenicity and Carcinogenicity
     Studies have not been conducted primarily for the pur-
pose of determining the teratogenic or mutagenic properties
of trichlorobenzene isomers.  Gotto, et al.  (1972), in a
study to examine hepatomas caused by hexachlorocyclohexane,
administered 1,2,4-TCB at a dose of 600 ppm  by inhalation
daily for six months to mice and reported no  incidence of
hepatomas.  There are no other studies which  have been de-
signed for the purpose,of studying carcinogenicity of TC3  nor
have there been any other reports indicating  such activity.
                             041

-------
                    CRITERION FORMULATION
Existing Guideline and Standards
     A proposed American Conference  of Governmental  and Ind-
ustrial Hygienists Threshold Limit Value  (TLV)  standard for
TCB's is 5 ppm  (mg/1) as a  ceiling value  (Am.  Conf.  Gov.  Ind.
Hyg. 1977).  Sax, et al.  (1951) recommends  a maximum allow-
able concentration of 50 ppm in air  for commercial TCB, a
mixture of isomers.  Coate, et al.  (1977),  citing  their
studies, recommends that the TLV  should be  set  below 25 ppm,
preferably 5 ppm  (mg/1).  Gurfein and Parlova  (1962) indicate
that in the Soviet Union the maximum allowable  concentration
for TCB in water  is 30 v.g/1, which  is an organoleptic limit.
They also report  that in a  study  of  40 rats and 8  rabbits ad-
ministered TCB  in drinking  water  at  a concentration  of 60
ug/1 for a period of  seven  to eight  months, no  effects were
observed.  This  information was obtained  from  an abstract and
evaluation of  the study  could not be done.
Basis -and Derivation  of  Criterion
     While the  committee  recognizes  a need  for  toxicological in-
formation in order  to establish a criterion,  there are no reli-
able published  toxicological data on TCB.   The  studies by Smith,
et  al.  (1978),  and  Coate, et al.  (1977) do  not  give  suffiecient
basis  for establishing  a toxicological criterion.  Therfore, in
lieu of a criterion based on toxicological  information, an or-
ganoleptic level  of  13  ug/1 (Varshavskaya,  1968) is  recommended.
It  should be emphasized  that  this is a criterion based on
aesthetic  rather  than on health  effects.  Data  on human health
effects need  to be  developed as  a more substantial basis for
setting a  criterion for the protection of  human health.
                              C-42

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                          REFERENCES







 Alexander,  M.  1972.   Pollution characteristics of 1,2,4-tri-



 chlorobenzene.   Dow  Chemical Co.,  Midland, Mich.  (Unpublish-



 ed.)  Cited  in  U.S.   EPA.  1977.








 Ariyoshi, T.,  et al.  1975a.   Relation between chemical struc-



 ture  and  activity.   I.   Effects of the number of chlorine



 atoms in  chlorinated  benzenes on the components of drug



 metabolizing systems  and  hepatic constitutents.  Chem. Pharm.



 Bull.  23: 817.








 Ariyoshi, T., et al.  1975b.   Relation between chemical struc-



 ture  and  activity.   II.   Influences of isomers of dichloro-



 benzene,  trichlorobenzene  and tetrchlorobenzene on the activ-



 ities  of drug metabolizing enzymes.   Chem.  Pharm. Bull.  23:



 824.








 Ariyoshi, T., et al.  1975c.   Relation between chemical struc-



 ture  and activity.  III.  Dose  response  on  tissue course  of



 induction of microsomal enzymes  following  treatment  with



 1,2,4-trichlorobenzene.  Chem.  Pharm.  Bull.  23:  831.








Brown, V.K.H.,  et al. 1969.   Acute  toxicity  and skin  irritant



properties of 1,2,4-trichlorobenzene.  Ann.  Occup. Hyg. 12:



209.
                             C-43

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Cameron, G.R., et  al.  1937.   The  toxicity  of  certain  chlorine



derivatives of benzene with  special  reference  to  o-dichloro-



benzene.  Jour. Path.  Bact.  44: 281.







Carlson, G.P. 1978.  Induction of cytochrome  P-450  by  halo-



genated benzenes.  Biochem.  Pharmacol. 27:  361.







Carlson, G.P., and R.G. Tardiff. 1976.  Effect of chlorinated



benzenes on the metabolism of foreign organic  compounds.



Toxicol. Appl. Pharmacol. 36: 383.







Coate, W.B., et al. 1977.  Chronic inhalation exposure of



rats, rabbits and monkeys to  1,2,4-trichlorobenzene.  Arch.



Environ. Health. 32: 249.







Cordle, F., et al. 1978.  Human exposure to polychlorinated



biphenyls and polybrominated biphenyls.  Environ. Health



Perspect. 24: 157.







Egyankor, K.B., and C.S. Franklin. 1977.   Interaction of the



trichlorobenzenes with cytochrome P-450.   Biochem. Soc.



Trans. 5: 1519.







Girard, R., et al. 1969.  Serious blood disorders and expo-



sure to chlorine derivatives of benzene.   (A report of 7



cases).  Jour. Med. Lyon 50: 771.
                             C-44

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

Gurfein, L.W., and Z.K. Parlova. 1962.  The limit of allow-
able concentrations of chlorobenzenes in water basins.  In'
B.S. Levine, ed. USSR literature on water pollution. Dep.
Commer., Washington, D.C.

Haas, J.M., et al. 1974.  Environmental considerations con-
cerning the selection of dye carrier solvents.  Presented  at
the 1974 Am. Assoc. Textile Chem. Colourists Natl. Tech.
Conf. October 9-11. Cited in U.S. EPA, 1977.

Hintz, M. 1962.  Pollution characteristics of 1,2,4-tri-
chlorobenzene.  Dow Chemical Co.  Midland, Mich.   (Unpublish-
ed.) Cited  in U.S.  EPA, 1977.

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

Kujawa, M., et al. 1977.  On the metabolism of  lindane.  Proc.
1st Int. Symp. Environ. Pollut. Human Health.

Lu, P.Y., and R.L. Metcalf. 1975.   Environmental  fate  and
biodegradability of benzene derivatives as studied in  a  model
aquatic ecosystem.  Environ. Health.  Perspect.10:  269.
                             C-45

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Parke, D.V., and R.T. Williams. 1960.  Studies  in  detoxica-
tion.  Metabolism of halobenzenes:  (a) Penta- and  hexachloro-
benzene:   (b) Further observations  on 1,3,5-trichlorobenzene.
Biochem. Jour. 74: 1.

Rimington, C., and G. Ziegler.  1963.  Experimental porphyria
in rats induced by chlorinated  benzenes.  Biochem.  Pharmacol.
12: 1387.

Sax, N.I.  1975.  Dangerous  properties of  industrial materi-
als. 4th ed. Van Nostrand Reinhold,  New York.

Sidwell, V.D., et al. 1974.   Composition  of  the edible  por-
tion of raw  (fresh or frozen)  crustaceans,  ffnfish, and mol-
lusks.  I.   Protein,  fat moisture,  ash, carbohydrate, energy
value,  and cholesterol.  Mar.  Fish.  Rev.  36:  21.

Simmons, P.,  et  al.  1976.   1,2,4-trichlorobenzene:  Biode-
gradable or  not?  Can.  Assoc.  Textile Colourists  Chem.  Int.
Tech. Conf.  Quebec.  October 13-15.  Cited  in  U.S.  EPA, 1977.

Smith,  C.C.,  et  al.  1978.   Subacute toxicity of 1,2,4-tri-
chlorobenzene (TCB)  in  subhuman primates.  Fed. Proc. 37:
248.

U.S.  EPA.  1975.   Preliminary assessment of  suspected carcino-
gens in drinking water.  Rep.  Cong. No. PB-250961.
                              C-46

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U.S. EPA. 1977.   Investigation of  selected  potential  environ-



mental contaminants: Halogenated benzenes.  EPA  560/2-77-004.







Varshavskaya, S.P. 1968.  Comparative  toxicological charac-



teristics of chlorobenzene and dichlorobenzene  (ortho-  and



para-isomers) in  relation to  the sanitary protection  of water



bodies (Russian translation).  Jour. Hyg. San.  33: 10.







Veith, G.D., et al. An evaluation  of using  partition  coeffi-



cients and water  solubility to estimate bioconcentration fac-



tors for organic  chemicals in fish  (Manuscript.)







Williams, R.T. 1959.  The metabolism of halogenated aromatic



hydrocarbons. Page 237 _in  "Detoxication mechanisms. 2nd ed.



John Wiley and Sons, New York.
                             C-47

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                       TETRACHLOROBENZENE

Mammalian Toxicology  and  Human  Health  Effects

                           EXPOSURE

Introduction

     Tetrachlorobenzene  (TeCB)  exists  as three  isomers-1,2,

3,4-TeCB, 1,2,3,5-TeCB and 1,2,4,5-TeCB.   Of  these,  1,2,4,5-

TeCB is the most widely  used.   In the  limited state,  1,2,3,5-

TeCB is used primarily in  the manufacture  of  2,4,5-trichloro-

phenoxyacetic acid  (2,4,5-T) and  2,4,5-trichlorophenol  (2,4,

5-TCP).  In 1973, an  estimated  ten million pounds of  1,2,4,5-

TeCB were utilized  in the  manufacture  of  2,4,5-T while  six

million pounds were utilized in the manufacture of 2,4,5-TCP

(U.S. EPA, 1977).   In the  Soviet Union,  1,2,4,5-TeCB  is  used
         9
as a soil and grain pesticide (Fomenko,  1965).  It is not

used for this purpose  in the United States.

     Tetrachlorobenzene  (TeCB) has been  found to be among the

metabolites of hexachlorobenzene  (Mehendale,  et al. 1975;

Rozman, et al. 1975), lindane, pentachlorocyclohexane, penta-

chlorobenzene and pentachlorophenol (Engst, et al. 1976a,b).

     1,2,4,5-TeCB has an extremely low vapor pressure, less

than 0.1 mm Hg at 25°C (Sax, 1975).   The octanol-water parti-

tion coefficient for TeCB  is 4.93.
                             C-48

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Ingestion from Water
     No literature was found which identified TeCB in water
in the United States.  However, a contamination of run-off as
a result of its industrial use is certainly feasible and may
in part, be responsible for the contamination of the aquatic
organisms described below.  Soil microorganisms are capable
of metabolizing lindane to tetrachlorobenzene, among others
(Tu, 1976; Mathur and Saha, 1977).  TeCB derived in this man-
ner is available from soil run-off.
Ingestion from Foods
     There are some data to show that TeCB will concentrate
in fish exposed to industrial effluent discharge.  Kaiser
(1977) identified two isomers of TeCB in three species of
fish caught at various distances from a pulp and paper mill.
Similarly, Lunde and Ofstad (1976) identified tetrachloro-
benzene in sprat (a small herring) from different  locations
in southeastern Norway.
     Qualitatively, tetrachlorobenzenes have been  identified
in the food chain as a result of the biotransformation of
lindane.  Saha and Burrage (1976) administered lindane to hen
pheasants and identified tetrachlorobenzene as part of the
array of metabolites found in eggs and chicks as well as  in
the body tissues of the hens.  Balba and Saha (1974) followed
the metabolism of 14C-lindane in wheat plants grown from
treated seeds and identified two and possibly three of the
isomers of TeCB.  Kohli, et al.  (1976 b,c) in laboratory
studies identified TeCB as a minor metabolite of lindane  in
lettuce and endives.
                             C-49

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     Tetrachlorobenzenes  have  also been  identified  as  metabo-
lites of gamma pentachlorocyclohexane  in  corn  and pea  seed-
lings.  Pentachlorbenzenes  have  also been identified  in  the
essential oil of marsh grass  (Miles, et  al.  1973).
     There is legitimate  doubt as  to whether exposure  to
TeCBs as breakdown products of lindane and other  substances
represents a significant  exposure, especially  considering
that concentrations  of the  more  toxic  parent compounds are
higher.
     A bioconcentration  factor (BCF) relates the  concentra-
tion of a chemical  in water to the concentration  in aquatic
organisms, but BCF's are  not  available for  the edible  por-
tions of all four major  groups of  aquatic organisms consumed
in  the United States.  Since  data  indicate  that the BCF  for
lipid-soluble compounds  is  proportional  to  percent  lipids,
BCF's can be adjusted  to edible  portions using data on per-
cent  lipids  and  the  amounts of various species consumed  by
Americans.   A recent survey on fish  and  shellfish consumption
in  the United States (Cordle,  et al.  1978)  found  that  the per
capita  consumption  is  18.7  g/day.   From the  data  on the  nine-
teen  major  species  identified in the  survey  and data  on  the
fat content  of  the  edible portion of  these  species  (Sidwell,
et  al.  1974),  the  relative  consumption of the  four  major
groups  and  the  weighted', average percent lipids for  each group
can be  calculated:
                              C-50

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                              Consumption    Weighted Average
          Groups               (Percent)      Percent Lipids

 Freshwater fishes                12                4.8

 Saltwater fishes                 61                2.3

 Saltwater molluscs                 9                1.2

 Saltwater decapods                18                1.2

 Using  the percentages  for  consumption and lipids for each of

 these  groups,  the weighted average percent lipids is 2.3 for

 consumed  fish  and shellfish.

     No measured steady-state bioconcentration factor (BCF)

 is  available for 1,2,4,5-tetrachlorobenzene,  but the equation

 "Log BCF  =0.76  Log  P  -  0.23" can be  used (Veith, et al.

 Manuscript) to  estimate  the BCF  for aquatic  organisms that

 contain about  eight  percent lipids from the  octanol-water

 partition  coefficient  (P).  An adjustment factor of  2.3/8.0 =

 0.2875 can be  used to  adjust  the estimated BCF from  the 8.0

 percent lipids  on which  the equation  is  based  to the 2.3 per-

 cent lipids that  is  the  weighted average for  consumed fish

 and shellfish.    Thus,  the  weighted  average bioconcentration

 factor for the edible  portion of all  aquatic  organisms

 consumed by Americans  can  be  calculated:



Compound                          P        BCF     Weighted BCF



1,2,4,5-tetrachlorobenzene     93,000    3,500         1,000
                             C-51

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Inhalation and Dermal



     No reliable  information  has  been  recovered  dealing with



inhalation or dermal exposure  to  TeCB.



                       PHARMACOKINETICS



Absorption/ Distribution,  Metabolism, Excretion



     Jondorf, et  al. (1958) administered  each  of the  three



isomers of TeCB to three  rabbits  at an oral dose of 0.5 g/kg.



The animals were  followed  for  six days after dosing.   The



percentage of administered dose recovered  in the feces  over



this time for the respective  compounds was:  1,2,3,4-TeCB, 5



percent; I,2,3,5-TeCBf  14  percent; 1,2,4,5-TeCB,  16 percent.



Considering that  this  is  over  a six-day period and that some



of the fecal content could possibly have  been a  result  of



biliary excretion, it  would appear that the gastrointestinal



absorption of TeCBs is  relatively efficient.



     Table 1 shows the  distribution of unchanged  TeCB  in rab-



bit tissues six days after dosing.  Comparative  distribution



among the three isomers shows  a relative  degree  of consis-



tency.  The one exception  is  in the gut contents  where  12



percent of the total remaining compound is present for  1/2,



4,5-TeCB which is about twice  that for the other  isomers.



This could reflect lesser  absorption of 1,2,4,5-TeCB or,



possibly, biliary excretion.



     Table 2 shows the  extent of  elimination of  the isomers



in expired air.
                             C-52

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                    TABLE 1

Unchanged Tetrachlorobenzene in Rabbit Tissues,
    Six Days After Dosing (0.5 g/kg orally)
             (Jondorf, et al. 1958)
TeCB
1,2,3,4
1,2,3,5
1,2,4,5


Liver Brain
0.1
<0.5 <0.2
0.1 <0.1

Percentage of Dose
Depot Gut Rest of .
Skin Fat Contents Body
2 5 0.5 2.0
5 11 1.4 5.2
10 25 6.2 6.4
TABLE 2
Total
10
23
48

Elimination of Unchanged Tetrachlorobenzenes
in Expired Air of Rabbits Following Oral Dosing
(Jondorf, et al. 1958)
TeCB

1,2,3,4
1,2,3,5
1,2,4,5
Dose
(g/kg)

0.5
0.3
0.5
0.3
0.5
Percentage of Dose in Expired Air
. Days after Dosing
1 2 3_ ± 5
1.9 2.2 1.6 0.2
0.8 1.7 6.7
2.1 2.1 1.2 2.9 2.6
0.9 3.2 9.8
1.2 0.2 0.2
Total

5.9
9.2
10.9
13.9
1.6
                       C-53

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           Table 3 shows the*urinary excretory  pattern  observed in
      the three isomers.  The 1,2,3,4-TeCB  isomer  is  more  freely
      metabolized than the other  two isomers, and  1,2,4,5-TeCB is
      metabolized the least.
                                  TABLE  3
         Urinary Excretion of Metabolites of Tetrachlorobenzenes
               in Rabbits Following Oral Dosing (0,. 5  g/kg/)
                           (Jondorf, et  al.  1958)

                       Percentage of Dose Excreted
TeCB
              Ethereals   Mercapturic     TeCP
Glucuronide    Sulfate       Acid         Fece
               Total
1,2,3,4   30(22-36)a      3(1-8)
              (5)b
                              <1
8(7,9)
43(38,48)
   (2)
1,2,3,4

1,2,4,5

6(2-10)
(9)
4(1-8)
(ID
2(1-6)
(9)
l«l-2)
(11)
0
(3)
0
' (3)
1.9(1.2,2.5)
(2)
1.3(0.9,1.6)
(2)
5(4.6)
(2)
2.2(0.9,
(2)


1.6)

           Kohli,  et  al.  (1976a)  studied  the  metabolism of TeCB iso-
      mers in  rabbits and  identified  the  nature  of  TCP metabolites.
      A dose of  60 to 705  mg/kg was administered to rabbits by in-
      traperitoneal injection and the urine  and  feces collected for
      ten days.   The  metabolism of both 1,2,3,4-TeCB and 1,2,3,5-
      TeCB yielded two common metabolites,  2,3,4,5- and 2,3,4,6-
      tetrachlorophenol (TeCP).  Another  metabolite of 1,2,3,5-TeCB
      was 2,3,5,6-TeCP.  This metabolite  2,3,5,6-TeCP was also the
      only metabolite identified following  the administration of 1,
      2,4,5-TeCB.  The relationships  among  the various isomers were
      strikingly similar to the data  reported by Jondorf, et al.
       (1958).
                                    C-54

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      Kohli,  et al.  (1976a)  proposed the formation of the



 phenol  metabolites  through  corresponding arene oxides.  The



 authors suggest the involvement of an NIH shift of the



 chlorine atom in the  formation of the metabolites (except for



 the  formation of 2,3,5,6-TeCP from 1,2,3,5-TeCB which can be



 derived from 2,3,5,6-TeCB and oxide without an NIH shift of



 chlorine).



      From  the above information,  it is reasonable to expect



 that  the metabolism of  the  TeCB is via liver microsomal



 enzymes.   Ariyoshi, et  al.  (1975)  reported an increase in



 cytochrome P-450  induced  by all three isomers in the rat



 liver as well as  an increase in delta aminolevulinic acid



 synthetase activity.  Rimington and Ziegler (1963) showed



 that  urinary  porphyria  and  porphyria precursors were in-



 creased  in rats  by  1,2,3,4-TeCB but not by 1,2,4,5-TeCB.



 This was correlated with  an increase in porphyrins,  porphoro-



 bilinogen and  catalase  activity in rats treated with 1,2,3,4-



 TeCB but not  the  1,2,4,5  isomer.



                            EFFECTS



Acute, Sub-acute  and Chronic  Toxicity



     Most of  the  information  on tetrachlorobenzene comes



from studies  done in the  Soviet Union and  is concerned with



1,2,4,5-TeCB.  The LD$Q for  white  mice  was reported  to be



1035 mg/kg when the compound  was  administered in sunflower



oil orally or  2650 mg/kg  as a  suspension  in  a 1.5 percent



starch solution.  In rats and  rabbits,  the LD$Q was  reported



to be 1500 mg/kg when the compound  was  administered  in sun



flower oil (Fomenko, 1965).    The  apparent  cumulative activity





                              C-55

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of this  isomer  of  TeCB was  demonstrated by Fomenko (1965).  A
dose of  300 mg/kg,  20  percent  of  the  LDso, was administered
to rats  daily;  50  percent of the  animals  died  when a  dose
equivalent to the  LD$Q was  obtained.   The same investigator
administered 1,2,3,5-TeCB in oral doses of 75  mg/kg daily for
two months.  While  there were  presumptive changes  in  liver
function/ prothrombin  index, blood cholesterol and number of
reticulocytes,  histopathological  examination showed no signif-
icant change that  would alter  liver function.   Adrenal
hypertrophy and decreased content of  ascorbic  acid in
adrenals were reported.  Histopathological examinations did
not reveal appreciable differences between control and
experimental groups.
     Further experiments are described  in the  foregoing re-
port from the Soviet Union  in  which 1,2,4,5-TeCB was  adminis-
tered in oral doses of .001, .005,  and  0.05 mg/kg  to  rats  and
rabbits  over an eight  month period.   The  report states  that
doses of 0.005 mg/kg and "especially" 0.05 mg/kg disrupted
the conditioned reflexes.   It  is  stated that "formation  of  a
positive condition  reflex became  slower but the latent  period
remained the same".  It is  also stated  that rabbits treated
with doses of 0.05 mg/kg "began to display disorders  in  gly-
cogen-forming function  in the  liver only  after six  experi-
mental months".  No hematologic changes were noted  in  the
animals.  At the end of the dosing period, liver weights were
increased in animals receiving doses of 0.005 and  0.05 mg/kg.
The conclusion made was that the two higher doses were active
and that the lower dose was not.
                             C-56

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     The data from the above studies (Fomenko, 1965) are only
partially presented and the bulk of the report consists of
the conclusions of the author.  The studies done on condi-
tioned reflexes in rats were done on a control group of five
animals, low and middle dose groups of seven animals each,
and a high dose group of six animals.  It is not clear as to
whether or not those represented the total number of animals
in a group.
     Braun, et al. (1978) administered 1,2,4,5-TeCB in the
diet to beagles at a dose of 5 mg/kg/day for two years.  No
changes in clinical chemistry parameters were noted after 18
months.  At 24 months there was a slight elevation of serum
alkaline phosphatase activity and bilirubin levels.  The ani-
mals were then allowed to recover.  After three months the
serum chemistry changes noted were no  longer evident.  Gross
and histopathological studies were done 20 months after
cessation of exposure.  No treatment related changes were
noted.
Synergism and/or Antagonism
     Since TeCBs can increase cytochrome P-450  levels,  it,
like other halogenated benzenes, appears to represent a  drug
metabolizing enzyme inducer  (Ariyoshi, et al. 1975).   In gen-
eral, the halogenated benzenes appear  to increase  the  activ-
ity of microsomal NADPH-cytochrome P-450-dependent  enzyme
systems.  Induction of microsomal enzyme activity  has  been
shown to enhance the metabolism of a wide variety  of  drugs,
pesticides and other xenobiotics.  Exposure to  TeCB could
                             C-57

-------
therefore result in decreased pharmacologic  and/or  toxico-
logic activity of numerous  compounds.  Frequently,  chemical
agents are metabolized  to more  active or  toxic  "reactive"
intermediates.  In this event/  exposure to TeCB would  result
in enhanced activity and/or toxicity of these agents.
Teratogenicity, Mutagenicity and Carcinogenicity
     No studies have been identified which directly or in-
directly address the teratogenicity or carcinogenicity of
TeCB.  An abstract of a study by Kiraly/  et  al.  (1976) de-
scribes a study of chromatid disorders among workers involved
in the manufacture of an organophosphorus compound.   Disor-
ders were said to be significantly higher in this group than
in a group  involved  in  the  manufacture of TeCB.  However/  the
abstract concludes "The mutagenic properties of  tetrachloro-
benzene were  confirmed".  This  is the only reference seen
referring to  mutagenic  activity of TeCB's.
                              C-58

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                     CRITERION FORMULATION



 Existing Guidelines and Standards



      The maximal permissible concentration of TeCB in water



 established by the Soviet Union is 0.02 mg/1 (U.S. EPA,



 1977) .



