TOXAPHENE
Ambient Water Quality Criteria
              Criteria and Standards Division
              Office of Water Planning and Standards
              U.S. Environmental Protection Agency
              Washington, B.C.

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                        CRITERION DOCUMENT



                            TOXAPHENE



CRITERIA



                           Aquatic Life



     For toxaphene the criterion to protect  freshwater  aquatic



life as derived using the Guidelines is 0.007  ug/1  as a 24-hour



average and the concentration should not exceed  0.47 ug/1  at  any



time.



     For toxaphene the criterion to protect  saltwater aquatic life



as derived using the Guidelines is 0.019 y.g/1  as  a  24-hour average



and the concentration should not exceed 0.12 y.g/1 at any time.



                           Human Health



     For the maximum protection of human health  from the potential



carcinogenic effects of exposure to toxaphene  through ingestion of



water and contaminated aquatic organisms, the  ambient water con-



centration is zero.  Concentrations of toxaphene  estimated to re-



sult in additional lifetime cancer risks ranging  from no addi-



tional risk to an additional risk of 1 in 100,000 are presented in



the Criterion Formulation section of this document.  The Agency is



considering setting criteria at an interim  target risk  level  in



the range of 10~5, 10"^, or 10~7 with corresponding criteria  of



4.7 x 10-4 ug/1, 4.7 x 10~5 ug/1, and 4.7 x  10~6  ug/1/  respec-



tively.

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Introduction
     Toxaphene is a commercially produced, broad spectrum,
chlorinated hydrocarbon pesticide consisting primarily of
chlorinated camphene and a mixture of related compounds
and isomers.  It was introduced in the United States in
1948 as a contact insecticide under various trade names
and is currently the most heavily used insecticide in the
United States, having replaced many of the agricultural
applications of DDT, for which registration has been cancelled,
Annual production of toxaphene exceeds 100 million pounds,
with primary usage in agricultural crop application, mainly
cotton.
     Toxaphene has demonstrated carcinogenic effects in
laboratory animals.  In addition, toxaphene is highly toxic
to many aquatic invertebrate and vertebrate species and
has been shown to cause the "broken back syndrome" in fish
fry.  These observations, together with reported bioconcentra-
tion factors as high as 91,000 indicate that toxaphene poses
                             i
a threat to living organisms,'; particularly in the aquatic
environment.  On May 25, 1977, the U.S. Environmental Protec-
tion Agency issued a notice of rebuttable presumption against
registration and continued registration of pesticide products
containing toxaphene.
     Toxaphene is a complex mixture of polychlorinated cam-
phenes and bornanes with the typical empirical formula
C10H10C18 and an average molecular weight of 414.  It is
an amber, waxy solid with a mild terpene odor, a melting
                              A-l

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point range of 65 to 90°C, a vapor pressure 0.17 to 0.40



mm Hg at 25°C, and a density of 1.64 at 25 C  (Brooks, 1974;



Metcalf, 1966).  Toxaphene has a solubility in water of



approximately 0.4 to 3.0 mg/1 and is readily  soluble in



relatively nonpolar solvents, with an octanol/water partition



coefficient of 825  (Brooks, 1974; Edwards, 1973; Metcalf,



1966; Sanborn, et al. 1976).  Paris, et al. (1977) reported



a toxaphene partition coefficient value of 3,300.  Gas chromato-



graphic analysis suggests the presence of approximately



177 components in technical toxaphene (Holmstead, et al.



1974).  Infrared absorptivity at 7.2 microns  aids in distinguish-



ing toxaphene from other chlorinated terpene  products such



as strobane.  Although tricyclene may accompany the camphene,



the commercial mixture contains less than five percent of other



terpenes.



     Toxaphene is commercially produced by reacting camphene



with chlorine in the presence of ultraviolet  radiation and



certain catalysts to yield chlorinated camphene with a chlorine



content of 67 to 69 percent (Metcalf, 1966).  The chlorine



content of the commercial product'is limited  to this narrow



range since the insecticidal activity peaks sharply at those



percentage levels.  Toxaphene is available in various formula-



tions as an emulsifiable concentrate, wettable powder, or



dust.



     The commercial product is relatively stable but may



dehydrochlorinate upon prolonged exposure to  sunlight, alkali,



or temperatures above 120°C (Metcalf, 1966; Brooks, 1974).
                              A-2

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     When dispersed in natural water systems,  toxaphene



tends to be adsorbed by the particulates present or to be



taken up by living organisms and bioconcentrated.  Thus,



it is seldom found at high levels as a soluble component



in receiving waters but can persist in sediments or remain



adsorbed on suspended solids for prolonged periods.
                              A-3

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                          REFERENCES






Brooks, G.T. 1974.  Chlorinated insecticides.  CRC Press,



Cleveland, Ohio.