 Current Levels of Exposure



      No data are available on current levels of exposure.



 However, the report by Morita,  et al. (1975) gives some in-



 dication of exposure.   Morita,  et al. (1975) examined adipose



 tissue  samples obtained at general hospitals and medical ex-



 aminers offices in central Tokyo.  Samples from 15 individ-



 uals  were  examined; this represented five males and ten fe-



 males between the ages of 13 and 78.  The tissues were ex-



 amined  for 1,2,4,5-TeCB as well as for 1,4-dichlorobenzene



 and hexachlorobenzene.   The TeCB content of the fat ranged



 from  0.006 to 0.039 mg/kg of tissue; the mean was 0.019



 mg/kg.   The  mean concentrations of 1,4-dichlorobenzene and



 hexachlorobenzene were  1.7 mg/kg and 0.21 mg/kg respectively.



 Interestingly,  neither  age nor  sex correlated with the level



 of any  of  the  chlorinated hydrocarbons in adipose tissue.



 Special  Groups  at Risk



     The primary  groups  at risk from the exposure to TeCB are



 those who  deal  with  it  in the workplace.   Since it is a



metabolite of  certain  insecticides,  it might be expected that



certain  individuals  exposed  to  those  agents  might experience



more exposure  to  TeCB especially since its  elimination rate



might be relatively  slow  in  man.   Individuals  consuming large
                             C-59

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quantities  of  fish may also be at risk due to the proven bio-
concentration  of  TeCB in fish.  U.S.  EPA Duluth laboratory
studies  show  that the bioconcentration factor for 1,2,4,5-
TeCB  is  1,000  times,  and for 1,2,3,5-TeCB is 4,100 times.
Basis and Derivation  of Criterion
      The dose  of  5 mg/kg/day reported for beagles (Braun,
1978) was utilized as the NOAEL for  criterion derivation.  An
acceptable  daily  intake (ADI)  can be  calculated from the
NOAEL by using a  safety factor of 1,000  based on a 70 kg/man:
             ,. _T    70 kg x 5 mg/kg   « ->c   /j
             ADI  = - 1000 — **—*• ~  0-35 mg/day

      For the sake of  establishing a water quality criterion,
it is assumed  that on the average, a  person  ingests  2 liters
of water and 18.7 grams of fish.   Since  fish  may biomagnify
this  compound,  a  biomagnif ication factor  (F)  is  used in  the
calculation.
     The equation for calculating an  acceptable  amount of
TeCB  in water  is:
Criterion = 2 3. +                 = 16'9 ^/l or    17
where:
          21=2 liters of drinking water consumed
   0.0187 kg  = amount of fish consumed daily
         1000 = biomagnif ication factor
          ADI = Allowable Daily Intake (mg/kg for a 70 kg/person)
     Thus, the recommended criterion for TeCB in water is 17
ug/1.
                             C-60

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o
I
              Figure 1:  Proposed  routes  for the biotransformation of tetrachlorobenzene

                             isomers via arene oxides (Kohli,  et al. 1976a)

-------
                           REFERENCES







Ariyoshi, T., et al. 1975.  Relation between  chemical  struc-



ture and activity.   II.   Influences of  isomers  in  dichloro-



benzene, trichlorobenzene  and  tetrachlorobenzene on  the  acti-



vities of drug-metabolizing enzymes.  Chem. Pharm. Bull.   23:
                                            :


824.
Balba, M.H., and J.G.  Sana.  1974.   Metabolism  of  lindane



by wheat plants grown  from  treated  seeds.   Environ.  Let.  7:



181.







Braun, W.H., et al.  1978.   Pharmacokinetics and  toxicological

                                                       9

evaluation of  dogs  fed 1,2,4, 5-tetrachlorobenzene in the  diet



for  two years.  Jour.  Environ.  Pathol.  Toxicol.  2:  225.







Cordle, F.,  et  al.  1978.   Human exposure  to polychlorinated



biphenyls  and  polybrominated biphenyls.   Environ. Health



Perspect.  24:  157.







Engst,  R. , et  al.  1976a.   The metabolism  of hexachlorobenzene



 (HCB)  in  rats.  Bull.   Environ. Contam. Toxicol.  16: 248.







Engst,  R. , et  al.  1976b.   The metabolism  of lindane and  its



metabolites  gamma-2,3,4,5,6-pentachlorocyclohexene,  penta-



chlorobenzene  and  pentachlorophenol in rats and  the pathways



of lindane metabolism.  Jour. Environ.  Sci. Health  Bull:  95.
                              C-62

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 Fomenko,  V.N.  1965.   Determination of the maximum permissible


 concentration  of  tetrachlorobenzene in water basins.   Gig.


 Sanit.  30:  8.




 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.




 Kaiser, K.L.E.  1977.   Organic contaminant  residues  in  fishes


 from  Nipigon Bay  Lake  Superior.   Jour.  Fish.  Res. Board Can.


 34: 850.




 Kiraly, J., et  al. 1976.   Chromosome studies  in  workers ex-

                                     ^
 posed to  organophosphorus  insecticides.   Mankavedelem  22:


 27.




 Kohli, J.,  et al.  1976a.   The metabolism  of  higher  chlori-


 nated benzene isomers.   Can. Jour.  Biochem.  54:  203.




 Kohli, J.,  et al.  1976b.   Balance  of conversion  of  [3.40]  lin-


dane in lettuce in hydroponic culture.  Pestic.  Biochem.  and


Physiol. 6: 91.




Kohli, J., et al.  1976c.   Contributions to ecological  chem-


istry.  CVII.   Fate of i4C-lindane  in  lettuce, endives  and


soil under outdoor conditions.  Jour.  Environ. Sci. Health


Bll: 23.
                             C-63

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Lunde, G.,  and  E.B.  Ofstad.  1976.   Determination of fat



soluble chlorinated  compounds  in  fish.   Jour.  Anal.  Chem.



282: 395.








Mathur, S.P., and J.G.  Saha. 1977.   Degradation  of  lindane-l4C



in a mineral soil and  in  an  organic  soil.   Bull.  Environ.



Contam. Toxicol. 17: 424.








Mehendale,  H.M./ et  al. 1975.  Metabolism  and  effect  of  hexa-



chlorobenzene on hepatic  microsomal  enzymes  in the  rat.



Jour. Agric. Food Chem. 23:  261.








Miles, D. Howard, et al.  1973.  Constituents of marsh grass.



Survey of the essentail oils in Juncus roemerians.  Phyto-



chemistry 12: 1399.








Morita, M., et  al. 1975.  A  systematic determination of



chlorinated benzenes in human adipose tissue.  Environ.



Pollut. 9:  175.








Rimington,  C.,  and G. Ziegler. 1963.  Experimental porphyria



in rats induced by chlorinated benzenes.   Biochem. Pharmacol.



12: 1387.








Rozman, K., et  al. 1975.  Separation, body distribution and



metabolism  of hexachlorobenzene after oral administration to



rats and rhesus monkeys.  Chemosphere 4:  289.
                             C-64

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Saha, J.G., and R.H. Burrage. 1976.  Residues of lindane and
its metabolites in eggs, chicks and body tissues of hen
pheasants after ingestion of lindane carbon-14 via treated
wheat seed or gelatin capsules.  Jour. Environ. Sci. Health
Bll: 67.

Sax, N.I. 1975.  Dangerous properties of industrial mater-
ials; 4th Ed., Van Nostrand Reinhold, New York. p. 1145.

Sidwell, V.D., et al. 1974.  Composition of  the edible  por-
tion of raw (fresh or frozen) crustaceans, finfish, and mol-
lusks.  I.  Protein, fat, moisture, ash, carbohydrate,  energy
value, and cholesterol.  Mar. Fish. Rev. 36:  21.

Tu, C.M. 1976.  Utilization and degradation  of  lindane  by
soil microorganisms.  Arch. Microbiol. 108:  259.

U.S. EPA. 1977.  Investigation of  selected potential  environ-
mental contaminants:  halogenated  benzenes.   560/2-77-004
U.S. Environ. Prot. Agency.

Veith, G.D., et al.  An evaluation of  using  partition coeffi-
cients and water solubility  to estimate  bioconcentration  fac-
tors for organic chemicals  in  fish.   (.Manuscript).
                              C-65

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                       PENTACHLOROBENZENE
Mammalian Toxicology and  Human  Health  Effects
                            EXPOSURE
Introduction
     Pentachlorobenzene  (QCB1)  is  used primarily as  a pre-
cursor in the synthesis of  the  fungicide,  pentachloronitro-
benzene  (PCNB, Quintozene,  Terraclor), and as  a flame retar-
dant.  It has been  suggested  as an intermediate in  the pro-
duction  of  thermoplastics (Kwiatkowski,  et al.  1976).  QCB is
a white  solid crystalline material at  room temperature and,
like other  halogenated benzenes,  is  both  lipophilic  and
hydrophobia.  Approximately 1.4 x  10^  kg  of pentachloroben-
zene was produced  in  1972 and it is  estimated  that  16.6 x 10^
kg of  the material  was discharged  into (ambient) water sources.
Much of  the exposure  of the population to QCB  is derived from
exposure to lindane,  hexachlorobenzerie (HCB),  and PCNB.  The
metabolism  of  lindane  to  QCB is well established and it has
been demonstrated  in  humans (Engst,  et al.  1976a),  rats
 (Engst,  et  al.  1976b,c;  Seidler,  et al.  1975;  Kujawa, et al.
1977), and  rabbits  (Karapally,  et  al.  1973).  Biotransforma-
tion of  lindane  to  QCB can occur earlier in the food chain.
 1QCB (for quintochlorob'enzene) rather than PCB will be used
 as  the abbreviation for pentachlorobenzene to avoid confusion
 with polychlorinated biphenyls.
                              C-66

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 Engst,  et al.  (1977)  identified QCB as a product of the metab-.



 olism of  lindane by mold  grown spontaneously on grated car-



 rots.  Tu (1976) identified 71 soil microorganisms which would



 biodegrade lindane.   Thirteen of these were examined further



 and  were  found to produce QCB as one of the metabolites of the



 insecticide.   Mathur  and  Saha (1977) have also reported QCB as



 a  soil  degradation product of lindane.



      QCB  has  been identified  as a metabolite of HCB in rats



 (Mehendale, et al.  1975;  Engst, et al. 1976c) and rhesus mon-



 keys  (Rozman,  et al.  1977, 1978;  Yang, et al. 1975, 1978).



      TCNB occurs as  a residue in technical grade PCNB.



 Borzelleca, et al.  (1971)  detected TCNB storage in tissue of



 rats, dogs  and cows  following feeding studies with PCNB.



 Rautapaa,  et al.  (1977) examined  soil samples in Finland from



 areas that  have  been  treated  with PCNB and found a maximum



 PCNB  level of  27 mg/kg of  soil  and the highest QCB level of



 0.09  mg/kg of  soil.



      Igarashi,  et  al.  (1975)  identified QCB as a further



 degradation product of pentachlorothioanisole in soil.



      The  importance of QCB as  a contaminant of PCNB in treated



 soil  is demonstrated  by the study of Beck and Hansen (1974).



 They  studied 22  soil  samples  from fields where technical PCNB



 had been  used  regularly during  the  foregoing 11 years.  The



 concentration  range for PCNB  in  the  samples was 0.01 to 25.25



mg/kg of  soil  and a concentration range for QCB of 0.003 to



0.84 mg/kg of  soil.   The samples  were studied for a period of
                             C-67

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600 days.  The half-life of QCB in two separate determinations



was 194 and 345 days.  The calculated log partition coefficent



for QBC OCT/H2O = 5.63.
                             C-68

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Ingestion from Water
     The following discussion concerning the ingestion of QCB
from food, especially as relates to its presence  in marine
organisms, also relates to the presence of the compound  in
water.  Burlingame (1977) has identified QCB in effluent from
a wastewater treatment plant in southern California.  Access
to water by QBC can occur by a number of means including in-
dustrial discharge or as a breakdown product or contaminant of
widely used organochlorine compounds.
Ingestion from Foods
     From the available information it would appear that the
appearance of QCB in soil and its persistence can  result in an
accumulation within the food chain.  This also holds  true  for
its ecological precursors.  For example, Balba and Saha  (1974)
treated wheat seed with isotopically labeled lindane  and ob-
served a number of metabolites, including QCB, in  the seed-
lings and mature plants.  Kohli, et al. (1976a) found that
isotopically labeled lindane added to the nutrient medium  for
lettuce was metabolized to a number of products including  QCB.
Dejonckheere, et al. (1975, 1976) examined samples from  soil
which had been used to grow lettuce and samples from  soil  used
to grow witloof-chicory.  The soil had been  treated with PCNB
for a six year period.  Sample averages ranged from 0.25 to
0.85 ppm of QCB.  Lunde (1976) has examined  fish  from south-
eastern Norway for the presence of polychlorinated aromatic
hydrocarbons.  QCB was among a number of compounds identified
in extracts of plaice, eel, sprat, whiting,  and cod.  Lunde
and Ofstad (1976) quantitated the amount of  chlorinated
                              C-69

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hydrocarbons in sprat  oil.   Six  samples  taken from different
locations and/or at different  times  contained 0.7  to 3.8 ppm
of QCB.  Ten Berge and Hillebrand  (1974)  identified the pres-
ence of a number of organochlorine compounds, including QCB,
in plankton, shrimp, mussels/  and  fish  from the North Sea and
the Dutch Wadden Sea.  The  compounds were  present  in part per
billion levels.
     Stijve  (1971) detected QCB  in chicken fat which was
ascribed to  residues of  HCB.   Kazama, et  al.  (1972) admin-
istered QCB  by  intramuscular injection  to  hens .and recovered
7.3 percent  of  the dose  in  the yolk  of  the egg.  No material
was found in the egg white.  Saha  and Burrage (1976) admin-
istered isotopically labeled lindane to  hen pheasants via
treated wheat seed or  gelatin capsules  and recovered QCB as
one of the metabolites in the body of the  hen, in  the eggs and
in  the chicks.  Dejonckheere,  et al. (1974) reported on the
presence of  QCB in animal fat and  suggested that it was 'de-
rived  from pesticide  residue in  feed.   That pesticide residue
included HCB and lindane.  Greve (1973)  identified QCB and HCB
in  wheat products  used for animal  feed  and detected QCB in the
fat of animals  utilizing that feed.
     A bioconcentration  factor (BCF) relates the concentration
of  a chemical  in water to the concentration in aquatic organ-
isms,  but BCF's are  not  available  for the edible portion of
all four major  groups.of aquatic organisms consumed in the
United States.   Since  data indicate  that the BCF for lipid-
soluble  compounds  is  proportional  to percent lipids, BCF's can
be  adjusted  to edible  portions using data on percent lipids
                              C-70

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 and the amounts of various species consumed by Americans.  A

 recent survey on fish and shellfish consumption in the United

 States (Cordle, et al.  1978)  found that the per capita

 consumption  is 18.7 g/day.  From the data on the nineteen

 major species identified in the survey and data on the fat

 content of  the edible portion of these species (Sidwell, et

 al.  1974),  the relative consumption of the four major groups

 and  the weighted average percent lipids for each group can be

 calculated:

                               Consumption     Weighted Average
          Group                 (Percent)        Percent Lipids

 Freshwater  fishes                 12                 4.8

 Saltwater fishes                  61                 2.3

 Saltwater molluscs                  9                 1.2

 Saltwater decapods                 18                 1.2

 Using  the percentages for consumption .and lipids for each of

 these  groups,  the weighted average percent lipids is 2.3 for

 consumed  fish  and shellfish.

      A measured  steady-state  bioconcentration  factor of 1,800

was obtained  for  pentachlorobenzene  using bluegills containing

about  one percent lipids  (U.S.  EPA,  1978).   An adjustment fac-

tor of  2.3/1.0 =  2.3  can  be used  to  adjust  the measured BCF

from  the  1.0 percent  lipids of  the bluegill to the 2.3 percent

lipids  that' is  the weighted average  for consumed  fish and

shellfish.  Thus, the weighted  average bioconcentration

factors for pentachlorobenzene  and the edible  portion of all

aquatic organisms consumed by Americans is  calculated to be

7,800.
                              C-71

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Inhalation



     There  is  very  little, information concerning atmospheric



exposure to QCB.  The  primary  site  for such  exposure could be



the workplace  in  industries  utilizing and/or producing QCB.



Dermal



     No information  was  obtained  which concerns  dermal



exposure to pentachlorobenzene.



                       PHARMACOKINETICS



Absorption, Distribution,  Metabolism,  Excretion



     Table 1 presents  data from Parke  and Williams  (1960)  on



the metabolism of pentachlorobenzene  by  rabbits.   It can  be



seen that a substantial  portion of  the oral  dose  was recov-



ered in the gut contents three to four days  after dosing.



Except for the possibility of  biliary  secretion,  which ap-



pears unlikely from  the  data obtained  after  a parenterally



administered dose, it  would appear  that  pentachlorobenzene is



very poorly absorbed from  the gastrointestinal tract.   It  is



also evident that distribution favors  deposition  in  the fat.



Engst, et al.  (1976c)  administered  QCB orally to  rats  at a



dose of 8 mg/kg for  19 days.  They  identified 2,3,4,5-tetra-



chlorophenol and pentachlorophenol  as  the major urinary



metabolites.  They also  detected 2,3,4,6-tetrachlorophenol



"and/or" 2,3,5,6-tetrachlorophenol  and unchanged  QCB.  They



reported the presence  of 1,3,5-trichlorobenzene in the liver.



Kohli, et al.  (1976b)  described 2,3,4,5-tetrachlorophenol  and



pentachlorophenol as urinary metabolites of QCB in the rab-
                              C-72

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bit.  They were detected at yields of one percent each of the
administered dose.  The authors suggest that the dechlorina-
tion hydroxylation step to the tetrachlorophenol derivative
proceeds through an arene oxide step.  Koss and Koransky
(1977) reported pentachlorophenol and 2,3,4,5-tetrachloro-
phenol as metabolites of QCB in the rat.  However,  they
stated that the amount of pentachlorophenol recovered  in  the
urine represented about nine percent of the administered
dose.  Quantitively, this is substantially greater  than  the
                               073

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                           TABLE 1

Disposition of Pentachlorobenzene in the Rabbit as Percentage
       of Administered Dose (Parke and Williams, 1960)





Dose/Route
Time
After
Dose
rag/kg (Days)



o
i
-4
0.5 p.o.
0.5 p.o.
0.5 s.c.
*Located mainly

3
4
10
at site





Urine
Triorpenta
Ch lorophenol
0.2
0.2
0.7
of injection.

Other
Phenol Feces
1 5
1 5
1 1.5


Cut
Contents
45
31
0.5


Depot
Pelt Fat
1 15
5 9
47* 22*.



Rest
of Un-
Body changed
6 0
5.5 0
10 0



Other
Hydro-
carbons
9
21
L2



Total
Accumulated
For
82
78
85



-------
 amounts of pentachlorophenol reported by Kohli, et al.



 (1976b) for the rabbit.  Parke and Williams (1960) reported



 that less than 0.2 percent of the dose was recovered as



 pentachlorophenol in rabbit urine, also a substantial dif-



 ference from that observed in the rat.  Rozman, et al. (in



 press)  found that biological half-life for QCB in rhesus mon-



 keys to be two to three months.   After 40 days ten percent of



 the total dose was excreted in the urine; of this 58 percent



 was pentachlorophenol.   After the same period, about 40 per-



 cent of the dose was excreted in the feces, 99 percent of



 which was unchanged QCB.   These  authors believe this is made



 up  of unabsorbed QCB that  is secreted by bile  into the GI



 tract.   Ariyoshi,  et al.  (1975)  reported that, in female



 Wistar  rats dosed  with  250 mg/kg QCB for three days by intu-



 bation,  QCB increased the  liver  content of cytochrome P450



 and  increased  the  activities of  aminopyrine demethylase and



 aniline  hydroxylase.   The  contents of microsomal protein and



 phospholipids  were also increased as was the activity of



 delta aminolevulinic acid.



      Further information on the  biotransformation and accumu-



 lation properties  of  QCB can be  obtained from  a study re-



 ported by Villeneuve  and Khera (1975).   They studied the



 placental transfer of halogenated benzene in rats.   They



 administered oral  doses of  QCB to pregnant rats on days 6



 through  15 of gestation.   Their  data are shown in Table 2.