Edwards, C.A. 1973.  Persistent pesticides in the environment,



2nd ed. CRC Press, Cleveland, Ohio.






Holmstead, R.L., et al. 1974.  Toxaphene composition analyzed



by combined gel chromatography - chemical ionization mass



spectrometry.  Jour. Agric. Food Chem. 22: 939.






Metcalf, R.L. 1966.  Kirk-Othmer encyclopedia of chemical



technology.  John Wiley and Sons, Inc., New York.






Paris, D.F., et al. 1977.  Bioconcentration of toxaphene
                            I


by microorganisms.  Bull. Environ. Contam. Toxicol. 17:



564.






Sanborn, J.R., et al. 1976.  The fate of chlordane and toxa-



phene in a terrestrial-aquatic model ecosystem.  Environ.



Entomol. 5: 533.
                              A-4

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AQUATIC LIFE TOXICOLOGY*



                       FRESHWATER ORGANISMS



Introduction



     Toxaphene has been used as an  insecticide  for  many  years.   At



one time toxaphene was used as a fish erraticant  and  there  are



early acute static test data on the toxicity of toxaphene which



showed it to be very toxic to freshwater  fish  (Henderson, 1959;



Katz, 1961).



     Chronic data were published recently  for  both  fish  and inver-



tebrate species.  Data for bioconcentration were  obtained from  the



fish chronic exposures but there are no appropriate invertebrate



bioconcentration data.



     The effect on aquatic plants is not  known  but  probably is  not



important since this chemical is formulated as  an insecticide  and



not as a herbicide.
*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 fol-



lowing tables contain the appropriate data  that were  found in the



literature, and at the bottom of each table  are the calculations



for deriving various measures of toxicity  as described  in the



Guidelines.
                              B-l

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Acute Toxicity



     As shown in Table  I, 52  96-hour LC50 values  are  available  for



18 species of fish.   Four of  the  52 LC50 values are from  flow-



through tests and  the rest are  from static  tests.  Johnson  and



Julin (In press) showed  that  exposures of bluegills and channel



catfish to toxaphene  in  flow-through test systems  did not produce



an appreciable  increase  in toxicity over static test  systems.



However, fathead minnows were three times more  susceptible  to



toxaphene poisoning  in  the flow-through system  (Johnson and Julin,



In press).



     Unadjusted LC50  values ranged from 0.8 to  28  ug/1 for  the  18



species of fish listed  in Table 1.  No single species appeared



uniquely sensitive or resistant.  When the  geometric  mean of all



values  in Table 1  is  divided  by the sensitivity factor (3.9) the



LC50 value calculated  (0.92 ug/1) is higher than  one  value  in



Table 1.  That  value  (0.8 ug/1) is for channel  catfish swim-up  fry



at 25°  C, suggesting  a  very reasonable fit  of the  data to the pro-



cedures in the  Guidelines.  The Final Fish  Acute  Value is 0.92



ug/1.



     The data base for  invertebrate species (Table 2) contains  17
                        ;
                        >

data points for 13 species; six species represent  rather  different



decapods and insects.   There  are  no toxicity data  with flowthrough



test procedures.   The range of  species sensitivity displayed in



Table 2 (the highest  LC50 value divided by  the  lowest is  large,



178.  The geometric mean of the invertebrate LC50  data is 9.6



ug/1.   When the geometric mean  is divided by the  sensitivity fac-



tor  (21), a value  of  0.46 ug/1  becomes the  Final  Invertebrate



Acute Value.  The  lowest LC50 value is 1.1  ug/1 which is  2.4 times



the  Final Invertebrate  Acute  Value.


                              B-2

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     Since the Final Invertebrate Acute Value of 0.46  ug/1  is



lower than the Final Fish Acute Value of 0.92 ug/1,  the  Final



Acute Value for freshwater aquatic life is 0.46 ug/1.



Chronic Toxicity



     There are two chronic test values for fathead minnows  and



channel catfish (Table 3).  A third chronic test result  with brook



trout is in Table 6 because even at the lowest concentration



tested (0.039 ug/D there was an effect on growth.   The  geometric



mean of the chronic values is 0.047 ug/1 which is 77 times  lower



than the geometric mean acute value for fish.  The chronic  value



divided by the sensitivity factor (6.7) from the Guidelines gives  a



95 percent species protection concentration of 0.007 ug/1.  A



different method of estimating the same value  is obtained  by



multiplying the Final Fish Acute Value by the application  factor



calculated from the chronic data.  This estimate is  0.018  ug/1,



about 2 1/2 times larger,.  This suggests the Guideline sensitivity



factor is reasonable for  fish chronic toxicity.  The Final  Fish



Chronic Value is th'e lowest of the three estimates  in  Table 3 • or



0.007  ug/1.