 It can be seen that  the accumulation in  the organs is dispro-



portionate  to the  increasing  dose implying that somewhere



between  100 and  200 mg/kg doses,  elimination approaches zero
                              C-75

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order kinetic behavior.   The  ease  of  accumulation  of the



compound within  the  fetus is  also  evident.   This will be



discussed further  below.



                            EFFECTS



Acute, Sub-acute and  Chronic  Toxicity



     Goerz, et al.  (1978)  administered  a  diet  of 0.05 percent



of QCB to female adult rats for a  period  of  60 days.   They



were primarily interested in  the comparative abilities of QCB



and HCB to induce  porphyria.  The  treatment  resulted  in an



increased urinary  excretion of porphyrins by the HCB  treat-



ment, but none with  the QCB treatment.  It is  uncertain from



these experiments  whether the dosage  levels  for QCB are ade-



quate.  Induction  of  experimental  porphyria  can be accom-



plished with all of  the other chlorinated benzenes and it



would appear that  a more  detailed  examination  of pentachloro-



benzene should be  done before any  final conclusions are made



concerning its activity in  this regard.   A survey of  the



literature has revealed no other published data on the acute,



subchronic or chronic toxicity of  QCB.  The  only exceptions



to this are data which have been gathered in association  with



pharmacokinetic and teratologic studies,  but on  the basis  of



the number of animals utilized and the time  of  administration,



these are not particularly useful  for establishing criterion



standards.  For example,  Khera and Villeneuve  (1975)  admin-



istered QCB in doses of 50, 100 and 200 mg/kg orally  to preg-



nant rats during days 6 to 15 of gestation.   The adult  rats



(20 in each group) did not display any "overt"   signs  of
                              C-76

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                              TABLE 2

Tissue Distribution of Pentachlorobenzene  (PPM wet tissue) Following
 Oral Administration to Pregnant Rats  (Villeneuve and Khera, 1975)







o
1
-J
-J
Dose
(mg/kg)
50
100
200
Represents
^Represents
cRepresents



Fata
470+106
824+116
3350+331
the mean of
the mean of
the mean of



Liver3
13.9+5.1
18.1+2.0
91.1+_6.6
5 animals +
two fetuses
five fetuses



Brain3 Heart3 Kidney3
6.9+ 1.2 6.2+1.0 6.0+1.1
12.0+ 1.7 12.6+2.0 10.6+1.5
62.5+10.2 57.5+9.6 43.5+2.6
o » ti *H •
from 15 litters + S.E.H.
each from a different litter + S.E.M.


Whole3 Fetalc Fetalc
Spleen3 Fetus Liver Brain
4.5+1.1 9.65+^1.3 4.37+0.69 3.08+0.55
8.3+1.3 21.2 +2.1 10.4 +1.31 5.31+0.60
46.2+8.1 55.1 +6.7 40.4 +6.02 20.5 +2.64






-------
toxicity, though it  is  not  certain whether  the  word  overt re-
fers to any particularly  informative  toxicological examina-
tion.
     There are no other studies which shed  light  as  to the
chronic toxicity of  pentachlororbenzene.
     Koss and Koransky  (1977) have suggested  that a  major con-
sideration in toxicity  of pentachlorobenzene  is its  biotrans-
formation to pentachlorophenol.   Considering  that the findings
by Rozman/ et al.  (in press); cited above,  showing a half-life
of pentachlorobenzene to  be two to three  months/  and the urin-
ary excretion of pentachlorophenol to be  six  percent of the
administered dose/  it is  questionable that  over a period of  40
days a substantial  quantity of pentachlorophenol  might event-
ually be made available to  the system.
Synergism and/or Antagonism
     The interaction of QCB with  microsomal enzyme systems
might result in effects on  biotransformation  and  toxicity of
drugs and other chemicals.   However/  there  are  no available
data on  synergistic or  antagonistic effects.
Carcinogenicity/ Mutagenicity/ Teratogenicity
     There  is one  report  that alludes to  the  carcinogenicity
of  pentachlorobenzene in  mice and the absence of  this activ-
 ity in  ratd  and dogs (Preussman/  1975).   This paper  has not
been evaluated  due to difficulties  in locating the source.
When made available it  will be evaluated  as a possible basis
 for a  criterion  standard.
     Teratogenicity studies with  QCB  have been reported by
 Khera  and Villeneuve (1975). As  indicated  above/ doses of
                              C-78

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 50,  100  and  200 mg/kg  were  administered  to pregnant rats on



 day  6  to 15  of gestation.   The  authors did not  interpret these



 data to  demonstrate  the  teratogenicity of  QCB.   However, the



 EPA  feels  that suprauni  ribs  represent an  adverse  effect on



 fetal  development.   Table 3 represents findings resulting from



 Cesarean sections done on day 22  of  pregnancy.   The high dose



 of QCB produced an increased  incidence of  uni-  or  bilateral



 extra  rib, as well as  sternal defects consisting of unossified



 or nonaligned sternabrae with cartilagenous precursors



 present.   The authors  considered  that the  sternal  defects



 suggested  a  retarded sternal  development,  and that these were



 related  to a decreased mean fetal weight.   At lower doses the



 sternal  defects were not noted, but  there  was an increased



 incidence of extra ribs.  The number of  litters with one or



 more litter mates showing an  anomalous rib number  (14th  and



 15th combined), versus numbers  of litters  examined for each



 dose group, was 3/19 for 0, 14/19 for 50,  11/19 for 100, and



 15/19 for 200 mg/kg,  showing  an apparent dose-related



 incidence.



     No data have been found  concerning  the mutagenicity of



QCB.
                             C-79

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                   TABLE 3

Prenatal Data on Rats Dosed on Days 6 to 15 of
      Gestation with Pentachlorpbenzene
        (Khera and Villeneuve, 1975)

                                      Dose mg/kg

                            0        50       100
200
No. of rats pregnant at term
No. of live fetuses, mean %
fetal death
(dead + deciduoma) 100
total implants
Fetal weight, g., mean
No. of fetuses examined
for skeletal anomalies
Anomalies, type and incidence
Extra ribs:
uni
bilateral
Fused ribs:
wavy ribs
sternal defects
No. of fetuses examined
for visceral defects
Runts
Cleft Palate
Other defects
19

12.1
1.3

4.8

127


2
2

5
5

67
1


18

12.5
4.2

4.9

129


18
10

2
4

69
2
1

19 17

11.5 10.7
3.1 3.2

4.8 4.4

122 100


10 17
11 46

2
31

67 52
2

2

-------
                    CRITERION FORMULATION
Current Levels of Exposure
     Morita, et al. (1975) examined levels of QCB  in adipose
tissue samples obtained from general hospitals and medical
examiners' offices in central Tokyo.  The samples  were  from a
total of 15 people.  The group found by gas chromatography a
residual level of QCB to be in the range of 0.004  y.g/g  to
0.020 ug/g* with a mean value of 0.09 ug/g of fat.  Lunde and
Bjorseth (1977) looked at blood samples from workers with
occupational exposure to pentachlorobenzene and  found  that
their blood samples contained higher levels of this compound
than a comparable group of workers not exposed to  chloro-
benzene.
Special Groups at Risk
     At risk groups would appear to be those in  the indus-
trial setting.  There might be an expected increase in  body
burdens of QCB in individuals on diets high in fish due to
the persistence of the compound in the food chain  and  to
those on diets high in agricultural products containing QCB
as residues of PCNB spraying.
Basis and Derivation of Criterion
     A survey of the QCB literature revealed no  acute,  sub-
chronic or chronic toxicity data with the exception of  the
studies by Khera and Villeneuve (1975).  These authors  found
an adverse effect on the fetal development of embryos  exposed
in utero to pentachlorobenzene.  The adverse effect has not
been labeled teratogenic because the abnormality was  an in-
creased incidence of extra ribs and sternal defects.   The
                             C-81

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lowest level of exposure  to  the  pregnant  rat  was  5  mg/kg.
The criterion rationale  is based on  this  exposure  level.
Since there was no  "no observable adverse effect  level"
(NOAEL) an uncertainty factor  of 5000  is  used.  The use  of
this factor has precedent in the pesticide literature.
     From this, the  acceptable daily intake (ADI)  can  be
calculated as follows:
                  ADI  =                  =  0.07  mg
The average daily  consumption  of  water  was  taken  to  be 2
liters and the  consumption of  fish  to  be  0.0187 kg daily.
The bioconcentration  factor for QCB is  7800.
     Therefore:
Recommended Criterion = 2 + (7800)  x 0.0187 = °*47 ug//1 (°r~°'5 ug/D

     The  recommended  water quality  criterion  for  pentachloro-
benzene  is 0.5  ug/1.
                              C-82

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                           REFERENCES



 Ariyoshi,  T.,  et al. 1975.   Relation between chemical struc-



 ture and activity.   I.   Effects of the number of chlorine



 atoms in chlorinated benzenes on the components of drug-



 metabolizing systems and the hepatic components.  Chem.



 Pharm.  Bull. 23: 817.







 Balba,  M.H., and J.G.  Saha.  1974.   Metabolism of Lindane-14C



 by wheat plants  grown  from  treated seed.   Environ. Let.  7:



 181.







 Beck, J.,  and  K.E.  Hansen.  1974.   Degradation of quintozene,



 pentachlorobenzene,  hexachlorobenzene  and  pentachloroaniline



 in soil.   Pestic. Sci.  5: 41.








 Borzelleca,  J.F., et al.  1971.   Toxicologic  and metabolic



 studies  on pentachloronitrobenzene.  Toxicol.  Appl.



 Pharmacol. 18: 522.








 Burlingame,  A.L. 1977.  Assessment of  the  trace organic



molecular composition of  industrial  and municipal  wastewater



effluents by capillary gas chromatography/real time  high



resolution mass  spectrometry:  a preliminary  report.



Ecotoxicol. Environ. Saf. 1: 111.








Cordle,  F., et al. 1978.  Human exposure to polychlorinated



biphenyls and polybrominated biphenyls.  Environ.  Health



Perspect. 24: 157.
                             C-83

-------
Dejonckheere, W.,  et  al.  1974.   Hexachlorobenzene (HCB) and



other organochlorine  pesticide  residues  analyses in pollard



pellets, cattle  feed,  and animal feed.   Rev.  Agric. 27: 325.







Dejonckheere, W.,  et  al.  1975.   Problems  posed  by residues  in



quintozene and hexachlorobenzene in  lettuce  and witlqof cul-



tures.  Rev. Agric.  (Brussels)  28: 581.







Dejonckheere, W.,  et  al.  1976.   Residues  of  quintozene, its



contaminants and metabolites  in  soil, lettuce and witloof



chicory, Belgium,  1969-1974.  Pestic. Monitor.  Jour.  10:  68.







Engst, R., et al.  1976a.   Hexachlorocyclohexane  metabolites



in human urine.  Z. Gesamte Hyg.  Ihre. Grenzgeb.  22:  205.







Engst, R., et al.  1976b.   The metabolism of hexachlorobenzene



(HCB) in rats.  Bull.  Environ. Contain. Toxicol.  16:  248.







Engst, R., et al.  1976c.   The metabolism of Lindane  and  its



metabolites gamma-2,3,4,5,6-pentachlorocyclohexane,  penta-



chlorobenzene and  pentachlorophenol  in rats and  pathways of



Lindane metabolism.  Jour. Environ.  Sci. Health,  Part B,



Bull:  95.







Engst, R., et al.  1977.   The metabolism of Lindane  in a cul-



ture of mold and the degradation scheme of Lindane.



Chemosphere 6: 401.
                             C-84

-------
Goerz, G., et al. 1978.  Hexachlorobenzene (HCB) induced



porphyria in rats.  Effect of HCB metabolites on heme biosyn-



thesis.  Arch. Dermatol. Res. 263: 189.








Greve, P.A. 1973.  Pentachlorobenzene as a contaminant of



animal feed.  Meded. Fac. Landbouwwet Rijksuniv Gent. 38:



775.








Igarashi, H., et al. 1975.  Studies on the metabolic degrada-



tion of pentachloronitrobenzene (PCNB).  Part 3.  Photodegra-



dation of pentachlorothioanisole and pentachloronitrobenzene.



Nogaku Kagaku 3: 90.








Karapally, J.C., et al. 1973.'  Metabolism of Lindane-l4C in



the rabbit:  ether soluble urinary metabolites.  Jour. Agric.



Food Chem. 21: 811.








Kazama, M., et al. 1972.  Chemical hygiene studies on organic



halogen compounds.  I.  Transfer of chlorobenzenes into  hen



eggs.  Tokyo Toritsu Eisei Kenkyusho Kenkya Nempo 23: 93.








Khera, K.S., and D.C. Villeneuve. 1975.  Teratogenicity



studies on halogenated benzenes (pentachloro-,  pentachloro-



nitro-, and hexabromo-) in rats.  Toxicology 5: 117.








Kohli, J., et al. 1976a.  Balance of conversion of carbon-14



labeled lindanes in lettuce in hydroponic culture.   Pestic.



Biochem. Physiol. 6: 91.
                             C-85

-------
Kohli, J. , et al. 1976b.  The metabolism of  higher  chlori-



nated 'benzene isomers.  Can. Jour. Biochem.  54:  203.








Koss, G. , and W. Koransky.  1977.   Pentachlorophenol  in  dif-



ferent species of vertebrates after administratin of  hexa-



chlorobenzene and pentachlorobenzene.   In:   Pentachloro-



phenol,  (Edit:  K.R.  Rao),  Plenum  Press, New York,  p. 131.








Kujawa,  M., et al.  1977.  Environ. Pollut. Human Health,



Proc.  Int. Symp.,  1st, p.  661.








Kwiatkowski, G.T.,  et al. 1976.  Chloroaromatic  ether amines.



Jour. Poly. Sci. 14:  2649.








Lunde, G. 1976.  Persistent and  non-persistent fat  soluble



chlorinated compounds in  marine  organisms.   Nordforsk,



Miljoevardssekr., Publ.,  Org. Miljoegifter Vatten Nord. Symp.



Vattenforsk,  12th,  p. 337.








Lunde,  G.,  and  E.B. Ofstad. 1976.  Determination of  fat-



soluble  chlorinated compounds  in fish.   Z. Anal. Chem.  282:



395.








Lunde,  G.,  and  A.  Bjorseth. 1977.  Human blood samples  as  in-



dicators of occupational  exposure  to' persistent  chlorinated



hydrocarbons.   Sci. Total Environ. 8:  241.

-------
 Mathur/ S.P., and J.G. Saha. 1977.  Degradation of Lindane-



 l^c in mineral soil and in organic soil.  Bull. Environ.



 Contam. Toxicol.  17: 424.








 Mehendale/  H., et al.  1975.  Metabolism and effects of hexa-



 chlorobenzene on  hepatic microsomal enzymes in the rat.



 Jour.  Agric.  Food Chem. 23: 261.








 Morita, M.,  et al. 1975.  A systematic determination of chlor-



 inated benzenes in human adipose tissue.  Environ. Pollut. 9:



 175.








 Parke,  D.V.,  and  R.T.  Williams.  1960.   Studies in detoxifica-



 tion LXXXI.   Metabolism of halobenzenes:  (a)  Penta- and



 hexachlorobenzene:  (b)   Further observations  of 1,3,5 tri-



 chlorobenzene.  Biochem. Jour..74:  1.








 Preussmann. R.  1975.   Chemical  carcinogens  in  the human en-



 vironment.  Hand.  Allg.  Pathol.  6:  421.








 Rautapaa, J.,  et  al. 1977.   Quintozene in some soils and



 plants  in Finland.   Ann. Agric.  Fenn.  16: 277.








 Rozman, K., et  al. 1977.   Longterm  feeding  study of hexa-



 chlorobenzene  in  rhesus monkeys.  Chemosphere  6:  81.








 Rozman, K., et  al. 1978.   Chronic low  dose  exposure of rhesus



monkeys to hexachlorobenzene.  Chemosphere  7:  177.
                             C-87

-------
Tu, C.M. 1976.  Utilization and degradation of Lindane by



soil microorganisms.  Arch. Microbiol.  108: 259.








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.








Villeneuve, D.C., and K.S. Khera. 1975.  Placental  transfer



of halogenated benzenes (pentachloro-, pentachloronitro-, and



hexabromo-) in rats.  Environ. Physiol. Biochem.  5:  328.







Yang, R.S.H., et al. 1975.  Chromatographic methods for  the



analysis of hexachlorobenzene and possible metabolites  in



monkey fecal samples.  Jour. Assoc. Off. Anal. Chem. 56:



1197.








Yang, R.S.H., et al. 1978.  Pharmacokinetics and  metabolism



of hexachlorobenzene in the rat.  Jour.  Agric.  Food Chem.



26: 1076.
                             C-89

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 systems far removed  from the original area of application.



 HCB's  impact on  agriculture  as  a  result of environmental con-



 tamination  may be  much  larger than its utility as a fungicide



 to  control  smut  diseases in  cereal grains.  Foodstuffs such



 as  eggs,  milk, and meat become  contaminated with HCB as a re-



 sult of ingestion  of  HCB-treated  cereals by livestock.



     Commercial  production of HCB in the United States was



 discontinued in  1976  (Chem.  Econ.  Hdbk., 1977).  However,



 even prior  to  1976, most HCB was  produced as a waste by-



 product during the manufacture  of perchloroethylene, carbon



 tetrachloride, trichloroethylene  and other chlorinated hydro-



 carbons.  (This  is still  the major source of HCB in the U.S.)



 In  1972,  an  estimated 2.2 x  106 kg of HCB were produced



 from these  industrial processes (Mumma and Lawless, 1975).



 Its generation as  a by-product  remains unabated.  HCB found



 in  Louisiana was apparently  related  to airborne industrial



 emissions, while residues in sheep from Texas and California



 were traced  to pesticide contaminated with HCB.  Until re-



 cently, HCB  was a  major  impurity  in  the herbicide dimethyl



 tetrachloroterephthalate and  the  fungicide pentachloronitro-



 benzene.  HCB has  been  found  in polyethylene plastic bottles



 from one source (Rourke, et  al. 1977).   HCB  is used in in-



dustry as a plasticizer  for  polyvinyl chloride as well as a



flame retardant.
                             C-91

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bodies of fresh water in cne world.  The total population



density around the lake is low and the concentrations of



trace elements have remained relatively small compared to



those in other Great Lakes (Veith, et al. 1977).  HCB was



detected in drinking water supplies at three locations, with



concentrations ranging from 6 to 10 ng/kg..  HCB was detected



in finished drinking water at two locations, with concentra-



tions ranging from 4 to 6 ng/kg (U.S. EPA, 1975).



     HCB has considerable potential to bioaccumulate  in the



aquatic environment and is very persistent.  The combination



of these two attributes makes HCB a potentially hazardous



compound in the environment.  Soil contaminated with  HCB



would retain HCB for many years.  If contaminated soil  finds



its way into the aquatic environment, it will become  avail-



able to aquatic organisms.



     HCB enters the environment in the waste streams  from  the



manufacture of chlorinated,hydrocarbons and from  its  agricul-



tural use as a preemergence fungicide for small grains.  HCB



becomes redistributed throughout the environment as a conse-



quence of its leaching from industrial waste dumps  and  its



volatilization from industrial sources and contaminated  im-



poundments.  HCB absorbed to soil may be transported  long



distances in streams and rivers.  HCB is now distributed



throughout the world.  The solubility of HCB in water is  low,



however, and its concentration in water rarely exceeds  2



ug/kg.



     HCB is sufficently volatile so that one air  drying of



moist soil or biological samples causes a 10 to  20  percent






                             C-93

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loss of HCB  (vapor pressure  1.089xlO""5 mm Hg at 20°C).  The

half-life of HCB  in  soil  (incorporated at 10 kg/ha) stored in

plastic-covered plastic pots is  about  4.2 years (Beck and

Hansen, 1976).  HCB  is not lost  from soil two to four cm be-

neath the surface during  19  months,  but 55 percent is lost

from the surface  two cm of soil  within two weeks (Beall,

1976).  Clearly/  volatilization  is  a significant factor in

the loss of  HCB from soil and  for its  entry into the atmos-

phere.  No HCB  is lost  from  soil treated with 0.1 to 100

mg/kg of HCB and  stored under  aerobic  (sterile and non-

sterile) and anaerobic  nonsterile conditions for one year in

covered containers to retard volatilization (Isensee, et-al.

1976).  Degradation  products of  HCB  have not been found in

plants and soil.  Hexachlorobenzene  is relatively resistant

to photochemical  degradation in  water.  Photolysis of HCB oc-

curs slowly  in  methanol,  62  percent  being degraded in 15

days.  It  is not  known  whether organic matter in natural

waters or  natural photosensitizers  in  the environment can en-

hance  the  rate  of degradation  of HCB (Plimmer and Klingebiel,

1976).  HCB  may be even more stable  than DDT or dieldrin in

the environment (Freitag, et al. 1974).  HCB has been singled

out as the only organic chemical contaminant present in the

ocean  at  levels likely  to cause  serious problems (Natl. Acad.

Sci. 1975).

     HCB,  adsorbed  to soil or  sand,  is released into water

and taken  up by aquatic organisms such as algae, snails,

daphnids  (Isensee,  et al. 1976), and fish (Zitko and Hut-

zinger,  1976).   The  alga  Chara,  collected from the lower

Mississippi  River (Louisiana)  contained 563 ug/kg wet weight.
                              C-94

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 An undefined planKtor.  ... jIf* cont ;                        . a,



 et al.  1976).



      The aquatic plants Najas and Ellocharis contained 147 ug



 HCB/kg  and 423  ug HCB/kg wet weight  respectively (Laseter, et



 al.  1976).  Three aquatic invertebrate genera:   snail Physa,



 crayfish Procambarus  and dragonfly larvae Anisoptera, also



 collected from  the lower Mississippi River, contained 294



 ug/kg,  48.67 ug/g and 4.7  ug/g respectively (Laseter, et al.



 1976).   The HCB levels in  inland  fish from the  United States



 ranged  from "none detected"  to 62 mg HCB/kg.  The high mean



 level of HCB in carp  (16 mg/kg) was  attributed  to runoff from



 an industrial chemical storage area.   The mean  HCB concentra-



 tion  in  seven other  inland  fish ranged from <1  to 130 ug/kg



 (Johnson,  et al.  1974).   The HCB  level in fish  collected from



 the contaminated  lower Mississippi River ranged from 3.3 to



 82.9 mg/kg  for  fish.   The HCB levels  in  mosquitofish col-



 lected some  distance  from the site of the HCB  industrial



 source on  the lower Mississippi River ranged from 71.8 to



 379.8 ug/kg, about 100-fold  lower than the HCB  content in



 fish near  the site of  industrial  contamination  (Laseter, et



 al. 1976).



     Marine  invertebrates collected  from the central North



 Sea contained substantially  less  HCB  than invertebrates  from



 the central  contaminated lower Mississippi River  (Schaefer,



 et al. 1976).   Residues of HCB were determined  in 104 samples



of marine organisms collected  at  various  sites  off  the At-



lantic Coast of  Canada during  1971 and 1972.  The results
                             C-95

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 indicated  a  widespread,  low-level distribution of HCB (<1 to



 20 ug HCB/kg).   The  highest levels of HCB were in fatty sam-



 ples  (1  ug/kg  in whole cod vs 39 ug/kg in cod liver; none



 detected in  whole lobster vs 54  ug/kg in lobster hepatopan-



 creas).  Herring contained the greatest whole body burden of



 HCB  (20  ug/kg)  (Sims,  et al. 1977).   The HCB levels in marine



 fish from  the  central  North Sea  ranged from 0.2 to 2.9 ug/kg



 for muscle and  from  2.9  to 10 ug/kg  for liver.   The organ



 concentrations  of HCB  increased  with increasing lipid content



 of the organ (Schaefer,  et al. 1976).



     HCB has been detected in a  number of water and land



 birds.   Carcasses of immature ducks  contained HCB ranging



 from >60 to  240  ugAg  (White and Kaiser,  1976).   The HCB



 levels ranged  from 110 to 500 ug/kg  in carcasses  of 4 of 37



 bald eagles  (Cromartie,  et al. 1975).   The HCB  levels in the



 eggs of  the  common tern  Sterna ranged  from 1.35  to 14.7  mg/kg



 dry weight (Gilbertson and Reynolds,  1972).   Eggs of double-



 crested  cormorants Phalacrocorax from  the  Bay of  Fundy were



monitored  from 1973 to 1975.  The  eggs contained  15  to 17  ug



HCB/kg wet weight (Zitko,  1976).



     Foxes and wild boars,  which feed  on  small  animals such



 as mice and  invertebrates,  accumulated large  amounts  of  HCB.



Because predators and scavengers contain  higher residues of



HCB than herbivores, it  would seem that bioaccumulation



through  the  food  chain is  occurring  (Koss  and Manz,  1976).



Ingestion from Foods



     Ingestion of  excessive  amounts of HCB has been  a con-



sequence of  carelessness,  lack of concern, and ignorance.






                              C-96

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There is a tendency to dispose of excess wheat seed by feed-



ing it to stock without due recognition of the toxic proper-



ties of the compounds concerned.  In the mid-1960's, a ship-



ment of Australian powdered eggs was rejected for importation



into the United States by the Food and Drug Administration on



the grounds of contamination with HCB.  The New South Wales



Egg Marketing Board tests samples of eggs that it handles and



will not accept for distribution any eggs which contain sig-



nificant amounts of HCB.



     Food materials were collected at retail and  department



stores in Tokyo, Japan, and were weighed out in the amounts



consumed a day.  The food materials were classified into  four



categories:  cereals, vegetal products  (vegetables, vegetal



oils, seasoning and seaweed), marine animal products,  and



terrestrial animal products including dairy products and



eggs.  The dietary intake of HCB ranged from 0.3  ug/day to



0.8 ug/day.  Contributions from cereals were low  (<0.05



ug/day).  The contribution from vegetal products  ranged from



<0.05 ug/day to 0.4 ug/day; that for marine animal products



from <0.05 ug/day to 0.3 ug/day; and that for terrestrial



animal products from 0.3 ug/day to 0.4 ug/day (Ushio and



Doguchi, 1977).



     Herds of cattle in Louisiana were  condemned  by the State



Department of Agriculture in 1972 for .excessive HCB residues,



that is, they exceeded 0.3 mg HCB/kg in fat.  Levels as high



as 1.52 mg HCB/kg. were reported.  Of 555 animals  tested among



157 herds, 29 percent of the cattle sampled contained  <0.5  mg



HCB/kg in fat.  HCB residues apparently did not arise  from





                             C-97

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agricultural application  of HCB  fungicide  but  from contamina-

tion of air, soil and grass by industrial  sources  (U.S.  EPA,

1976).  In a total diet study conducted  in Italy  between 1969

and 1974, the average intake was  estimated to  be  4.2  ug

(Leoni and D'Arca, 1976).   In an  effort  to reduce  the amount

of HCB entering the environment,  the  Federal Republic of Ger-

many no longer allows application of  HCB-containing pesti-

cides  (Geike and Parashar,  1976a).  The  New South  Wales

Department of Health  (Australia)  has  recommended  that the

concentration of HCB  in eggs must not exceed 0.1 mg/kg

(Siyali, 1973).  The NHMRC  (Australia) has set the tolerance

for cows' milk at 0.3 mg  HCB/kg  in  fat (Miller and Fox,

1973).  The Louisiana Department  of Agriculture has set  the

tolerance for meat at 0.3 mg HCB/kg in fat (U.S. EPA, 1976).

     There is a substantial body  of information on HCB levels

in human milk for a number  of countries.   In the United

States, human milk contained a mean concentration  of  78  ppb

(Savage, 1976).  Milk from  45 women living in  a metropolitan
                                    v
area  (Sydney, Australia)  was found  to contain  HCB.  The  mean

HCB concentration in  human  milk was 15.6 ug/kg, and seven

percent of the samples  contained  51 to 100 ug  HCB/kg. In ad-

dition, 49 human milk samples from France  and  50 from the

Netherlands contained HCB,  but no values were  reported.   Hu-

man milk samples from Germany contained  153 ug HCB/kg of

whole  milk and those  from Sweden  1 ug/kg  (Siyali,  1973).  HCB

was also detected .in  all  of 40 human  milk  samples  from Bris-

bane,  Australia, and  a  rural area (Mareeba on  the  Atherton

Tablelands).  The excretion of HCB into  human  milk was higher


                             C-98

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Hexachlorobenzene Content of Food (u.g HCB/kg)
             (Italy:  1969 - 1974)
       Food

 Bread                        1.1            n.d.
 Noodles                      0.7            0.2
 Maize flour
 Rice                         0.8            0.3
 Preserved legumes            1.1            n.d.
 Dry legumes                  2.4            0.2
 Fresh legumes
 Fresh vegetables             0.5            n.d.
   and artichokes
 Tomatoes
 Potatoes
 Onions                       0.6            0.6
 Carrots and other
   root vegetables
 Fresh fruit
 Dried fruit
 Exotic fruit
 Citrus fruit
 Bovine meat

 Mutton,  game
   and rabbits
 Giblets

 Pork meat

 Chicken

 Eggs
 Fresh fish
 Preserved fish
 Whole milk
 Butter
 Cheese

 Olive  oil
 Seed  oil
 Lard

Wine                          0.1             n.d.
 Beer
 Sugar                         0.2             n.d.
Coffee

Values in parentheses are for extracted  fat.
 (a)n.d. — not detected
Adapted from  Leoni and D'Arca, 1976.
 Mean

   1.1
   0.7
   n.d.
   0.8
   1.1
   2.4
   n.d.
   0.5

   n.d.
   n.d.
   0.6
   n.d.

   n.d.
   n.d.
   n.d.
   n.d.
   0.7
(33.6)
   1.0
(25.4)
   0.7
(27.0)
 25.0
(96.3)
   5.7
(49.0)
  4.7
  0.7
  n.d.
  4.1
133.0
 12.6
(63.0)
 13.1
  4.7
 46.2
 63.4
  0.1
  n.d.
  0.2
  n.d.
                                          Range
                                                2.9
                                                2.9

                                                1.1
                                                3.1
                                                5.1

                                                1.8
                                                0.6
n.d .

n.d.

n.d.

9.1
(74.3)
n.d.

1.7
n.d.
0.2
n.d.

n.d.
n.d.
1.4
- (78.4)
2.6
- (51.3)
1.3
- (53.9)
- 40.9
-(118.3)
- 11.5
- (75.0)
7.5
1.8
- 17.2
- 25.1
-(126.0)
- 53.8
- 27.9
                                                0.6

                                                0.6
                      C-99

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 in  Brisbane  samples than in Mareeba samples (2.22 versus 1.23



 mg  HCB/kg  in milk fat).  The higher levels of HCB in Brisbane



 donors  may be related to the close proximity to a major grain



 growing  area,  the Darling Downs.   The daily intake of HCB by



 infants  was  estimated to be 39.5  ug per day per 4 kg baby in



 Brisbane and 14  ug per day per 4  kg baby in Mareeba.  The



 calculated average daily intake of HCB by breast-fed babies



 in  both  areas  exceeded the acceptable daily intakes  recom-



 mended  by  the  FAO/WHO (1974)  (2.4 ug/kg/day).   The HCB con-



 tent of  human  milk also exceeded  the Australian NHMRC toler-



 ance for cows' milk (0.3 mg/kg in milk fat).   The dietary in-



 take by young  adults  (15-to-18-year old males)  was estimated



 to  be 35 ug  HCB  per person per day (Miller and  Fox,  1973).



 Similarly, HCB was found in all of 50 samples of  human breast



milk collected in Norway.   The mean HCB level was 9.7 ug/kg,



with a maximum value  of 60.5  ug/kg.   The HCB  content of  colo-



 strum (7.7 ug/kg)  was within  the  range of that  for milk  1  to



 16 weeks after birth  (5.9  to  10.0  ug/kg).   The  HCB content  of



 the human  milk samples in  this survey exceeded  the maximum



concentration for cows'  milk  approved  by FAO/WHO  (20  ug/kg).



The milk sample  with  the highest  HCB  level  exceeded  this



standard by  threefold  (Bakken  and  Seip,  1976).



     A bioconcentration factor (BCF)  relates the  concentra-



 tion of a chemical  in  water to the  concentration  in  aquatic



organisms, but BCF's  are not  available  for  the  edible por-



tions of all four  major  groups  of  aquatic organisms  consumed



 in the United States.   Since  data  indicate  that the  BCF for



lipid-soluble compounds  is proportional  to  percent lipids,

-------
BCF's can be adjusted to edible portions using data on per-

cent lipids and the amounts of various species consumed by

Americans.  A recent survey on fish and shellfish consumption

in the United States (Cordle, et al. 1978) found that the per

capita consumption is 18.7 g/day.  From the data on the nine-

teen major species identified in the survey and data on the

fat content of the edible portion of these species  (Sidwell,

et al. 1974), the relative consumption of the four major

groups and the weighted average percent lipids for each group

can be calculated:

                              Consumption    Weighted Average
        Group                  (Percent)      Percent Lipids

Freshwater fishes                 12                4.8

Saltwater fishes                  61                2.3

Saltwater molluscs            "9                1.2

Saltwater decapods                18                1.2

Using the percentages for consumption and lipids for each of

these groups, the weighted average percent lipids  is 2.3 for

consumed fish and shellfish.

     No measured steady-state bioconcentration factor  (BCF)

is available for hexachlorobenzene but  the equation "Log BCF

= 0.76 Log P - 0.23" can be used (Veith, et al., Manuscript)

to estimate the BCF for aquatic organisms that contain  about

eight percent lipids from the octanol- water partition  coef-

ficient (P).  An adjustment factor of 2.3/8.0 = 0.2875  can  be

used to adjust the estimated BCF from the 8.0 percent  lipids
                               C-101

-------
m  which the equation is based to  the  2.3 percent  lipids that
      •*-.
•s  the weighted average for consumed fish and  shellfish.

'hus,  the weighted average bioconcentration  factor for the

;dible portion of all aquatic organisms  consumed by Americans

:an be calculated:
:ompound                          P          :BCF      Weighted
	'	        BCF

iexachlorobenzene             2,450,000     42,000     12,000
 nhalation and Dermal

     HCB enters the air by various mechanisms  such  as  release

 rom stacks and vents of  industrial plants,  volatilization

 rom waste dumps and  impoundments, intentional spraying and

 usting, and unintentional dispersion of HCB-laden  dust from

 anufacturing sites, during  transport of finished material or

 astes, and by wind from  sites where HCB has been applied.

 •lasma HCB levels in a sample of  86 individuals living in

 ouisiana adjacent to a plant producing chlorinated

 ut not occupationally exposed, averaged 3.6 up^>/  with a

 aximum of 23 ug/kg.  Plasma HCB  concentr^xi^'s were higher
                                      &~
 n males than in females  (4.71 ug/kg compared  with  2.79

 g/kg, respectively), but there was no  significant  difference
                                                    _  r-t;   f*
 etween age groups^ ... The re was no evidenc^^aJE--cutajno^j^    —

                     ^"•^ -- <^~~^L-^m'g*~w\*hhi$c\ plasma con-
 :entrations of HCB  showed  elevated  coproporphyrin and lactic

 lehydrogenase levels.   Only  two  of  48  household  meals sampled
                               C-102

-------
 contained significant quantities of nCii, L -: _.ie,.» ,4^^



 correlation between concentration in plasma and the concen-



 tration of HCB in household dust.  Some household dust con-



 tained as much as 3.0 mg/kg.   Affected households were on the



 route of a truck which regularly conveyed residues containing



 HCB  from a factory to a dump.   Workers in the adjacent plant



 engaged in manufacturing carbon tetrachloride and perchloro-



 ethylene had  plasma HCB concentrations from 14 to 233 ug/kg



 (Burns and Miller,  1975).



      Pest control operators in their day-to-day work handle a



 variety of toxic chemicals, including chlorinated hydrocarbon



 pesticides.   Pesticide may enter the body by inhalation of



 spray mist which exists in confined spaces.   The levels of



 HCB  in blood  of  pest control  operators in New South Wales/



 Australia,  were  found  to be elevated in a 1970-71 study (1 to



 226  ug/kg).   The pest  control  operators seldom used respira-



 tors,  and  those  in  use appeared to  be ineffective due to poor



 service  maintenance.   It is essential that the respirator



 cartridges  be  changed  regularly.  The respiratory exposure



 values  were many-fold  higher  than the acceptable daily intake



 as applied  to  food  by  WHO  (0.1  ug/kg/day or  7 ug/day intake



 for  a  70 kg man)  (Simpson  and  Shandar,  1972).



     HCB may enter  the  body by  absorption through the intact



 skin as  a  result  of  skin contamination.   Workers involved in



 the application  or manufacture  of HCB-containing products are



at greater  risk.



     HCB enters  the  body as a  result of  ingestion and presum-



ably by  inhalation and  absorption through the skin.   HCB re-
                             C-103

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 mains  in  the  blood  for only a short period before it is trans-

 located to  fatty  tissues  or is  excreted.   HCB blood levels

 reflect either  recent  exposure  or  mobilization of HCB from

 body fat depots.  HCB  finds its  way into  air,  water and food

 as a result of  unintentional  escape from  industrial si^es,'

 intended application of HCB containing  prod-acts,  volatiliza-

 tion from waste disposal  sites  and  impoundments  and uninten-

 tional dispersion during  transport" and  storage.   The result

 has been the  worldwide dissemination  of HCB  and  ubiquity in

 man's food, at  least in low
      All blood samp^fr^taken  from  children  (1  to  18  years

 old) in upper B^^ia  in 1975 contained HCB  at  2.6 to  77.9

 ug/kg.  The^study included 90 males and 96  females.  HCB
         /•'
 levels in blood showed a positive, hyperbolic  correlation

 with age, tending to an uper limit of 22 ug/kg for  boys and

                                  increase, in HCB  concentra-

          inversely proportioria
JSJ*'-
 stantial accumulation of HCB became evident nine to ten

 months after birth (Richter and Schmid, 1976).  HCB was found

 in all of a series of human fat samples collected from au-

 topsy material throughout Germany.  The highest levels of HCB

 were in specimens from Munster (22 mg HCB/kg in fat) and

Munich (21 mg HCB/kg in fat) (Acker and Schulte, 1974).  The

 presence of HCB in Japanese autopsy adipose tissue^ was"~dej:er-,

 mined for a total of 241 samples from Aichi Cancer Center

 Research Institute, Chikusa-Ka Nagoya, Japan.  The concentra-

 tion of HCB in these fat samples was 90 ug/kg + 6 ug/kg stan-

 dard -error (Curley, et al. 1973).
                              C-104

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     HCB was found in all of 75 specimens of Australian human



body fat (1.25 mg/kg).  Perirenal fat was taken at autopsy



from a random selection of bodies at the City Morgue, Sydney,



Australia.   All ages and both sexes were included  in the



study (Brady and Siyali, 1972).  The incidence  (63 percent of



samples tested) and concentration of HCB (0.26 mg/kg) in 38



specimens of human body fat from Papua and New Guinea were



lower than the Australian values.  The concentration of HCB



in whole blood of 185 people who had some occupational expo-



sure to organochlorine compounds in their working  conditions



and of 52 who had no known exposure was determined.  None of



the subjects displayed apparent signs of intoxication.  Over



95 percent of the subjects had HCB in their blood.  The HCB



blood level in the exposed population was 55.5  ug/kg, with



nine percent having more than 100 ug/kg.  The HCB  blood level



in the population with no known exposure was 22 ug/kg, with



none having as much as 100 ug/kg.  Levels of 50 to 100 ug/kg



whole blood indicate either recent exposure over and above



that normally assimilated from the environment  or  the mobili-



zation of fat depots associated with a loss in  total body



weight.  The mean HCB level in 81 samples of human body  fat



was 1.31 mg/kg, with a maximum of 8.2 mg/kg.  All  81 human



fat samples contained HCB (Siyali, 1972).



     The HCB levels in adipose tissue of Canadians,  col-



lected in 1972 by Burns and Miller (1975), were determined.



The regional distribution of the samples was as follows:   16



from the eastern region (Newfoundland, Prince Edward  Island,



Nova Scotia and New Brunswick), 50 from Quebec, 57 from





                             0105

-------
Ontario, 22 from  the  central  region  (Manitoba and Saskatche-



wan) and 27 from  the  western  region  (Alberta  and British



Columbia).  All of  the  adipose  samples  contained HCB,  with an



overall mean value  of 62  ug/kg.   HCB values were lowest in



the samples from  the  eastern  (25  ug/kg)  and central (15



ug/kg) regions and  highest  in Quebec (107  ug/kg).  The



Ontario samples averaged  60 ug  HCB/kg and  those from the



western region 43 ug/kg.  The HCB content  of  adipose tissue



from females (82  ug/kg) was greater  than that for males (52



ug/kg).  The HCB  content  of human adipose  tissue did not show



an age-related trend:  0  to 25  years, 76 ug/kg; 26 to 50



years, 45 ug/kg;  and  51+  years,  70 ug/kg (Mes,  et al.  1977).



In the study of Richter and Schmid,  the'age-related accumula- .



tion of HCB was marked  only for  the  first  five  years of life



(Richter and Schmid,  1976).  Plasma  HCB levels  in a Louisiana



population exposed  through  the  transport and  disposal  of



chemical waste containing HCB averaged  3.6 ug/kg in a study



of 86 subjects.   The  highest  level was  345 ug/kg in a  sample



from a waste disposal worker, while  the highest level  in a



sample from a member  of the general  population  was 23  ug/kg



 (Burns and Miller,  1975).



                        PHARMACOKINETICS



Absorption



      To  date,  only  absorption of HCB from the gut has been



 examined  in  detail.  Fish fed HCB-contaminated  food take up



 the  material  in  a reasonably  direct  relationship to the con-



 centration in  the food (Sanborn,  et  al. 1977).   Intestinal



 absorption of  HCB from an aqueous suspension  was poor in both

-------
 rabbits (Parke and Williams,  1960)  and rats (Koss and



 Koransky,  1975).   The amount  of HCB left in the intestinal



 contents 24 hours after administration was small.  Intestinal



 absorption of HCB by rats was substantial when the chemical



 was given  in cotton seed oil  (Albro and Thomas, 1974) or



 olive  oil  (Koss  and Koransky, 1975).   Between 70 percent and



 80  percent of doses of HCB ranging  from 12 mg/kg to 180 mg/kg



 were absorbed.   The fact that HCB is  well absorbed when dis-



 solved in  oil is  of particular relevance for man.  HCB in



 food products will selectively partition into the lipid por-



 tion,  and  HCB in  lipids will  be absorbed far better than that



 in  an  aqueous milieu.   This  is consistent with the observa-



 tion that  the highest HCB levels ever observed have been in



 tissues  of  carnivorous  animals (Acker and Schulte, 1971;



 Koeman,  1972).  HCB is  readily absorbed from the abdominal



 cavity after  intraperitoneal  injection of the  chemical dis-



 solved in  oil.



     Data  of  toxicological experiments should  take into ac-



 count  how HCB was  administered.   Relatively little HCB was



 absorbed by  the walls  of  the  stomach  and duodenum of rats one



 hour after oral administration  of HCB suspended in aqueous



 methylcellulose.   After  three  hours,  the ingested HCB reached



 the jejunum and ileum,  resulting  in increasing concentrations



 in  the walls  of these parts of  the  intestine.   Liver and kid-



 ney contained some  HCB; however,  the  concentrations  in lymph



 nodes  and adipose  tissue  were  much higher.   During the re-



maining 45 hours,  the concentrations  in  liver  and  kidney de-



creased, whereas those  in lymph  nodes and adipose  tissue re-
                             C-107

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mained  relatively constant or rose slightly. . Formal venous



transport  to  the  liver seemed to be a minor pathway because,



in spite of  its  slow metabolism, HCB never achieved high con-



centrations  in the liver.   The majority of the ingested HCB



was absorbed  by  the lymphatic system in the region of the



duodenum and  jejuno-ileum,  and deposited in fat,  bypassing



the systemic  circulation and excretory organs.  There1appears



to be an equilibrium between lymph nodes and fat  (latropoulos,



et al.  1975) .