     Chronic data for invertebrate species are in Table  4.   Chronic



values for three species  vary by a factor of 20, indicating the



sensitivity difference between the tested species.   Daphnia magna



was the most sensitive of the three species.  The chronic  value



divided by the sensitivity factor (5.1) from the Guidelines gives



a 95 percent species protection concentration of 0.06  ug/1. This



value is lower than the lowest chronic value of 0.09 ug/1/  and



0.06 ug/1 becomes the Final Invertebrate Chronic Value.
                              B-3

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Plant Effects
     No data for plant effects were  found.
Residues
     Table 5 contains equilibrium bioconcentration  data  for  three
species of fish.  The geometric mean of  the bioconcentration  fac-
tors is 44,000.  A residue  limit for consumers of aquatic  life,
established by the U.S.  Food and Drug Administration  is  0.5  mg/kg
in animal feed.  Fish meal  is used in domestic animal  feed and  the
0.5 mg/kg value is used  to  calculate a Residue Limited Toxicant
Concentration  (RLTC) value.  By dividing  the  FDA limit of  0.5
mg/kg by the bioconcentration factor of  44,000 a RLTC  value  of
0.011 ug/1 is obtained.   The Final Fish  Chronic Value  (0.007
ug/1), Final Invertebrate Chronic Value  (0.06 ug/1),  Final Plant
Value (no data) and  the  RLTC Value (0.011 ug/D are the  values
derived to protect aquatic  life and  the  consumer of aquatic  life.
The lowest value is  the  Final Fish Chronic Value and  this  becomes
the Final Chronic Value.
Miscellaneous
     Table 6 contains no data that would  alter the  selection  of
0.007 ug/1 for the Final Chronic Value.
                              B-4

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CRITERION FORMULATION



                     Freshwater-Aquatic Life



Summary of Available Data



     The concentrations below have been rounded  to  two  significant



figures.



     Final Fish Acute Value = 0.92 ug/1



     Final Invertebrate Acute Value = 0.46 ug/1



          Final Acute Value = 0.47 ug/1



     Final Fish Chronic Value = 0.007 ug/1



     Final Invertebrate Chronic Value = 0.06 ug/1



     Final Plant Value = not available



     Residue Limited Toxicant Concentration =  0.011  ug/1



          Final Chronic Value = 0.007 ug/1



          0.44 x Final Acute Value = 0.20 ug/1



     The maximum concentration of toxaphene is the  Final  Acute



Value of 0.47 ug/1 and the 24-hour average concentration  is  the



Final Chronic Value of 0.007 ug/1-  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 toxaphene the criterion to  protect freshwater



aquatic life as derived using the Guidelines is  0.007 ug/1 as a



24-hour average and the concentration should not exceed 0.47 ug/1



at any time.
                             B-5

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    Table  1.    Freshwater  iiuh acute values  for  toxaphcne
E
Q£2jiliiuiH fj
Coho salmon.
Qncorhynchiis kisutch
Coho salmon,
Oncorhynchus kiautch
Chinook salmon,
Oncorhynchus tshawytcha
Rainbow trout,
Salino tsatrdneri
Rainbow trout,
Salino galrdnerl
Rainbow trout.
Salino gajrdnerl
Rainbow trout,
Sa|nio jfairdnerl
Rainbow trout.
Sal mo gairdnerl
Rainbow trout.
Salnio Eairdncrl
Brown trout,
§2i 15°. £F!iE£i
Brook trout.
Sal veil nils fontinalia
Stoneroller,
Campos toma annum 1 urn
Goldfish.
Carasuius auratua
Goldfish,
Carassius auratua
Goldfish.
ilodsuay
lethod*
S

S

S

S

S

S

S

S

S

S

FT

S

S

S

S
Teat
Cope.**
U

U

U

U

U

U

U

U

U

U

M

1)

U

U

U
Time
itlll)
96

96

96

96

96

96

96

96

96

96

96

96

96

96

96
LC50
luq/H
9.4

8

2.5

8.4

8.4

5.4

2.7

1.8

11

3

10.8

14

5.6'