Distribution



     It is well known that  HCB has a low solubility in  water



(6 y.g/kg)  (Lu and Metcalf,  1975) and a high solubility  in fat



(calculated log partition  coefficient in octanol/H2O=6.43).



Accordingly,  the  highest concentrations  of HCB are in  fat



tissue  (Lu and Metcalf,  1975).   The concentration  of HCB in



fish fed contaminated food  (100  mg/kg)  for three days was



4.99 mg/kg in liver and  1.53 mg/kg in muscle (Sanborn,  et al.



1977).  The concentration of HCB in Japanese quail  fed  con-



taminated food (5  mg/kg) for 90  days was  6.88  mg HCB/kg  in



liver and 0.99 mg/kg  in  brain of female  birds  and  8.56 mg/kg



in liver and  1.44  mg/kg  in  brain of male  birds (Vos, et  al.



1971).  As noted  above,  HCB  accumulated  in  fatty tissues.



After prolonged feeding  of  a constant'level  of HCB,  the  con-



centration of compound in the  fat  of  laying  hens reached  a



plateau.  This indicates that  an equilibrium between uptake



and excretion can  be  achieved.   This  phenomenon allows one to



calculate the ratio of the  concentration  of  HCB in  fat to the



concentration in  the  feed.   This  accumulation  or storage




                              C-108

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ratio apparently is independent of HCB concentration in the



feed over a wide range.  The accumulation ratio for HCB in



laying hens is about 20 (Kan and Tuinstra, 1976).



     The distribution of HCB in rat tissues was similar for



animals given a single oral dose or a single  intraperitoneal



injection of HCB dissolved in olive oil.  Adipose  tissue con-



tained about 120-fold, liver, 4-fold; brain,  2.5-fold; and



kidney, 1.5-fold more HCB than muscle.  The HCB content of



adrenals, ovaries and the Harderian gland was  essentially  the



same as skin whereas that for heart, lungs, and intestinal



wall corresponded to the level in liver.  The  thymus content



was similar to that of brain (Koss and Koransky,  1975).



     The distribution of HCB in mice fed a diet containing



167 mg HCB/kg was determined after three and  six  weeks.  The



HCB level in the serum was 23 mg/kg after three weeks  and  12



mg/kg after six weeks; for liver, 68.9 mg/kg  after three



weeks and 56 mg/kg at six weeks; for spleen,  20.9 mg/kg at



three weeks and 47 mg/kg at six weeks; for lung,  85.1  mg/kg



at three weeks and 269 mg/kg at six weeks; and for the



thymus, 48.6 mg/kg at three weeks and 152 mg/kg at six weeks.



The only histological alterations seen in tissues of mice  fed



HCB for six weeks was a centrilobular and pericentral  hepatic



parenchymal cell hypertrophy; hepatic Kupffer cells appeared



normal in number and morphology (Loose, et al. 1978).



     Adipose tissue serves as a reservoir for HCB, and deple-



tion of fat depots results in mobilization and redistribution



of stored pesticide.  For example, food restriction caused



mobilization of HCB stored within the fat depots  of rats  that





                             C-109

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had been fed HCB-contaminated  food  for 14 days.   Although HCB



was redistributed  into  the  plasma and  other tissues of the



body, food restriction  did  not increase the excretion of HCB,



therefore the  total  body  burden  was not reduced.  • Rats re-



ceiving 100 mg HCB/kg/day orally for 14 days developed trem-



ors, lost appetite and  some died during subsequent food re-



striction.  Weight loss from whatever  cause results in redis-



tribution of HCB contained  in  adipose  tissue,  and if the



initial level  of the pesticide is sufficiently high, toxic



manifestations may develop  (Villeneuve, 1975).



Metabolism



     Although  HCB  appears to be  relatively stable in the



soil, it is metabolized by  a variety of animal species.



About half of  HCB  taken into the body  of fish  fed contami-



nated food is  converted into pentachlorophenol (Sanborn, et



al. 1977).  The  rabbit  does not  appear to oxidize HCB to



pentachlorophenol  (Kohli, et al. 1976).  In rats  given HCB



intraperitoneally  on two or three occasions (total dose 260



to  390 mg HCB/kg), pentachlorophenol,  tetrachlorohydroquinone



and pentachlorothiophenol were the  major metabolites in



urine.  More  than  90 percent of  the radiolabeled  HCB material



in  the urine  had been metabolized whereas only 30 percent of



the starting  radiolabeled HCB  material in the  feces was



metabolized.   Of the HCB administered  intraperitoneally, 65



percent was  in the animal body (almost all as  HCB), 6.5 per-



cent was excreted  in the urine (mostly as metabolites)  and



27.2 percent  was excreted in the feces (about  70  percent as



HCB).  The metabolites  in feces  were (in decreasing order)





                             C-110

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 pentachlorophenol >



 substance (Kpss,  et al. 1976).



      In organs of rats given 8  mg/HCB/kg dissolved in sun-



 flower oil by gavage,  only HCB, pentachlorobenzene and penta-



 chlorophenol could be  identified.   The metabolites were pres-



 ent in small concentrations.  The  HCB level in fat was 83



 mg/kg, in muscle-17 mg/kg; in liver-125 ug total; in kidneys-



 21  ug each;  in spleen-9 ug total;  in heart-1.5 ug total and



 in  adrenals-0.5 ug each.   In urine,  the main metabolites of



 orally administered HCB were pentachlorophenol,  tetrachloro-



 phenol,  trichlorophenol and pentachlorobenzene.   Small



 amounts  of trichlorophenol and  tetrachlorophenol were present



 as  glucuronide conjugates.  The feces contained  a little



 pentachlorobenzene,  but mostly  the  parent HCB (Engst, et al.



 1976) .



      HCB  in  corn  oil given orally  to rats at a dose of 20



 mg/kg  for  14  days  caused  an elevation of the levels of cyto-



 chrome P-450  and  NADPH-cytochrome  c  reductase activity.  HCB



 appears  to be  an  inducer  of the hepatic microsomal system



 of  the phenobarbital type (Carlson,  1978).   In a separate



 study, the cytochrome  P-450 level was elevated in rats



 (Porton strain) fed  HCB mixed into  the diet (dose about 19



 mg/kg) for 14 days,  but not in  rats  (Agus strain) fed HCB-



 containing food for  90 days.  In both HCB-exposed groups,



 benzo(a)pyrene hydroxylation activity was elevated,  but



 aminopyrine N-demethylation activity was not significantly



 enhanced.  It has been proposed  that HCB is  an inducer of



hepatic microsomal enzyme  activity having properties  of both






                             C-lll

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 the  phenobarbital type and the 3-methylcholanthrene type



 (Stonard,  1975;  Stonard and Greig, 1976).  Although HCB is a



 well-documented  inducer of hepatic microsomal enzyme activ-



 ity,  the hexobarbital sleeping times of rats fed 2000 mg



 HCB/kg/day for 14 days were the same as unexposed control



 rats.   The duration of hexobarbital-induced sleep decreased



 14 days after eliminating HCB from the diet.  In rats fed 500



 mg HCB/kg/day for 14 days,  hepatic glucose-6-phosphatase
            "1


 activity was  decreased and  serum isocitrate dehydrogenase



 activity remained undetectable.   In rats fed 10 mg HCB/kg/day



 for  14  days,  the  liver was  enlarged;  the cytochrome P-450



 level,  detoxification of  EPN  (O-ethyl O-p-nitrophenyl  phenyl-



 phosphonothioate) ,  benzpyrene hydroxylase activity and azore-



 ductase activity  were increased  whereas cytochrome c reduc-



 tase and glucuronyl  transferase  activities were unaltered.



 Excretion



     As described  in earlier  sections,  HCB is  excreted mainly



 in the  feces  and  to  some  extent  in the  urine  in  the  form of



 several metabolites  that  are  more  polar than  the parent  HCB.



 Usually a  plateau  is reached  in most  tissues when the  dose  is



 held relatively constant.   If  the  exposure increases,  how-



ever, the  body concentrations  will  increase, and  vice  versa.



     Fish  fed HCB contaminated food  (100 mg/kg)  for  three



days have  relatively high levels of HCB  and pentachlorophenol



 in their stomach  (27.16 mg/kg  and  19.14 mg/kg,  respectively)



and intestine  (26.82  mg/kg  and'15.94 mg/kg, respectively) on



 the fourth day.  The  half-life of  HCB in  the stomach,  intes-



 tine and muscle was  8  to  8.5 days,  that for the  carcass  10






                              C-112

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days and that for the liver 19.6 days.  During the  initial



elimination period, the clearance of HCB in the  intestine and



muscle lagged behind that for the stomach and liver, and may



indicate biliary excretion with enterohepatic recirculation



(Sanborn, et al. 1977).  Biliary excretion and enterohepatic



recirculation of HCB have been described in dogs  (Sundlof, et



al. 1976).



     HCB accumulates in the eggs of laying hens  fed  contami-



nated food.  The accumulation ratio (level of HCB  in whole



egg/level in the feed) was 1.3.  The actual HCB  concentration



in eggs was 20 ug/kg for hens fed 10 ug HCB/kg of  feed  and



140 ug/kg for hens fed 100 ug HCB/kg.  Although  the  concen-



tration of HCB in eggs is usually viewed from the  perspective



of accumulation in a human food, it can also be  viewed  as an



excretion process.  Whereas 10 percent of the daily  HCB in-



take is excreted in the feces, 35 percent is excreted  in  the



eggs of laying hens (Kan and Tuinstra, 1976).  The  rate of



elimination of HCB from swine was greatest 48 to 72  hours



after a single intravenous injection of drug.  The  rate of



release of HCB from fat was the rate limiting factor for



excretion at later times.  Half of the starting  HCB material



in the feces was unmetabolized HCB.  All of the  HCB material



excreted in the urine was metabolites of HCB.  Excretion  of



HCB from swine was five to tenfold slower than excretion  from



dogs (Wilson and Hansen, 1976).



     Clearance of HCB from brain of rats given a single in-



jection intraperitoneally occurs in two steps:   a slow  phase



days 1 to 14 and a very slow phase thereafter.   The half-life
                             C-113

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for the slow phase was  ten days  and  that  for the very slow



phase was 57 days.   Similarly,  the half-life of HCB in testes



was 15 days for  the  initial slow clearance and 62 days for



the later very slow  phase.   The  initial clearance rates



(half-lives) for the heart, lung and kidney were 15, 13 and



16 days respectively.   In  contrast to the pattern for in-



dividual organs,  the clearance  of HCB from the whole body



proceeded as a single step process,  with  a half-life of 60



days.  The  initial clearance of  HCB  from  individual organs



therefore reflects a redistribution  of the chemical among the



tissues of  the body  (Morita and  Oishi, 1975).  Clearance of



HCB from organs  of rats given a  single dose of HCB dissolved



in olive oil by  gavage  occurred  in two stages also:  a very



slow phase  between day  two and  day five or day eight, and a



slow phase  thereafter.   The overall  half-life of HCB for fat,



skin, liver, brain,  kidney, blood and muscle was eight to ten



days.  The  administered chemical was retained in the tissue



as unaltered HCB.  During  a two  week period, five percent of



the administered HCB was excreted in the  urine; essentially



all as metabolites of HCB,  and  34 percent was excreted in the



feces, mostly as unaltered HCB.   The fecal excretion of a



fairly high amount of unmetabolized  HCB is presumed to be due



to biliary  secretion.   Unchanged HCB has  been detected in



bile of rats after intraperitoneal administration of the



chemical  (Koss and Koransky, 1975).



     No radioactivity was  detected  in the expired air of rats



administered radiolabeled  HCB (Koss  and Koransky, 1975).

-------
                            EFFECTS



 Acute, Sub-acute/ and Chronic Toxicity



      Japanese quail are among the most sensitive species to HCB.



 Japanese quail fed a diet containing 5 mg HCB/kg for 90 days de-



 veloped enlarged livers,  had slight liver damage and excreted



 increased amounts of coproporphyrin in the feces.  Increased ex-



 cretion of coproporphyrin was noticeable after ten days (Vos, et



 al.  1971).



      The acute toxicity of HCB for vertebrates is low:  500 mg/



 kg  intrapertioneally is not lethal in rats; the oral lethal dose



 in  guinea pigs is greater than 3  g/kg; and the oral lethal dose



 in  Japanese  quail is greater than 1 g/kg (Vos, et al. 1971).  In



 acute  studies, HCB was  more toxic for guinea pigs than rats, but



 accumulated  to a  lesser degree in the guinea pig.  Male rats ap-



 peared  to be  more susceptible to  HCB than females (Villeneuve



 and Newsome,  1975).   HCB  is able  to induce rat microsomal  liver



 enzymes;  HCB  was  more effective in stimulating aniline hydroxy-



 lase than aminopyrine demethylase or hexobarbital oxidase.   HCB



 is not  a  particularly effective inducer of these microsomal en-



 zymes  (den Tonkelaar  and  van Esch,  1974).   Although HCB has a



 low acute toxicity  for  most species (>1000 mg/kg),  it has  a wide



 range of  biological  effects  at prolonged  moderate exposure.



     Subacute  toxic  effects  of HCB  were examined in rats after



 feeding with HCB  for  15 weeks.  Histopathological changes  were •



confined  to the liver and  spleen.   In the  liver,  there was  an



 increase  in the severity of  centrilobular  liver lesions with as



little as 2 mg HCB/kg/day  in  the  food.   In contrast to the  re-



sults of others,  females were more  susceptible to HCB than  male





                              C-115

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 rats.   It would appear that 0.5 mg HCB/kg/body weight per



 day, where diet was adjusted weekly 3.4 to 11.6 mg HCB/kg, is



 the  no-effect level in the rat (Kuiper-Goodman, et al. 1977).



 Unlike  in the rat,  it was not possible to induce porphyria in



 dogs with HCB (Gralla, et al. 1977).   Swine are more suscept-



 ible to HCB in subacute studies than  rats.   Liver microsomal



 enzymes were induced in swine and excretion of coproporphyrin



 was  increased by 0.5 mg HCB/kg/day after 13 and 8 weeks,  re-



 spectively.   It would appear that 0.05 mg HCB/kg/day in the



 diet is the "no-effect" level for swine (den Tonkelaar,  et



 al.  1978).



     In rats given  50 mg HCB/kg every other day for  53 weeks,



 an equilibrium between intake and elimination was achieved



 after nine  weeks.   In general,  the most changes observed  in



 the long  term studies resembled those  described for  short



 term studies.   When the administration of HCB was discon-



 tinued,  elimination of the  xenobiotic  continued slowly for



 many months  (Koss,  et al.  1978).



     HCB  caused  a serious  outbreak of  hepatic  porphyria  in



 Turkey  involving cutanea  tarda  lesions  and  porphyrinuria  (Cam



 and Nigogosyan,  1963).   This  has  been  confirmed  in a number



 of laboratory animals including rats  (San Martin  de Viale,  et



 al. 1976),  rabbits  (Ivanov,  et  al.  1976), Japanese quail



 (Vos, et  al.  1971),  guinea  pigs (Strik,  1973),  swine (den



 Tonkelaar,  et  al. 1978), mice  (Strik,  1973) and Rhesus mon-



keys (latropoulos,  et al. 1976).   Rats  given  50 mg HCB/kg  or-



 ally for  30  days showed enlarged  livers, elevated liver por-



phyrin  and  elevated  urine porphyrin (Carlson, 1977).   In both

-------
rabbits and rats, HCB produced an increase in the excretion



of uroporphyrin and coproporphyrin.  The mechanism of action



of HCB is not known, but it elicits an increase in ^~- ami-



nolevulinic acid synthetase, which is the rate limiting en-



zyme in the biosynthesis of porphyrins (Timme, et al. 1974).



The development of HCB-induced porphyria is accompanied by a



progressive fall in hepatic uroporphyrinogen decarboxylase



activity.  This change may be causally related to the disease



(Elder, et al. 1976).  The mitochondrial membrane may also be



a factor in limiting the rate of porphyrin biosynthesis since



some critical enzymes are intramitochondrial and others are



cytoplasmic.  It has been proposed that HCB may damage the



mitochondrial membrane thereby facilitating the flow of por-



phyrin intermediates through-it  (Simon, et al. 1976).  Con-



sistent with this proposal is the observation that HCB causes



marked enlargement of rat hepatocytes, proliferation of



smooth endoplasmic reticulum, formation of eosinophilic



bodies, generation of large lipid vesicles, and mitochondrial



swelling (Mollenhauer, et al. 1975).



     It should be noted that the principal metabolite of  HCB,



pentachlorophenol, is not porphyrinogenic in the rat, so  the



formation of this metabolite is  unlikely to play a role in



HCB-induced porphyria (Lui, et al. 1976).  Nevertheless,  it



is conceivable that metabolites  of HCB, particularly as a re-



sult of microsomal enzyme induction, might be the  actual  por-



phyrogenic agent (Lissner, et al. 1975).
                             C-117

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     An epidemic of  HCB-induced  cutanea  tarda porphyria oc-



curred in Turkey during  the period  1955  to 1959  (Cam and



Nigogosyan, 1963).   More than  600 patients were  observed dur-



ing a five year period,  and it was  estimated that a total of



3000 people were affected.  The  outbreak was traced to the



consumption of wheat as  food after  it  had been prepared for



planting by treating it  with hexachlorobenzene.   The syndrome



involves blistering  and  epidermolysis  of the exposed parts of



the body/ particularly  the  face  and hands.  It was estimated



that the subjects  ingested  50  to 200 mg  HCB/day  for a rela-



tively long period  before the  skin  manifestations became ap-



parent.  The  symptoms were  seen  mostly during the summer



months, having been  exacerbated  by  intense sunlight.  The



disease subsided and symptoms  disappeared 20 to  30 days after



discontinuation of  intake of HCB-contaminated bread.  Re-



lapses were often  seen,  either because the subjects were eat-



ing HCB-containing  wheat again,  or  because of redistribution



of HCB stored in body fat.



     A disorder called  pembe yara was  described  in infants of



Turkish mothers who  either  had HCB-induced porphyria or had



eaten HCB-contaminated  bread  (Cam,  1960).  The maternal milk



contained  HCB.  At  least 95 percent of these infants died



within a year and  in many villages, there were no children



left between  the ages of two and five  during the period 1955-



60.  With  human  tissue  levels  of HCB increasing  measurably



throughout  the world, the effect of low  chronic  doses of this



pesticide  must be  considered.   HCB  is  stored in  the body fat



and  transmitted  through maternal milk.  It is not known
                              C-118

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 whether HCB is responsible for genetic damage to the progeny
 (Peters, 1976).
      There was no evidence of cutaneous porphyria in 86
 Louisiana residents having an average plasma HCB level of 3.6
 ug/kg, with a maximum level of 345 u.g HCB/kg.  There was a
 possible correlation between plasma HCB levels and urinary
 coproporphyrin excretion or plasma lactate dehydrogenase
 activity, but none with urinary uroporphyrin excretion (Burns
 and Miller,  1975).  It should be noted that the people in
 Turkey showing symptoms of porphyria had ingested 1 to 4 mg
 HCB/kg/day for a relatively long period (Cam and Nigogosyan,
 1963).   It is speculated that some of the Louisiana workers
 had taken in several mg HCB/kg/day,  at least sporadically.
 Synergism and/or Antagonism
      HCB,  at doses far below those causing mortality,  en-
 hances  the capability of animals to  metabolize foreign or-
 ganic compounds (see section on Metabolism).  This type of
 interaction  may be of importance in  determining  the effects
 of  other  concurrently encountered  xenobiotics on the animal
 (Carlson  and  Tardiff,  1976).   An increase  in paraoxon  dealky-
 lation  activity was  a more  sensitive indicator of induction
 of  microsomal  enzyme  activity in a liver fraction from rats
 fed a diet containing  2  mg  HCB/kg  for two  weeks  than cyto-
 chrome  P-450  content  or  N-demethylase activity (Iverson,
 1976) .
     HCB elicits  significant  and rather selective changes in
Lindane metabolism  in  rats  (Chadwick,  et al.  1977).  Rats ad-
ministered 7.5 mg HCB/kg/day  orally  for seven days  had in-
creased capability to metabolize arid  eliminate 1,2,3,4,5,6
                              C-119

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hexachlorocyclohexane (Lindane).  As noted before, HCB caused



liver  enlargement and enhanced EPN metabolism.  Rats fed HCB



also had  significantly increased ability to metabolize



p-nitroanisole,  but not methyl orange.   HCB-treated rats ex-



creted 35  percent of the administered Lindane in their feces



and 13.7  percent in their urine within  24 hr/ in contrast to



12.7 percent  in  feces and 5.0 percent in urine of unexposed



rats.   The amount of Lindane in fat and liver 24 hr after



administering  12.5 mg of Lindane/kg orally was less in HCB-



treated rats  than in unexposed controls (117 versus 60.7



mg/kg  in  fat  and 9.57 versus 5.24  mg/kg in liver).   The Lin-



dane content of  the kidney was not significantly reduced



(6.91  versus  5.94 mg/kg for HCB-treated versus unexposed



rats).  Rats pretreated with HCB excreted a significantly



higher proportion of free chlorophenols,  with a  corresponding



decrease  in polar metabolites  as compared to unexposed  rats.



     Prior exposure to HCB may alter  the  response  of  an ani-



mal to any of  a  variety of challenges.   Mice fed a  diet con-



taining 167 mg HCB/kg have altered susceptibility  to  Salmon-



ella typhosa 0901  lipopolysaccharide  (endotoxin).   The  LDso



for exposed mice  was  about 40  mg endotoxin/kg, for  mice  fed



HCB for three  weeks  7.4  mg/kg,  and  for  mice  fed HCB for  six



weeks, 1.4 mg/kg.   Mice  fed  HCB  were  also  somewhat  more  sus-



ceptible to the  malaria  parasite Plasmodium  than unexposed



mice (Loose, et  al.  1978).



Teratogenicity



     The effect  of  HCB on  reproduction  has  received limited



atte'ntion.  Dietary  HCB  adversely  affected reproduction  in




                             C-120

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the rat by decreasing the number of litters whelped and the



number of pups surviving to weaning (Grant, et al. 1977).