28

14
Adjusted
LCbO
( ii()/ll
5.1

4.4

1.4

4.6

4.6

3.0

1.5

0.98

6.0

1.6

10.8

7.7

3.1

15

7.7

Keferenca
Katz, 1961

Macek & McAllister,
1970
Katz, 1961

Katz, 1961

Mahdl. 1966

Cope, 1965

Cope, 1965

Cope. 1965

Mucek £. McAllister,
1970
Macek & McAllister.
1970
Mayer, et al. 1975

Mahdl. 1966

Henderson, et al. 1959

Mahdl, 1966

Macek 6, McAllister.
uurafua
                                                                1970

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1.    (Oonti (mud)


Organism
Carp ,
Cflllia'Ji carplo
Golden shiner,
Notemlgonus crysoleucas
Bluntnose minnow.
Pimcphales notatua
Fathead minnow.
Pimephalcs promelas
Fathead minnow,
Pimup_hales proinclaa
Fathead minnow.
Cd Pimcphales promelas
1
"^ Fathead minnow,
Pimcphales promelas
Fathead minnow,
Plmephales promelaa
Fathead minnow.
I'iincjihales gromelaa
Black bullhead.
Ictalurus melaa
Black bullhead.
Ictalurus melas
Channel catflch,
Ictalurim punctatus
Channel catfish.
Ictajtmis punctatua
Channel catfish,
Ictalurus punctatus
Channel catfish,
Tctalurus puncLatus

Uiodtioay
Met nod*
S

S

S

S

S

S


S

S

FT

S

S

S

FT

S

S


Teat
Cone,**
U

U

U

U

U

U


U

U

U

U

U

U

U

U

U


Time
-UlEfi) .
96

96

96

96

96

96


96

96

96

96

96

96

96

96

96


I.C50
Jim/il
4

6

6.3

7.5

5.1

14


13

20

7

1.8

5

13

5.5

2.8

O.B

Adjusted
LCSO
J»a/il —
2.2

3.3

3.4

4.1

2.8

7.7


7.1

11

5.4

0.98

2.7

7.1

4.2

1.5

.0.44



li£i£££L£S
Macek & McAllister,
1970
Mahdl, 1966

Mahdl, 1966
-
Henderson, et al. 1959

Henderson, et al. 1959

Macek & McAllister.
1970

Cohen, et al. 1960

Johnson & Julln, In
press
Johnson & Julln, In
press
Mahdl, 1966

Macek & McAllister.
1970
Macek & McAllister.
1970
Johnson & Julln, In
press
Johnson & Julln, In
"press
Johnson & Julln. In
press

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                      Tablu  1.   (Continued)
CO
Or^anlgin
Channel catfish,
Ictalurua punctatus
Channel catfish.
Ictaluvus punctatus
Channel catfish,
Ictalurus punctatua
Channel catfish,
Ictalurua piinctatua
Channel catfish.
Ictalurus punctatua
Channel catfish,
Ictalurus punctatua
Channel catfish,
Ictalurus punctatus
Channel catfish,
Tctalurus punctatua
Channel catfish,
Ictalurus punctatua
Channel catfish,
Ictalurus punctatus
Mosquitoflsh,
Gamhusia aff inls
Cuppy.
l.chititos reticulatus
Bluegill,
Lep_om|a_ niacrochj rua
llluei-ill,
l.epoinls macrochl rus
Blue-gill.
ftetliocl*
S
S

S

S

S

S

S

S

S

S

S

S

S

S

S
Teat
£2Ii£i**
U
U

u

u

u

u

u

u

u

u

u

u

u

u

u
TlBIO
JlltS)
96
96

96

96

96

96

96

96 -

96

96

96

96

96

96

-96
LCSO
Juq/1 I
4.7
4.2

3.7

2.7

3.4

3.0

3.9

3.2

3.9

4.7

8

20

3.2

2.6

2.4
Adjusted
LC50
2.6
2.3

2.0

1.5

1.9

1.6

2.1

1.7

2.1

2.6

4.4

11

1.7

1.4

1.3
Johnson & Julin, In
press
Johnson & Julin, In
press
Johnson. & Julin, In
preas
Johnson & Julin, In
press
Johnson & Julln, In
press
Johnson & Julln, In
press
Johnson & Julin. In
preas
Johnson & Julin, In
press
Johnson £> Julin, In
preas
Johnson & Julin, In
press
Chalyarach, et al. 1975