The fertility (numbers of litters whelped/number of females



exposed to mating) of rats fed a diet containing 320 mg



HCB/kg was decreased.  This concentration of HCB in the food



led to accumulative toxicity (convulsions and death) in some



of the animals.  The proportion of pups surviving  five days



was reduced when the parents had been fed a diet containing



160 mg HCB/kg and when the rats had been fed a diet of 80 mg



HCB/kg for three generations.  The birth weight of rats was



reduced in rats fed a diet containing 320 mg HCB/kg and  in



rats fed a diet containing 160 mg HCB/kg for two generations.



The weight of five-day old pups was markedly less  when the



parents had been fed a diet containing 80 mg HCB/kg.  The



tissue of 21-day-old pups whose dam had been fed graded



dietary levels of HCB contained progressively more drug;  for



example, the level of HCB in body fat was about 250 mg/kg



when the dietary level was 10 mg/kg; 500 mg/kg  in  fat for  20



mg/kg in diet; 800 mg/kg in fat for 40 mg/kg in diet; 1900



mg/kg in fat for 80 mg/kg in diet; and 2700 mg/kg  in  fat  for



160 mg/kg in diet.  The highest HCB levels were in  the body



fat; for pups whose dam had been fed a diet containing 10  mg



HCB/kg, the body fat contained 250 mg HCB/kg, liver-9 mg/kg;



kidney and brain-4 mg/kg and plasma-1.3 mg/kg.  HCB  crossed



the placenta of rats and accumulated in the fetus  in  a dose-



related manner.  HCB 'fed to pregnant mice and rats  was de-



posited in the tissues in a dose-related manner.   The HCB



content of placentas was greater than that of the  correspond




                             C-121

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 respect to the incidence of pregnancies,  corpora lutea, live



 implants or deciduoraas (Khera,  1974).



      HCB injected  intraperitoneally into  rats at 10 mg/kg



 elicited a marked  induction of  the  hepatic cytochrome P-450



 system.  This  liver  microsomal  fraction mediated the meta-



 bolic activation of  2,4-diaminoanisole  to a mutagen (as mea-



 sured by the Ames  test)  (Dybing and Aune, 1977).  The muta-



 genic activities of  several aromatic and  polycyclic hydro-



 carbons are not associated  with the parent compound but with



 metabolically  activated  products  that  react covalently with



 nucleic acid.  As  noted  previously,  HCB stimulates the



 hepatic cytochrome P-450  system and  thereby has  the potential



 to enhance  the mutagenicity of  other chemicals.



 Carcinogenicity



      Two  studies have  been  conducted which indicate that HCB



 is a  carcinogen.  The  carcinogenic  activity of HCB in ham-



 sters  fed  4, 8, or 16 mg/kg/day for  life  was assessed



 (Cabral,  et  al. 1977).  HCB  appears  to  have multipotential



 carcinogenic activity; the  incidence of hepatomas, haemangio-



 endotheliomas and thyroid adenomas was  significantly in-



 creased.  Whereas 10 percent of the  unexposed hamsters de-



 veloped tumors, 92 percent of the hamsters  fed 16  mg HCB/kg/



 day developed tumors.  The  incidence of tumor-bearing animals



was dose-related:  56 percent for hamsters  fed 4  mg HCB/kg/day



 and 75 percent for 8 mg/kg/day.  No  thyroid tumors, hepatomas



 or liver haemangioendotheliomas were detected in the unex-



posed group.  An intake of 4 to 16 mg HCB/kg/day in hamsters



 is near the exposure range estimated for  Turkish people who
                             C-123

-------
accidentally  consumed KGB-contaminated grain (Cabral, et al.



1977).



     The  carcinogenic activity of  HCB  in  mice  fed 6.5,  13 or



26 mg/kg/day  for  life was  assessed.  The  incidence of hepato-



mas was increased significantly in mice fed  13  or 26  mg



HCB/kg/ day.  None of the  hepatomas metastasized  or occurred



in the untreated  control groups.   The  results presented in



the abstract  of Cabral, et al.  (1978)  confirm their earlier



conclusion that HCB  is carcinogenic.   However,  the incidence



of lung tumors in strain A mice  treated three times a week



for a total of 24 injections of  40 mg/kg  each was  not signif-



icantly greater than  the incidence in  control mice (Theiss,



et al. 1977).  Moreover, HCB did not induce  hepatocellular



carcinomas in ICR mice fed HCB  at  1.5  or  7 mg/kg/day  for  24



weeks (Shirai, et al. 1978).

-------
                    CRITERION FORMULATION



Existing Guidelines and Standards



     As far as can be determined, the Occupational Safety and



Health Administration has not set a standard for occupational



exposure of HCB.  HCB has been approved for use as a preemer-



gence fungicide applied to seed grain.  The Federal Republic



of Germany no longer allows the application of HCB-containing



pesticides (Geike and Parasher, 1976a).  The government of



Turkey discontinued the use of HCB-treated seed wheat  in 1959



after its link to acquired toxic porphyria cutanea tarda was



reported (Cam, 1959).  Commercial production of HCB in the



United Staes was discontinued in 1976  (Chem. Econ. Hdbk.,



1977).  The Louisiana State Department of Agriculture  has set



the tolerated level of HCB in-meat fat at 0.3 mg/kg (U.S.



EPA, 1976).  The NHMRC (Australia) has used this same  value



for the tolerated level of HCB in cows' milk (Miller and Fox,



1973).  WHO has set the tolerated level of HCB in cows' milk



at 20 ug/kg in whole milk (Bakken and  Seip, 1976).  The New



South Wales Department of Health (Australia) has recommended



that the concentration of HCB in eggs  must not exceed  0.1



mg/kg (Siyali, 1973).  The value of 0.6 ug HCB/kg/day  was



suggesce'd by FAO/WHO in -1-974 as a reasonable upper limit for



HCB residues in food for human consumption  (FAO/WHO, 1974).



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.  Russia and Yugoslavia have set the  maximum



tolerated'level of HCB in air at 0.9 mg/m3  (Int. Labor Off.



1977).
                             C-125

-------
Current Levels of Exposure



     HCB appears to be  distributed  worldwide,  with  high



levels of contamination found  in agricultural  areas  devoted



to wheat and related  cereal grains  and  in  industrial areas.



HCB is manufactured and formulated  for  application  to seed



wheat to prevent bunt;  however, most  of the  HCB  in  the en-



vironment comes from  industrial processes. =  HCB  is  used as  a



starting material for the production  of pentachlorophenol



which is marketed as  a  wood preservative.  HCB is one of  the



main substances in the  tarry residue  which results  from the



production of chlorinated hydrocarbons.  HCB is  formed as a



by-product in the production of chlorine gas by  the  electrol-



ysis of sodium chloride using  a mercury electrode  (Gilbertson



and Reynolds, 1972).



     People  in the United States are  exposed to  HCB  in air,



water.and food.  HCB  is disseminated  in the  air  as dust par-



ticles and as a result  of volatilization from sites  having  a



high HCB-concentration. Airborne HCB-laden  dust particles



appear to have been a major factor  in producing  the  blood



levels in the general public living near an  industrial site



in Louisiana  (Burns and Miller, 1975).   HCB  is found in river



water near industrial sites in quantities of as  much as 2



ug/kg  (Laska, et al.  1976) and even in  finished  drinking



water at 5 ng/kg  (U.S.  EPA, 1975).  HCB occurs in a  wide



variety of foods,  in  particular, terrestrial animal  products,



including dairy products and eggs  (U.S.  EPA, 1976).   The



dietary  intake of  HCB has  been estimated to  be 0.5  ug/day in



Japan  (Ushio and Doguchi,  1977) and 35  ug/day in Australia




                             C-126

-------
 (Miller and Fox,  1973).   Breast-fed  in^^	,.^_^_u  and

 Norway may  consume  40  ug  HCB/day  (Miller  and  Fox,  1973; Bakken

 and Seip, 1076).  HCB  is  found  in human tissues collected

 throughout  the world.

      The HCB content of human adipose  tissue  taken at  autopsy

 is  as follows:

                            Mean Values
                             -(mg/kg  in
                                                   Reference

                                            Brady  and  Siyali, 1972

                                            Siyali, 1972

                                            Brady  and  Siyali, 1972

                                            Curley, et al. 1973

                                            Mes and Campbell, 1976

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Acker  and  Schulte, 1974

                                            Acker  and  Schulte, 1974

                                            Aoker  and  Schulte, 1974

                                            Acker  and  Schulte, 1974

                                            Acker  and  Schulte, 1974

                                            Acker  and  Schulte, 1974

The maximum  HCB level reported was 22 mg/kg (Acker and Schulte,

1974) .
Source
Australia
Papua and
New Guinea
Japan
Canada
»
»
-
"
"
Germany
"
"
»
"
n
No. samples
75
81
38
241
3
16
50
57
22
27
56
54
•• 04 - . -
59
59
93
Human Fat)
1.25
1.31
0.26
0.08
0.09
0.025
0.107
0.060
0.015
0.043
2.9
8.2
•- Q
4.8
6.4
4.8
                             C-127

-------
   The HCB content  of  human  blood  samples  is  as follows:



                                Mean  Values

                                  (mg/kg

 Source       No. Samples        in Blood)               Reference



Bavaria        98 boys           0.022          Richter and Schmid,  1976



   "           96 girls          0.017          Richter and Schmid,  1976



Australia     185 exposed        0.055          Siyali, 1972



   "           52 unexposed      0.022          Siyali, 1972



   "           76                0.058          Siyali  and  Ouw,  1973



Louisiana      86                0.0036         Burns and Miller,  1975



   The maximum HCB  level reported  was 0.345 mg/kg,  that in a



   Louisiana waste  disposal  worker (Burns and Miller,  1975).



        The levels  of HCB  in body  fat of swine  and  sheep were



   sixfold and eightfold greater,  respectively  than the dietary



   level (Hansen, et al. 1977).  If  these comparisons  are  valid



   when applied to  man, it would appear that some adult humans



   have been exposed to several mg HCB/kg/day.  A similar  con-



   clusion is reached by extrapolating the values for  human



   blood.  The HCB  levels  in blood of rats are  about tenfold



   less than the dietary level  (Kuiper-Goodman, et al.  1977).



        Current evidence would  indicate that food intake may be



   the primary source of the body  burden of HCB for the general



   population although inhalation and dermal exposure may  be



   more important in selected groups (e.g., industrial wor-



   kers) .



   Special Groups at Risk



        Several groups appear to be at risk.  These include wor-



   kers engaged directly in:  (1) the manufacture of HCB or in



   processes in which HCB is a by-product,  (2)  the formulation
       •


   of HCB-containing products,  (3)  the disposal of HCB-containing

-------
wastes; and (4) the application of HCB-containing products.



Other groups at risk are the general public living near in-



dustrial sites, populations consuming large amounts of con-



taminated fish/ pregnant women, fetuses and breast-fed in-



fants.  Two lines of evidence indicate that infants may be at



risk.  It has been demonstrated that human milk contains HCB,



and some infants may be exposed to relatively high concentra-



tions of HCB from that source alone (Miller and Fox, 1973;



Bakken and Seip, 1976).  Moreover, some infants of Turkish



mothers who consumed HCB-contaminated bread developed a fatal



disorder called pembe yara.  In some Turkish villages in the



region most affected by HCB-poisoning, few infants survived



during the period 1955-1960 (Cam, 1960).



     Occupational exposure is associated with an  increased



body burden of HCB.  Plant workers in Louisiana have about



200 ug HCB/kg in blood (Burns and Miller, 1975).  The HCB



content of body fat exceeded 1 mg/kg in many parts of the



world where HCB contamination of the environment  is extensive



(Brady and Siyali, 1972; Acker and Schulte, 1974).



     The massive episode of human poisoning resulting from



the consumption of bread prepared from HCB-treated seed wheat



brought to light the misuse of HCB-treated grain  (Cam and



Nigogosyan, 1963).  In spite of warnings, regulations and



attempts at public education, HCB-treated grain apparently



still finds its way into the food chain, for example, in fish



food (Hansen, et al. 1976; Laska, et al. 1976).   The diffi-



culty in tracing the source of HCB contamination  in a diet



for laboratory animals emphasizes the difficulties encoun-




                             C-129

-------
tered in tracing the  source  of  HCB  in  foodstuffs for man



(Yang, et al. 1976).



     As noted previously,  adipose tissue  acts as a reservoir



for HCB.  Deletion of  fat  depots can result  in mobilization



and redistribution of  stored HCB.   Weight loss for any reason



may result in a dramatic redistribution of HCB contained in



adipose tissue; if the stored levels of HCB  are high, adverse



effects might ensue.   Many humans restrict their dietary in-



take voluntarily or because  of  illness.   In  these instances,



the redistribution of  the  HCB body  burden becomes a potential



added health hazard  (Villeneuve, 1975).



Basis and Derivation  of Criterion



     Among the  studies reviewed by  this document, only two



appear  suitable for use in the  risk assessment:  the mouse



study of Cabral, et al. (1978)  and  the hamster study of



Cabral, et al.  1977.   These  two studies are  described in



detail  in Appendix I.



     Under the  Consent Decree  in NRDC  v.  Train, criteria are



to  state "recommended maximum permissible concentrations



(including where appropriate,  zero) consistent with the pro-



tection of aquatic organisms, human health,  and recreational



activities".   HCB  is  suspected  of being a human carcinogen.



Because there  is no  recognized  safe concentration for a human



carcinogen,  the recommended  concentration of HCB in water for



maximum protection of human  health  is  zero.



      Because attaining a zero  concentration  level may be un-



feasible  in  some  cases, and  in  order  to assist the Agency and



States  in  the possible future  development of water quality




                              C-130

-------
     regulations/  the concentrations of HCB corresponding  to

     several  incremental lifetime cancer  risk  levels  have  been

     estimated.  A cancer risk level provides  an  estimate  of the

     additional  incidence of cancer that  may be expected  in  an

     exposed  population.  A risk of 10"^  for example,  indicates a

     probability of one additional case of cancer  for  every

     100,000  people exposed, a risk of 10~6 indicates  one  addi-

     tional case of cancer for every million people exposed,  and

     so forth.

          In  the Federal Register notice  of availability of  draft

     ambient  water quality criteria, EPA  stated that  it is consid-

     ering setting criteria at an interim target  risk  level  of

     10~~5, 10~6, or 10"? as shown in the  table below:

Exposure Assumption           Risk Levels and Corresponding  Criteria  (1)
    (per day)
                                2       10~7           IP"6          10~5

2 liters of drinking water      0    0.0125 ng/1   0.125 ng/1   1.25  ng/1
and consumption of 18.7 grams
fish and shellfish. (2)

Consumption of fish and         0    0.0126 ng/1   0.126 ng/1   1.26  ng/1
shellfish only.


     (1)  Calculated by applying a modified "one-hit"  extrapola-

          tion model described in the Federal Register, FR 15926,

          1979.  Appropriate bioassay data used in the calculation

          of the model  is  presented  in Appendix I.  Since the  ex-

          trapolation model  is linear at low doses, the additional

          lifetime  risk  is  directly  proportional to the water
                                  C-131

-------
     concentration.   Therefore,, water concentrations corres-



     ponding  to other risk  levels  can be  derived by multiply-



     ing or dividing  one  of the risk  levels and corresponding



     water concentrations shown in the table by factors such



     as 10, 100, 1,000, and so  forth.



(2)  Ninety-nine percent  of the HCB exposure results from the



     consumption of aquatic organisms  which exhibit an  aver-



     age bioconcentration potential of 12,000-fold.   The  re-



     maining  one percent  of HCB exposure  results from drink-



     ing water.



     Concentration levels were  derived assuming a lifetime



exposure to various amounts of  HCB, (1) occurring from  the .



consumption of both drinking water and aquatic  life  grown in



waters containing the  corresponding HCB concentrations  and,



(2) occurring solely  from consumption  of-aquatic life grown



in the waters containing  the corresponding  HCB  concentra-



tions.  Because data  indicating  other  sources of HCB exposure



and their contributions to  total body  burden are  inadequate



for quantitative use,  the figures  reflect the incremental



risks associated with  the indicated routes  only.

-------
                           REFERENCES








 Acker,  L. ,  and  E.  Schulte.  1971.   Zum  Vorkommen  von Hexa-



 chlorbenzol  und  polychlorierten  Biphenylen  neben chlorierten



 Insektiziden in  menschlichem  Fettgewebe  und  in Humanmilch.



 Ernahrungsforschung.  16:  559.








 Acker,  L. ,  and  E.  Schulte.  1974.   Chlorkohlenwasserstoffe im



 menschlichen fett. Naturwissensch.  61:  32.








 Albro,  P.W.,  and R. Thomas. 1974.   Intestinal  absorption  of



 hexachlorobenzene  and hexachlorocyclohexane  isomers in  rats.



 Bull. Environ. Contam. Toxicol.  12: 289.








 Andrews, J.E., and K.D. Courtney.  1976.   Inter-  and intra- •



 litter  variation of hexachlorobenzene  (HCB)  deposition  in



 fetuses.  Toxicol. Appl.  Pharmacol. 37:  128.








 Bakken, A.F., and M. Seip. 1976.   Insecticides in  human



 breast milk.  Act. Paediat. Scand.  65:  535.








 Beall, M.L., Jr. 1976.  Persistence of aerially  applied HCB



 on grass and soil.  Jour. Environ.  Qual.  5:  367.








Beck, J.,  and K.E. Hansen. 1974.  The degradation  of  quinto-



zene, pentachlorobenzene, hexachlorobenzene  and  pentachloro-




aniline in soil.  Pestic. Sci. 5: 41.
                             C-133

-------
Brady, M.N.,  and  D.S.  Siyali.  1972.   Hexachlorobenzene in



human body  fat.   Med.  Jour.  Australia.  1:  518.








Burns, J.E.,  and  F.M.  Miller.  1975.   Hexachlorobenzene con-



tamination:   Its  effects  in  a  Louisiana population.   Arch.



Environ. Health 30:  44.








Cabral, J.R.P., et  al.  1977.   Carcinogenic  activity  of hexa-



chlorobenzene  in  hamsters.   Nature  (London).  269:  510.








Cabral, J.R.P., et  al.  1978.   Carcinogenesis  study in  mice



with hexachlorobenzene.   Toxicol. Appl. Pharmacol. 45:  323.








Cam, C. 1959.  Cutaneous  porphyria  related  to intoxication.



Dirim (Istanbul)  34: 11.  (In Turkish.)








Cam, C. 1960.  Une  nouvelle  dermatose epidemique des enfants.



Ann. Dermatol. Syphiligr. 87:  393.








Cam, C., and G. Nigogosyan.  1963.  Acquired toxic porphyria



cutanea tarda due to hexachlorobenzene.  Jour. Am. Med.



Assoc. 183: 88.








Carlson, G.P. 1977.  Chlorinated benzene induction of  hepatic



porphyria.  Experientia 33: 1627.








Carlson, G.P. 1978.  Induction of cytochrome P-450 by  halo-



genated benzenes.    Biochem. Pharmacol. 27: 361.
                             C-134

-------
Carlson, G.P., and R.G.  Tardiff. 1976.  Effect of chlorinated



benzenes on the metabolism of foreign organic compounds.



Toxicol. Appl. Pharmacol. 36: 383.







Chadwick, R.W., et al. 1977.  Comparative enzyme induction



and lindane metabolism in rats pre-treated with various



organochlorine pesticides.  Xenobiotica 7: 235.







Chemical Economic Handbook. 1977. Chlorobenzenes-Salient



statistics.  In: Chemical Economic Handbook, Stanford Res.



Inst. Int., Menlo Park,  Calif.







Cordle, F., et al. 1978.  Human exposure  to polychlorinated



biphenyls and polybrominated biphenyls.   Environ. Health



Perspect. 24: 157.







Courtney, K.D., et al. 1976.  The effects of pentachloro-



nitrobenzene, hexachlorobenzene,  and  related compounds  on



fetal development.  Toxicol. Appl. Pharmacol.  35: 239.








Cromartie, E., et al. 1975.  Residues of  organochlorine



pesticides and polychlorinated  biphenyls  and autopsy data  for



bald eagles, 1971-72.  Pestic.  Monitor. Jour.  9:  11.








Curley, A., et al. 1973.  Chlorinated hydrocarbon pesticides



and related compo-unds in  adipose  tissue from people  of  Japan.



Nature  (London) 242:  338.
                              C-135

-------
den Tonkelaar, E.M., and G.J. van Esch. 1974.  No-effect



levels of organochlorine pesticides based on  induction  of



microsomal liver enzymes in short-term toxicity experiments.



Toxicology 2: 371.








den Tonkelaar, E.M., et al. 1978.  Hexachlorobenzene  toxicity



in pigs.  Toxicol. Appl. Pharmacol. 43: 137.








Dybing, E.,  and T. Aune. 1977.   Hexachlorobenzene  induction



of 2,4-diaminoanisole  mutagenicity in vitro.   Acta Pharmacol.



Toxicol.  40:  575.








Elder, G.H.,  et al.  1976.   The  effect of  the  porphyrogenic



compound, hexachlorobenzene,  on the activity  of hepatic



uroporphyrinogen  decarboxylase  in  the rat.  Clin.  Sci.  Mol.



Med.  51:  71.








Engst,  R.,  et al.  1976.  The  metabolism of  hexachlorobenzene



 (HCB)  in  rats.  Bull.  Environ.  Contam. Toxicol. 16:  248.








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.








 Freitag,  D., et  al.  1974.   Ecological Chemistry.   LXXVI:



 Fate of HCB-l^C in summer  wheat and  soil  after seed treat-



 ment.  Chemosphere 3:  139.
                              C-136

-------
 Geike,  F.,  and  C.D.  Parasher.  1976a.   Effect of hexachloro-



 benzene  (HCB) on  some  growth parameters  of  Chlorella



 pyrenoidosa.  Bull.  Environ. Contain.  Toxicol.  15:  670.








 Gilbertson, M., and  L.M.  Reynolds.  1972.  Hexachlorobenzene



 (HCB)  in  the eggs  of common  terms  in  Hamilton  Harbour,




 Ontario.  Bull. Environ.  Contam. Toxicol. 7:  371.








 Gralla, E.J., et  al. 1977.   Toxic  effects of hexachloroben-



 zene after daily  administration  to  Beagle dogs for one  year.




 Toxicol.  Appl.  Pharmacol. 40:  227.








 Grant, D.L./ et al.  1977.  Effect of  hexachlorobenzene  on re-




 production in the  rat.  Arch.  Environ. Contam.  Toxicol.  5:




 207.








 Hansen, L.G., et  al. 1976.  Effects of dietary Aroclor  1242




 on channel catfish  (Ictalurus  punctatus) and  the  selective




 accumulation of PCS  components.  Jour. Fish  Res.  Board  of




 Canada. 33:  1343.








 Hansen, L.G., et al. 1977.  Effects and  residues  of dietary




 hexachlorobenzene  in growing swine.   Jour. Toxicol.  Environ.




 Health 2:  557.








 latropoulos, M.J., et al. 1975.  Absorption,  transport  and




organotropism of dichlorobiphenyl  (DCB), dieldrin,  and  hexa-




chlorobenzene (HCB)  in rats.   Environ. Res.  10:  384.





                             C-137

-------
latropoulos,  M.J. ,  et  al.  1976.   Morphological effects of



hexachlorobenzene  toxicity in  female  Rhesus  monkeys.



Toxicol. Appl.  Pharmacol.  37:  433.








International Labor Office. 1977.  Occupational  exposure



levels for airborne substances.   In:  Occupational  Health



Series No. 37.   International  Labor Office,  Geneva.








Isensee, A.R.,  et  al.  1976.  Soil persistence  and aquatic



bioaccumulation  potential  of hexachlorobenzene  (HCB).  Jour.



Agric. Food. Chem.  24:  1210.







Ivanov, E., et  al.  1976.   Studies on  the mechanism  of  the



changes in serum and liver  -glutamyl transpeptidase



activity.  Enzyme  21:  8.








Iverson, F. 1976.   Induction of paraoxon dealkylation  by



hexachlorobenzene  (HCB) and Mirex.  Jour. Agric. Food. Chem.



24: 1238.







Johnson, J.L.,  et al.  1974.  Hexachlorobenzene (HCB) residues



in fish.  Bull.  Environ. Contam. Toxicol. 11: 3T3.







Kan, C.A., and  L.G.M.T. Tuinstra. 1976.   Accumulation and



excretion of certain organochlorine insecticides in broiler



breeder hens.   Jour. Agric. Food. Chem.  24:  775.
                             C-138

-------
Khera, K.S. 1974.  Teratogenicity and dominant lethal studies



on hexachlorobenzene in rats.  Food Cosmet. Toxicol. 12:



471.








Koeman, J.H., ed. 1972.  Side-effects of persistent



pesticides and other chemicals on birds and mammals in  the



Netherlands.  TNO-Nieuws.








Kohli, J./ 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., and D. Manz. 1976.  Residues of  hexachlorobenzene



in wild mammals of Germany.  Bull. Environ. Contain. Toxicol.



15: 189.








Koss, G., et al. 1976.   Studies  on the toxicology of  hexa-



chlorobenzene.   II.  Identification  and determination  of



metabolites.  Arch.  Toxicol. 35:  107.








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



chlorobenzene.   III.   Observations in  a  long-term experiment.



Arch. Toxicol.  40:  285.
                              C-139

-------
Kuiper-Goodman, T., et  al. 1977.  Subacute  toxicity  of  hexa-



chlorobenzene in the rat.  Toxicol. Appl. Pharmacol.  40:



529.







Laseter, J.L., et al. 1976.  An ecological  study  of  hexa-



chlorobenzene (HCB).  EPA  560-6-76-009,  U.S.  Environ. Prot.



Agency, Washington, D.C.








Laska, A.L., et al. 1976.  Distribution  of  hexachlorobenzene



and hexachlorobutadiene in water, soil,  and  selected  aquatic



organisms along the lower  Mississippi  River,  Louisiana.



Bull.  Environ. Contain.  Toxicol. 15: 535.








Leoni, V.,  and S.U. D'Arca.  1976.   Experimental data  and



critical review of  the  occurrence of hexachlorobenzene  in  the



Italian environment.  Sci. Total. Environ.  5:  253.








Lissner, R., et al. 1975.  Hexachlorobenzene  induced  por-



phyria in rats.   Relationship  between  porphyrin excretion  and



induction of drug metabolizing liver enzymes.  Biochem.



Pharmacol.  24:  1729.







Loose, L.D., et al.  1978.   Impaired host resistance  to  endo-



toxin and malaria  in  polychlorinated bipheynl  and hexachloro-



benzene-treated mice.   Infect. Immun.  20:  30.
                              C-140

-------
Lu, P.Y., and R.L. Metcalf. 1975.  Environmental  fate  and



biodegradability of benzene derivatives as studied  in  a model



aquatic ecosystem.  Environ. Health Perspect. 10: 269.







Lui, H., et al. 1976.  Hexachlorobenzene porphyria.  In:



Porphyrins in Human Diseases.  Karger, Basel, p.  405.







Mes, J., and D.S. Campbell. 1976.  Extraction efficiency of



polychlorinated biophenyl, organochlorine pesticides and



phthalate esters from human adipose tissue.  Bull.  Environ.



Contam. Toxicol. 16: 53.







Mes, J., et al. 1977.  Polychlorinated 'biphenyl and organo-



chloride pesticide residues in adipose tissue of  Canadians.



Bull. Environ. Contam. Toxicol. 17: 196.







Miller, G.J., and J.A. Fox. 1973.  Chlorinated hydrocarbon



pesticide residues in Queensland human milks.  Med. Jour.



Australia 2: 261.







Mollenhauer, H.H., et al. 1975.  Ultrastructural  changes in



liver of the rat fed hexachlorobenzene.  Am. Jour. Vet. Res.



36: 1777.







Morita, M., and S. Oishi. 1975.  Clearance and tissue  distri-



bution of hexachlorobenzene in rats.  Bull. Environ. Contam.



Toxicol. 14: 313.
                             C-141

-------
Mumma, C.E., and E.W. Lawless. 1975.  "Task I - Hexachloro-



benzene and hexachlorobutadiene pollution from chlorocarbon



processes".  EPA 530-3-75-003, U.S. Environ. Prot. Agency,



Washington, D.C.







National Academy of Sciences. 1975.  Assessing potential



ocean pollutants.  Washington, D.C. p. 188.








Parke, D.V., and R.T. Williams. 1960.  Studies in detoxica-



tion.  Biochem. Jour. 74: 5.








Peters, H.A. 1976.  Hexachlorobenzene poisoning in Turkey.



Fed. Proc.  35: 2400.








Plimmer, J.R., and U.I. Klingebiel. 1976.-  Photolysis of



hexachlorobenzene.  Jour. Agric. Food Chem. 24: 721.








Richter, E., and A. Schmid. 1976.  Hexachlorbenzolgehalt  im



Vollblut von Kindern.  Arch. Toxicol. 35: 141.








Rourke, D.R., et al. 1977.  Identification of hexachloroben-



zene as a contaminant in laboratory plastic wash  bottles.



Journal of  the A.O.A.C. 60: 233.








Sanborn, J.R., et al. 1977.  Uptake and elimination of  [14C]



hexachlorobenzene (HCB) by  the green sunfish Lepomis cyanel-



lus Raf., after feeding contaminated food.  Jour. Agric.  Food



Chem. 25: 551.




                             C-142

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San Martin de Viale, L.C., et  al.  1976.   Experimental por-



phyria induced in rats by hexachlorobenzene.   In:  Porphyrins



in Human Diseases.  Karger, Basel, p.  453.







Savage, E.P. 1976.  National study to  determine  levels of



chlorinated hydrocarbon insecticides in  human  milk.   EPA



Contract No. 68-01-3190.  Off. Tox. Subst. Washington', B.C.







Schaefer, R.E., et al. 1976.   Residues of chlorinated hydro-



carbons in North Sea animals in relation  to biological para-



meters.  Ber. At. Wiss. Komm.  Merrlsforsch. 24:  225.







Shirai, T., et al. 1978.  Hepatocarcinogenicity  of poly-



chlorinated terphenyl (PCT) in ICR mice and its  enhancement



by hexachlorobenzene (HCB).  Cancer Lett. 4: 271.







Sidwell,  V.D., et al. 1974.  Composition of the  edible por-



tion of raw (fresh or frozen)  crustaceans, finfish, and  mol-



lusks.  I.   Protein, fat,  moisture, ash, carbohydrate,  energy



value, and  cholesterol.  Mar.  Fish. Rev. 36: 21.







Simon, N.,  et al. 1976.  The role of damages in  cellular



membrane  structures in the development  of porphyria cutanea



tarda.  In: Porphyrins in  Human Diseases.  Karger, Basel, p.



423.

-------
 Simpson, G.R., and A. Shandar. 1972.  Exposure to chlorinated



 hydrocarbon pesticides by pest control operators.  Med.  Jour.



 Australia. 2: 1060.







 Sims, G.G., et al.  1977.  Organochlorine residues in fish and



 fishery products from the Northwest Atlantic.   Bull. Environ.



 Contain. Toxicol. 18:  697.








 Siyali, D.S.  1972.   Hexachlorobenzene and other organo-



 chlorine pesticides in human blood.   Med. Jour.  Australia.  2:



 1063.








 Siyali,  D.S.  1973.   Polychlorinated  biphenyls,  hexachloro-



 benzene  and other organochlorine  pesticides  in  human milk.



 Med.  Jour.  Australia.  2:  815.








 Siyali,  D.S.,  and K.H.  Ouw.  1973.   Chlorinated  hydrocarbon



 pesticides  in  human blood -  Wee Waa  survey.  Med. Jour.



 Australia.  2:  908.








 Stonard, M.D.  1975.  Mixed type hepatic  microsomal enzyme



 induction  by hexachlorobenzene.   Biochem.  Pharmacol.   24:



 1959.








Stonard, M.D., and  J.B. Greig. 1976.   Different patterns  of



hepatic microsomal  enzyme activity produced by administration



of pure hexachlorobiphenyl isomers and hexachlorobenzene.



Chem.-Biol. Interact. 15: 365.




                             C-144

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Strik, J.J.T.W.A. 1973.   Species differences in experimental



porphyria caused by polyhalogenated aromatic compounds.



Enzyme 16: 224.







Sundlof, S.F., et al.  1976.   Pharmacokinetics of hexachloro-



benzene in male laboratory beagles.  Pharmacologist 18:  149.







Theiss, J.C., et al. 1977.  Test for carcinogenicity of or-



ganic contaminants of United States drinking waters by pul-



monary tumor response in strain A mice.  Cancer Res. 37:



2717.








Timme, A.H., et al. 1974.  Symptomatic porphyria.  Part II.



Hepatic changes with hexachlorobenzene.  S. African Med.



Jour. 48: 1833.








U.S. EPA. 1975.  Preliminary assessment of  suspected carcino-



gens in drinking water.   Report to Congress.  EPA  560/4-75-



003.  Environ. Prot. Agency, Washington, D.C.








U.S. EPA. 1976.  Environmental contamination from  hexachloro-



benzene.  EPA 560/6-76-014.  Off. Tox. Subst.  1-27.








Ushio, P., and M. Doguchi. 1977.  Dietary  intakes  of  some



chlorinated hydrocarbons and heavy metals  estimated  on  the



experimentally prepared diets.  Bull.  Environ.  Contam.



Toxicol. 17: 707.
                             C-145

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Veith, G.D., et al. An evaluation of using partition  coeffi-


cients and water solubility  to estimate bioconcentration


factors for organic chemicals in fish.  (Manuscript).




Veith, G.D., et al. 1977.  Residues of PCB's  and  DDT  in the


western Lake Superior ecosystem.  Arch. Environ.  Contam.


Toxicol. 5: 487.




Villeneuve, D.C. 1975.   The  effect of food restriction on  the


redistribution of  hexachlorobenzene in the rat.   Toxicol.


Appl. Pharmacol. 31: 313.




Villeneuve, D.C.,  and W.H. Newsome. 1975.  Toxicity and tis-


sue levels  in  the  rat and guinea pig following  acute  hexa-


chlorobenzene  administration.  Bull. Environ. Contam.


Toxicol. 14: 297.




Vos,  J.G. ,  et  al.  1971.   Toxicity of hexachlorobenzene  in


Japanese quail with  special  reference to porphyria, liver
                               i

damage,  reproduction, and tissue residues.   Toxicol.  Appl.


Pharmacol.  18: 944.




White,  D.E.,  and T.E. Kaiser. 1976.  Residues of  organo-


chlorines  and  heavy  metals  in ruddy ducks  from  Delaware


River,  1973.   Pestic. Monitor. Jour. 9: 155.
                              C-146

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Wilson, D.W.,  and L.G. Hansen. 1976.   Pharmacokinetics  of



hexachlorobenzene in growing swine.  Pharmacologist  18:



196.







Yang, R.S.H.,  et al. 1976.  Hexachlorobenzene  contamination



in laboratory  monkey chow.  Jour. Agric. Food. Chem.  24:



563.







Zitko, V. 1976.  Levels of chlorinated hydrocarbons  in  eggs



of double-crested cormorants from 1971 to 1975.  Bull.



Environ. Contain. Toxicol. 16: 399.








Zitko, V., and 0. Hutzinger. 1976.  Uptake of  chloro- and



bromobiphenyls, hexachloro- and hexabromobenzene by  fish.



Bull. Environ. Contam.  Toxicol. 16: 665.
                             C-147

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                 SUMMARY-CRITERION FORMULATION



Existing  Guidelines and Standards



Monochlorobenzene



     The  Threshold Limit Value (TLV)  for MCB as adopted by



the American  Conference of Governmental Industrial Hygienist.c



(1971)  is 75  ppm (350 mg/m-^J.   The American Industrial Hygiene



Association Guide (1964)  considered 75 ppm to be too 'high.



The recommended  maximal allowable concentrations in air in



other countries  are:   Soviet Union, 10 ppm;  Czechoslovakia,



43 ppm; Romania,  0.05 mg/1.  The  latter value for Romania was



reported  by Gabor and Raucher  (1960)  and is  equivalent to 10



ppm.



Trichlorobenzene



     A proposed  ACGIH Threshold Limit  Value  (TLV)  standard



for TCB's  is  5 ppm (mg/1)  as a  cealing value (Am.  Conf.  Gov.



Ind. Hyg.  1977).   Sax,  et  al.  (1951)  recommends a maximum



allowable  concentration of  50 ppm  in  air for commercial  TCB,



a mixture  of  isomers.   Coate, et  al.  (1977),  citing  their



studies,  recommends that the TLV  should  be set  below 25  ppm,



preferably 5  ppm  (mg/1).  Gurfein  and  Parlova (1962)  indicate



that in the Soviet Union the maximum allowable  concentration



for TCB in water  is 30  ug/1  which  is an  organoleptic  limit.



They also  report  that  in a study of 40  rats  and 8  rabbits



administered  TCB  in drinking water  at  a  concentration  of  60



ug/1 for a period  of  seven to eight months,  no  effects were



observed.  This  information  was obtained  from an abstract  and



evaluation of the  study could not be done.
                               148

-------
suggested by FAO/WHO in 1974 as a reasonable upper limit for



HCB residues in food for human consumption (FAO/WHO), 1974).



The FAO/WHO recommendations for residues in foodstuffs were



o.5 mg/kg in fat for milk and eggs, and 1 mg/kg  in fat for



meat and poultry.  Russia and Yugoslavia have set the maximum



tolerated level of HCB in air at 0.9 mg/m3 (Int. Labor Off.



1977).



Current Levels of Exposure



Monochlorobenzene



     MCB has been detected in water monitoring  surveys of



various U.S. cities (U.S. EPA, 1975; 1977) as was presented



in  Table 1.  Levels reported were:  ground water —1.0  ug/1;



raw water contaminated by various discharges -  0.1 to 5.6



ug/1; upland water - 4.7 ug/1; industrial discharge  - 8.0  to



17.0 ug/1 and municipal water - 27 ug/1-  These  data show  a



gross estimate of possible human exposure to MCB through the



water route.



     Evidence of possible exposure from food ingestion  is  in-



direct.  MCB is stable in water and thus could  be bioaccumu-



lated by edible fish species.



     The only data concerning exposure to MCB via air are



from the industrial working environment.  Reported industrial



exposures to MCB are 0:. 02 mg/1 (average value)  and 0.3 mg/1



(highest value) (Gabor and Raucher, 1960); 0.001 to  0.01 mg/1



(Levina, et al. 1966); and 0.004 to 0.01 mg/1  (Stepangen,



1966).
                             C-150

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Tetrachlorobenzene
     The maximal permissible  concentration of TeCB in water
established by  the  Soviet Union  is  0.02  mg/1  (U.S. EPA,
1977).
Pentachlorobenzene
     No guidelines  or  standards  for pentachlorobenzene were
found.
Hexachlorobenzene
     As far as  can  be  determined,  the Occupational Safety and
Health Administration  has not set  a standard  for occupational
exposure of HCB.   HCB  has been approved  for use as a preemer-
gence  fungicide applied to seed  grain.  The Federal Republic
of Germany no longer allows the  application of HCB-containing
pesticides (Geike  and  Parasher,  1976a).   The  government of
Turkey discontinued the use of HCB-treated seed wheat in 1959
after  its  link  to  acquired toxic porphyria cutanea tarda was
/reported  (Cam,  1959).   Commercial production  of HCB in the
United States was  discontinued in 1976 (Chem. Econ. Hdbk.,
1977).  The Louisiana  State Department of Agriculture has set
the  tolerated level of HCB in meat fat at 0.3 mg/kg (U.S.
EPA,  1976).   The NHMRC (Australia)  has used this same value
for  the  tolerated  level of HCB in cows'  milk (Miller and Fox,
1973). WHO has set the tolerated level of HCB in cows' milk
at  20  ug/kg in whole milk  (Bakken and Seip, 1976).  The New
South Wales Department of Health (Australia)  has recommended
 that the  concentration of HCB in eggs must not exceed 0.1
mg/kg (Siyali, 1973).   The value of 0.6 ug HCB/kg/day was

-------
Trichlorobenzene



     Possible human exposure  to TCB's  might  occur from munici-



pal and industrial wastewater and  from surface  runoff (U.S.



EPA, 1977).  Municipal and  industrial  discharges  contained



from 0.1 ug/1 to 500 ug/1.  Surface runoff has  been found



to contain  .006 to .007 ug/1.



     In the National Organic Reconaissance Survey conducted



by EPA (1975) trichlorobenzene was found  in  drinking  water



at a level of 1.0 ug/1.



Tetrachlorobenzene



     No data are available  on current  levels of exposure.



However, the report by Morita, et al.  (1975)  gives  some  in-



dication of exposure.  Morita, et al.  (1975)  examined adipose



tissue samples obtained at general hospitals  and  medical



examiners' offices in central Tokyo.   Samples from  15



individuals were examined;  this represented  five  males and



ten females between the ages of 13 and 78.   The tissues were



examined for 1,2,4,5-TeCB as well as for  1,4-dichlorobenzene



and hexachlorobenzene.  The TeCB content  of  the fat ranged



from 0.006 to 0.039 mg/kg of tissue; the mean was 0.019



mg/kg.  The mean concentrations of 1,4-dichlorobenzene and



hexachlorobenzene were 1.7 mg/kg and 0.21 mg/kg respectively.



Interestingly, neither age nor sex correlated with  the level



of any of the chlorinated hydrocarbons in adipose tissue.
                               -1.51

-------
 Pentachlorobenzene
      Morita, et al.  (1975) examined levels of QCB in adipose
 tissue samples obtained from general hospitals and medical
 examiners' offices in central Tokyo.  The samples were from a
 total of 15 people.  The group found by gas chromatography a
 residual level of QCB to be in the range of 0.004 ug/g to
 0.020 ug/g/ with a mean value of 0.09 ug/g of fat.  Lunde and
 Bjorseth (1977) looked at blood samples from workers with
 occupational exposure to pentachlorobenzene and found that
 their blood samples contained higher levels of this compound
 than  a comparable group of workers not exposed to chloro-
 benzene.
 Hexachlorobenzene
      HCB  appears to be distributed worldwide, with high
 levels of contamination found in agricultural areas devoted
 to wheat  and related  cereal grains and in industrial areas.
 HCB is manufactured and formulated for application to seed
 wheat  to  prevent bunt;  however,  most of the HCB in the
 environment comes  from industrial  processes.   HCB is used as
 a starting  material for the production of pentachlorophenol
which  is  marketed  as  a  wood preservative.   HCB is one of  the
main substances in the  tarry residue which results from the
production  of chlorinated  hydrocarbons.   HCB  is formed as a
by-product  in the  production of  chlorine  gas  by the  electrol-
ysis of sodium  chloride  using  a  mercury electrode (Gilbertson
and Reynolds, 1972).
                             C-152

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      People  in  the  United  States are exposed to HCB in air,



 water and  food.   HCB  is  disseminated in the air as dust par-



 ticles and as a result  of  volatilization from sites having a



 high  HCB-concentration.  Airborne HCB-laden dust particles



 appear to  have  been a major factor in producing the blood



 levels in  the general public living near an industrial site



~fh  Louisiana (Burns and  Miller,  1975).  HCB is found in river



 water near industrial sites in quantities of as much as 2



 ug/kg (Laska, et al.  1976) and even in finished drinking



 water at 5 ng/kg (U.S.  EPA, 1975).  HCB occurs in a wide



 variety of foods, in  particular, terrestrial animal products,



 including  dairy products and eggs (U.S. EPA, 1976).  The



 dietary intake  of HCB has  been estimated to be 0.5 ug/day  in



 J*apan (Ushio and Doguchi,  1977)  and 35 u.g/day in Australia



 (Miller and  Fox, 1973).  Breast-fed infants in Australia and



 Norway may consume  40 yg HCB/day (Miller and Fox, 1973; Bakken



 Seip, 19761. HCB is  found in human tissues collected



 throughout the  world.
                              C-153

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     The HCB content of human adipose tissue  taken at  autopsy

is as follows:

                            Mean Values
                             (mg/kg in
                                                  Reference

                                            Brady and  Siyali, 1972

                                            Siyali, 1972

                                            Brady and  Siyali, 1972

                                            Curley, et al. 1973

                                            Mes and Campbell, 1976

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Mes, et al. 1977

                                            Acker and  Schulte, 1974

                                            Acker and  Schulte, 1974

                                            Acker and  Schulte, 1974

                                            Acker and  Schulte, 1974

                                            Acker and  Schulte, 1974

                                            Acker and  Schulte, 1974

The maximum HCB level  reported was 22 mg/kg (Acker and Schulte,

1974) .
Source
;tralia
n
)ua and
/ Guinea
jan
lada
»
it
n
n
n
•many
n
.11
it
ii
n
No. samples
75
81
38
241
3
16
50
57
22
27
56
54
54
59
59
93
Human Fat)
1.25
1.31
0.26
0.08
0.09
0.025
0.107
0.060
0.015
0.043
2.9
8.2
5.9
4.8
6.4
4.8
                              C-154

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 Special Groups at Risk

 Monochlorobenzene

      The major group at risk of MCB intoxication are  individ-

 uals exposed to MCB in the workplace.  Table 3 shows  recorded

    us trial expos 'u^-asT^o rr?-13 -- ^-ir.ard.^et al. (1969) reported
 the case of an elderly female exposed to"aT g 1 ut— 3

 0.07 percent MCB for a period of six years.  She had symptoms

 of headache, irritation of the eyes and the upper respiratory

 tract,  and was diagnosed to have medullary aplasia.  Smirnova

 and Granik (1970)  reported on three adults who developed

 numbness,  loss of  consciousness, hyperemia of the conjunctiva

 and the pharynx following exposure to "high" levels of MCB.

 Information concerning the ultimate course of these individ-

 uals is not available.   Gabor, et al. (1962) reported on in-

 dividuals  who were  exposed to benzene,  chlorobenzene and

 vinyl chloride.  Eighty-two workers examined for certain bio-

 chemical indices showed a decreased catalase activity in the

 blood and  an increase  in peroxidase,  indophenol oxidase and

 glutathione levels.  Dunaeveskii (1972)  reported on the occu-

 pational exposure of workers  exposed  to  the chemicals in-
                                             *
 volved  in  the  manufacture of  chlorobenzene at limits below

 the  allowable  levels.   After  over three  years cardiovascular

 effects  were  noted  as  pain in the area  of the heart, brady-

 cardia,  irregular variations  in  electrocardiogram,  decreased

 contractile  function of myocardium and  disorders in adapta-

 tion to physical loading.   Filatova,  et  al.  (1973)  reported

on the prolonged exposure  of  individuals involved in the pro-

duction of diisocyanates  to the  factory-  air which contained


                              C-155

-------
MCB as well  as  other chemicals. . Diseases noted include asth-



matic bronchitis,  sinus arrhythmia,  tachycardia, arterial



dystrophy  and anemic tendencies.   Petrova and Vishnevskii



(1972) studied  the course of pregnancy and deliveries in



women exposed to  air in a varnish manufacturing factory where



the air contained  three times the maximum permissible level



of MCB but also included toluene, ethyl chloride,  buta'nol,



ethyl bromide and  orthosilisic acid  ester.   The only reported



significant  adverse effect of this mixed exposure  was toxemia



of pregnancy.



Tetrachlorobenzene



     The primary  groups at risk from the exposure  to TeCB are



those who deal  with it  in the workplace.   Since it is a



metabolite of certain  insecticides,  it might be expected that



certain individuals exposed  to those  agents  might  experience



more exposure to TeCB especially  since its  elimination rate



might be relatively slow in  man.   Individuals  consuming  large



quantities of fish may  also  be at risk due  to  the  proven bio-



concentration of TeCB  in fish.  U.S.  EPA  Duluth laboratory



studies show that  the bioconcentration factor  for  1,2,4,5-



TeCB is 1,000 times, and for 1,2,3,5-TeCB  is  4,100  times.



Pentachlorobenzene



     At risk groups would  appear  to  be'those  in the  indus-



trial setting.  There might  be  an  expected  increase  in body



burdens of QCB  in  individuals on  diets  high  in  fish  due  to



the persistence of  the  compound in the  food  chain  and  to



those on diets  high in  agricultural products containing  QCB



as residues of  PCNB  spraying.





                              C-156

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Hexachlorobenzene



     Several groups appear to be at risk;  these  include wor-



kers engaged directly in:  (1) the manufacture of  HCB or in



processes in which HCB is a byproduct;  (2)  the formulation of



HCB-containing products;  (3) the disposal  of  HCB-containing



wastes; and (4) the application of HCB-containing  products.



They also include the general public living near industrial



sites/ pregnant women, fetuses, and breast-fed infants and



populations consuming large amounts of  contaminated  fish.



Two lines of evidence indicate that infants may  be at risk.



It has been demonstrated  that human milk contains  HCB, and



some infants may be exposed to relatively  high concentrations



of HCB from that source alone (Miller and  Fox, 1973;  Bakken



and Seip, 1976).  Moreover, some infants of Turkish  mothers



who consumed HCB-contaminated bread developed a  fatal disor-



der called pembe yara.  In some Turkish villages in  the re-



gion most affected by HCB-poisoning, few infants survived



during the period 1955-1960 (Cam, 1960).



     Occupational exposure is associated with an increased



body burden of HCB.  Plant workers in Louisiana  have about



200 ug HCB/kg in blood (Burns and Miller,  1975).  The HCB



content of body fat exceeds 1 mg/kg in  many parts  of the



world where HCB contamination of the environment is  extensive



(Brady and Siyali, 1972;  Acker and Schulte, 1974).



     The massive episode  of human poisoning resulting from



the consumption of bread  prepared from  HCB-treated seed wheat
                              C-157

-------
brought to  light  the  misuse of KGB-treated grain  (Cam  and



Nigogosyan, 1963).  In  spite of warnings, regulations  and



attempts at public  education, HCB-treated grain apparently



still finds its way into  the food chain, for example,  in fish



food  (Hansen, et  al.  1976; Laska, et al. 1976).   The diffi-



culty in tracing  the  source of HCB contamination  in a  diet



for laboratory animals  emphasizes the difficulties encoun-



tered in tracing  the  source of HCB in foodstuffs  for man



(Yang, et al. 1976).



     As noted previously, adipose tissue acts  as  a reservoir



for HCB.  Deletion  of fat depots can result  in mobilization



and redistribution  of stored HCB.  Weight loss for any reason



may result  in a dramatic  redistribution of HCB contained in



adipose tissue; if  the  stored levels of HCB  are high,  adverse



effects might ensue.  Many humans restrict their  dietary in-



take voluntarily  or because of illness.  In  these instances,



the redistribution  of the HCB body burden becomes a potential



added health hazard (Villeneuve, 1975).
                              C-158

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   The HCB content of human blood•samples  is  as  follows:

                               Mean Values
                                  (mg/kg
 Source       No. Samples       in Blood)               Reference

Bavaria        98 boys           0.022         Richter  and Schmid,  1976

   "           96 girls          0.017         Richter  and Schmid,  1976

Australia     185 exposed        0.055         Siyali,  1972

   11           52 unexposed      0.022         Siyali,  1972

   "           76                0.058         Siyali and  Ouw,  1973

Louisiana      86                0.0036        Burns and Miller,  1975

   The maximum HCB level reported was 0.345 mg/kg,  in a

   Louisiana waste disposal worker (Burns and Miller, 1975).

        The levels of HCB in body fat of swine and  sheep were

   sixfold and eightfold greater respectively than  the dietary

   level (Hansen, et al. 1977).  If these comparisons are  valid

   when applied to man,  it would appear that some adult humans

   have been exposed to  several mg HCB/kg/day.  A similar  con-

   clusion is reached by extrapolating the values for human

   blood.  The HCB levels in blood of rats are about tenfold

   less than the dietary level (Kuiper-Goodman,  et al.  1977).

        Current evidence would indicate that food intake may be

   the primary source of the body burden of HCB  for the general

   population although inhalation and dermal exposure may be

   more important in selected  groups  (e.g.  industrial workers).
                                C-159

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     Considering that there are relatively  little  human  ex-


posure data, that there is no long-term animal data,  and  that


some theoretical questions, at least, can be  raised  on  the


possible effects of chlorobenzene on blood-forming tissue,  it


was decided to use an uncertainty factor of 1,000.  From this


the acceptable daily intake (ADI) can be calculated  as  fol-


lows:


           .._...   70 kg x 14.4 mg/kg   . nAO    .,
           ADI = 	? 1,000	**—*- = 1.008 mg/day






     The average daily consumption of water was  taken to be


two liters and the consumption of fish to be  0.0187  kg  daily.


A bioconcentration factor of 13 was utilized.  "This  is  the


value reported by the Duluth EPA Laboratories (see Ingestion


from Foods section).  The following calculation  results in  an


acceptable criterion based on the available toxicologic data:


                   	1.008	   A-.n    ,,

                   2 + (13 x 0.0187) = 45°  ug/1


     Varshavskya (1968), the only report available,  has re-


ported the threshold concentration for odor and  taste of MCB


in reservoir water as being 20 ug/1.  This  value  is  about 4.5


percent of the possible standard calculated above.  It  is,


however, approximately 17 times greater than  the  highest con-


centration of MCB measured in survey sites  (see  Table 1).


Since water of disagreeable taste and odor  is of  significant


influence on the quality of life, and thus, related to


health, it would appear that the organoleptic level  of  20


ug/1 should be the recommended criterion.
                              C-161

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Trichlorobenzene


     While the  committee  recognizes  a need  for toxicological


information  in  order  to establish  a  criterion, there are no


reliable published  toxicological data on  TCB.   The studies by


Smith, et al.  (1978),  and Coate, et  al.  (1977) do not give


sufficient basis  for  establishing  a  toxicological criterion.


Therefore, in  lieu  of  a criterion  based on  toxicological in-


formation, an  organoleptic level of  13 y.g/1 (Varshavskaya,


1968)  is recommended.   It should be  emphasized that this is a


criterion based on  aesthetic  rather  than  on health effects.


Data on human  health  effects  need  to be developed as a more


substantial  basis for  setting a criterion for  the protection


of human health.


Tetrachlorobenzene


     The dose  of  5  mg/kg /day  reported for beagles (Braun,


1978)  was utilized  as  the NOAEL for  criterion  derivation.   An


acceptable daily  intake  (ADI) can  be calculated from the NOAEL


by using a safety factor  of 1,000  based on  a 70 kg/man:


              . _T    70  kg  x 5  mg/kg   n • c • ' .,
             ADI  =  -    — **—  = °-35 mg/day
      For  the  sake of establishing a water quality criterion,


 it  is  assumed that on the average,  a person  ingests  2 liters


 of  water  and  18.7 grams of fish.   Since fish may biomagnify


 this  compound,  a biomagnif ication factor (F) is  used in the


 calculation.

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      The equation for calculating an acceptable amount of TeCB
 in water is:
 Criterion = 2  1  + (IQOO^CKOIS?)  = 16-9 *g/l or   17 ug/1

 where:
           21=2 liters of drinking water consumed
    0.0187 kg   =  amount  of fish  consumed daily
          1000  =  biomagnification factor
           ADI  =  Allowable Daily Intake (mg/kg for a 70 kg/person)
     Thus,  the recommended criterion for TeCB in water is 17
 ug/1.
 Pentachlorobenzene
     A survey of  the  QCB literature  revealed  no acute, sub-
 chronic  or  chronic toxicity data with  the exception of the
 studies  by  Khera  and  Villeneuve (1975).   These authors found
 an adverse  effect on  the fetal  development of embryos exposed
 in utero  to pentachlorobenzene.  The adverse  effect has  not
 been labeled teratogenic because the abnormality was  an  in-
 creased  incidence of  extra  ribs  and  sternal defects.   The
 lowest level of exposure  to  the  pregnant  rat  was 5  mg/kg.
The criterion rationale  is  based on  this  exposure  level.
Since there was .no no-observable-adverse  effect  level (NOAEL)
an uncertainty factor of  5000 is used.   The use  of  this  factor
has precedent in  the pesticide literature.
                             C-163

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      From this/ the acceptable daily intake  (ADI) can be  cal-
 culated as follows:
                   ADI = 7° kg5Q0o "•*'"* - 0.07 mg
 The  average daily consumption of water was taken to be 2
 liters  and the consumption of fish to be 0.0187 kg daily.
 The  bioconcentration factor for QCB is 7800.
      Therefore:

 Recommended Criterion = 2 + (7800)°x 0.0187 = *47 U9/1 (or °'5

      The  recommended water quality criterion for pentachloro-
 benzene  is 0.5 ug/1.
 Hexachlorobenzene
      Among the studies reviewed by this  document, only two ap-
 pear  suitable  for use in the  risk assessment:   the  mouse  study
 of Cabral,  et  al.  (1978) and  the hamster study of Cabral,  et
 al.  (1977).  These  two studies  are described  in  detail in
Appendix  I.
      Under the Consent Decree  in NRDC  v.  Train,  criteria  are
 to state  "recommended maximum permissible concentrations  (in-
cluding where  appropriate, . zero)  consistent  with the protec-
tion  of aquatic.organisms,  human health,  and recreational
activities".   HCB  is suspected  of being  a human  carcinogen.
Because there  is  no  recognized  safe concentration for  a human
carcinogen,  the recommended concentration of HCB in water  for
maximum protection of  human health  is  zero.

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      Because  attaining  a  zero concentration level may be un-

 feasible  in some  cases, and  in order to assist the Agency and

 States  in the possible  future development of water quality

 regulations,  the  concentrations of HCB corresponding to

 several incremental  lifetime cancer risk levels have been

 estimated.  A cancer risk level provides an estimate of the

 additional  incidence of cancer that may be expected in an

 exposed population.   A  risk  of 10"^ for example, indicates a

 probability of one additional case of cancer for every

 100,000 people exposed, a risk of 10~6 indicates one addi-

 tional  case of cancer for every million people exposed, and

 so forth.

      In the Federal  Register notice of availability of draft

 ambient water quality criteria, EPA stated that it is consid-

 ering setting criteria  at an interim target risk level of

 10~5, 10~6, or 10~7  as  shown in the table below:

sure Assumption           Risk Levels and Corresponding Criteria  (1)
(per day.)                             ,
                           £       IP"7          1Q-Q         1Q-5

ters of  drinking water     0   0.0125 ng/1    0.125 ng/1   1.25  ng/1
consumption of 18.7 grams                                .          .  .
 and shellfish. (2)

amption  of fish and          0   0.0126 ng/1    0.126 ng/1   1.26  ng/1
Lfish only.


 (1)  Calculated by  applying  a modified "one-hit" extrapola-

      tion model described in the Federal Register, FR 15926,

      1979.  Appropriate bioassay data used in the calculation

      of the model is presented in Appendix I.  Since the ex-

      trapolation model  is linear at low doses, the additional

      lifetime risk  is directly proportional to the water


                              C-165

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     concentration.  Therefore, water concentrations  corres-



     ponding to other risk levels can be derived by multiply-



     ing or dividing one of  the risk levels  and corresponding



     water concentrations shown in the table by factors  such



     as 10, 100, 1,000, and  so forth.



(2)  Ninety-nine percent of  the HCB exposure results  from  the



     consumption of aquatic  organisms which  exhibit an  aver-



     age bioconcentration potential of 12,000-fold.   The re-



     maining one percent of  HCB exposure results from drink-



     ing water.



     Concentration levels were derived assuming a  lifetime



exposure to various amounts  of HCB,  (1) occurring  from  the



consumption of both drinking water and aquatic  life grown  in



waters containing the corresponding HCB concentrations  and,



(2) occurring solely from consumption of aquatic life grown



in the waters containing the corresponding HCB  concentra-



tions.  Because data indicating other sources of HCB  exposure



and their contributions to total body burden are inadequate



for quantitative use, the figures reflect the incremental



risks associated with the indicated routes only.
                              C-166

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  Summary of Recommended Criterion for Chlorinated Benzenes

    Substance          Criterion      Basis for Criterion

Monochlorobenzenel      20 ug/1       organoleptic effects

Trichlorobenzene        13 ug/1       organoleptic effects

Tetrachlorobenzene      17 ug/1       toxicity studies

Pentachlorobenzene      .5 ug/1       toxicity study

Hexachlorobenzene2       5 ng/1       carcinogenicity
IA toxicological evaluation of monochlorobenzene resulted
in a level of 450 ug/1; however,  organoleptic effects have
been reported at 20 ug/1-
2The value 5 ng/1 is at a risk level of 1 in 100,000.

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                          APPENDIX I

             Summary and Conclusions  Regarding the
            Carcinogenicity of Chlorinated Benzene*

      Monochlorobenzene (MCB)  is used industrially as  a solvent,

 and as a synthetic intermediate primarily for production

 of  phenol,  DDT and aniline.   MCB has been detected  in water

 contaminated by industrial  or agricultural waste,  and human

 exposure is mainly via water.  There are  no studies available

 concerning  the mutagenic  or carcinogenic  potential of MCB,

 so  that it  is not  possible  to calculate a water  quality

 criterion on the basis of an  oncogenic effect.

      There  are three  isomers  of trichlorobenzene (TCB).

 1,2,4-TCB is used  as  a carrier  of dyes, as a  flame retardant,

 and  in  the  synthesis  of herbicides.   1,2,3-TCB and 1,3,5-

 TCB  are used as synthetic intermediates,  while a mixture

 of  the  three isomers  is used  as a solvent or  lubricant.

 TCB's are likely intermediates  in mammalian metabolism of

 lindane, and TCB's  metabolize to trichlorophenols  (TCP)

 (e.g.,  1,3,5-TCB produces 2,4,6-TCP).  TCB is present in

 drinking water, but there are no studies  concerning the

 mutagenicity or carcinogenicity of these  compounds and,

 hence,  a criterion  cannot be  calculated on this  basis.

     Tetrachlorobenzene (TeCB)  exists as  three isomers.

Two of  these,  1,2,4,5-TeCB and  1,2,3,6-TeCB,  are used in

the manufacture of  2,4,5-trichlorophenoxyacetic  acid  (2,4,5-



*This summary  has been  prepared  and approved  by  the Carcinogens

 Assessment Group of EPA.
                                C-168

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T) and 2,4,5-trichlorophenol (2,4,5-TCP).   TeCB is one of
the metabolites of hexachlorobenzene and lindane.   TeCB
has not been identified in water in the United States.
However, industrial effluent may contain TeCB which causes
contamination of aquatic organisms.  Soil microorganisms
can metabolize lindane to TeCB,  which may further  contaminate
water due to soil run-off.  There are no carcinogenicity
studies available for TeCB's so that a water quality criterion
cannot be derived on this basis.
     Pentachlorobenzene (QCB) is used mainly as a precursor
in the synthesis of the fungicide pentachloronitrobenzene,
and as a flame retardant.  Lindane metabolizes i-n humans
to QCB.  QCB has entered water from industrial discharge,
or as a breakdown product of organochlorine compounds.
There is no data available concerning the mutagenicity of
QCB.  There is a translated abstract of an article by Preussman
(1975) which states that PCB is carcinogenic in mice, but
not in rats and dogs.  The abstract does not report the
data and, since the article has been difficult to obtain,
the study is not yet available to evaluate for a water quality
criterion.
     Hexachlorobenzene (HCB) is used as a fungicide and
industrially for the synthesis of chlorinated hydrocarbons,
as a plasticizer and as a flame retardant..  HCB has been
detected in water near sites of industrial discharge, and
leaches from industrial waste dumps.  HCB is very stable
in the environment and bioaccumulates, so that it is  present
                                C-169

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in many food sources  (e.g., cereals, vegetables, fish, meat,



and dairy products).  It is stored in human adipose tissue



and is present in human milk.  There is only one mutagenicity



study reported for HCB which is negative for the induction



of dominant lethal mutations in rats.



     Studies by Cabral, et al.  (1977, 1978) indicated that



oral administration of HCB induced hepatomas and liver hemangio-



endotheliomas in male and female Syrian Golden hamsters,



and hepatomas in male and female Swiss mice.  The data from



the hamster study was reported  in detail for evaluation,



whereas the mouse study was only described in an abstract.



In the hamster study, there was a statistically significant



incidence of hepatomas in males fed 50, 100, and 200 ppm



(p =7.5 X 10~7, 2.45 X 10~15,  and 1.30 X 10~19, respectively),



and of liver hemangioendtheoliomas in males fed 100 and



200 ppm  (p = 4.5 X 10~3 and 4.0 X 10~6, respectively).



There was a statistically significant incidence of hepatomas



in females fed 50, 100, and 200 ppm  (p = 7.5 X 10~7, 2.0


    — 8              —19
X 10   and 3.05 X 10    , respectively), and of liver hemangio-



endotheliomas in females fed 200 ppm  (p =  .026).



     The water quality criterion for HCB is based on the



induction of hepatomas and nemangioendotheliomas in male



Syrian Golden hamsters given a  daily oral dose of 100 ppm



 (Cabral, et al. 1977) .  The concentration of HCB in drinking



water  calculated  to  limit  human lifetime cancer risk from



HCB  to less  than  10~5 is 1.25 nanograms per liter.
                                C-170

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                  Summary of Pertinent Data
     The water quality criterion for HCB is based on  the
induction of hepatomas and hemangioendotheliomas in male
Syrian Golden hamsters given a daily oral dose of 100 ppm
for 80 weeks (Cabral, et al. 1977).  The hepatoma incidence
was 26/30 in the treated group compared with 0/40 in  the
control group,  and the hemangioendothelioma incidence was
6/30 in the treated group compared with 0/40 in the control
group.  The criterion was calculated from the following
parameters.
                                d = 100 ppm, X 0.8 = 8 mg/kg/day
                                W = .100 kg
                                F = .0187 kg
                                R = 12,000
nfc hepatoma = 26
N.  hepatoma = 30
nc hepatoma =  0
N~ hepatoma = 40
 c
n.  hemangioendothelioma =  6
N.  hemangioendothelioma = 30
n_ hemangioendothelioma =  0
 C
No hemangioendothelioma = 40
Le = 80 wk
le = 80 wk
L  = 80 wk
     Based on these parameters,  the one-hit slope (B^) is
2.2363 (mg/kg/day)    for hepatomas and 0.2477 (mg/kg/day)
for hemangioendotheliomas.   The  resulting water  concentration
of HCB calculated to keep the individual lifetime cancer
risk below 10~  is 1.25 nanogramj;  per liter.

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