Henderson, et al. 1959

Macek, et al. 1969

Macek, et al. 1969

Macek. et al. 1969
                niacrochirus

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              Table 1.    (Continued)
Bioassay Teat
Or
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               Table 2.   Freshwater invertebrate acute  values for toxapliene
                         Biuibuay  Test       Time
                                   Cone.**
                                                        LC50
Adjusted
LCtiO
(iHi/ll    hertirengfc
Cladoceran,
Simocephalua aorrulutua
Cladoceran,
Slmocephalus serrulatus
Cladoceran,
Duli!H!i.a pulex
Cladoceran,
Dajihnia magna
Scud,
Gaininarus lacuatrls
Scud.
7 Gaininarus fasclatua
o Scud;
Gaimiiarua faaclatus
Scud,
Gaininarus pseudollinnaeus
Glass shrimp,
Palucmonetea kadiakcna j a
Glass uhriuip.
Palaemonetes kadlakensis
Glass shrimp.
Pill .'icmonetes kadtakenals
Crayfish,
Procamharua siuiulans
Crayfish,
Procambarus acutus
Midge (larva),
Chlronnmus plumosus
Stonef ly,
S

S

S

S

S

S

S

S

S

S

S

S

S

S

S
U

U

U

U

U

U

U

U

U

U

U

U

U

U

U
•»••.••>
48

48

48

48

96

96

96

96

96

96

24

96

48

48

96
19

10

15

10

26

35

6

24^
V
36

28

21

210

61

180

2.3
6.9

3.6

5.5

3.6

22

30

5.1

20

30

24

4.6

178

22

66

1.9
Sanders

Sanders

Sanders

Sanders

Sanders

Sanders

Sanders

Sanders

& Cope, 1966

& Cope, 1966

& Cope. 1966

, In press

. 1969

. 1972

, 1972

, In press

Chaiyarach, et al.

Sanders

Naqvi &


. 1972

















1975



Ferguson. 1970

Chaiyarach, et al.

Albaugh

Sanders

Sanders

, 1972

, In press

& Cope. 1968

1975






I'teroiiarcya callfurnlca

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                                 Table  2.   (Continued)
Bioaaaay Teat
Qiaduiaa ttsiLsli- cone.**
Stoneflv. S U
Ptcronurcclla badla
Stonefly. S U
Claassenla aahnlosa
Adjusted
Tine LC50 I.C50
(hra) |uq/l| (U9/H {tetecence
96 3.0 2.5 Sander a & Cope, 1968

96 1.3 1.1 Sanders & Cope. 1968

         *  S - atatlc


         ** U • unmeasured
                                                               96
            Geouiecrlc mean of adjusted  valuea  » 9.6 vig/l     -AT- -0.46 iig/1
09
I

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               Table  3.   Freuhuater  fitih chronic values for toxaphenc (Mayer, et al. 1977)


                                                  Chronic
                                        Liuiita    Value
Or^artigm                      Tgat*     (ufl/1)
Fathead minnow,               LC      0.025-0.054   0.037
Plmephaleg promelaa

Channel catfish,              LC      0.049-0.072   0.059
Tct.alurua punctatua
  I.C u life cycle or partial  life  cycle

  Geometric mean of chronic values -  0.047  Mg/1     —tT7   " 0.007 ng/1

  Lowest chronic value ** 0.037  iig/1
                   Application Factor Values  (Mayer,  et al.  1977)

                        96-hr LC50      MATC
Organism                _JjJ6ZlL_     lilfiAil.        AF

Fathead minnow,              7         0.037        0.0053
Pimeplialea promelaa

Channel catfish,             5.5       0.059        0.011
Ictajiirug punctatua
Ueomutric mean AF " 0.0076                              Geometric mean LC50 "6,2 ng/1 "
                       0.0076 /0.92  ug/1 x  6.2  |.g/l  -  0.018 ng/1

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                  Table 4.  Freuliwuter invertebvute chronic  values for toxapher.e
to
I
         Oiqaniam
                                                  Chronic
                                        Liiaica    Value
                              ffegt*      luq/ll    luq/ll
                                                            0.31
Deference
Cladoceran.
l)aphnta magna
Scud.
Gaiuoarua paeudallanaeua
Mldjje (larva),
Chi ronomus pluonaiis

I.C
I.C
LC
0.07-0.12
0.13-0.25
1.0-3.2
0.09
0.18
1.8
Sanders,
Sanders ,
X
Sandera ,
In preaa
In preaa
In preaa
*  Life cycle ov partial life cycle
   Geometric mean of chronic value* - 0.31  ng/l    J7I~ -0.06 tig/l
   Lowoac chronic value • 0.09

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               Table   5.   Freshwater realduea  fur toxaphene
(-•
•u
Brook crout  (fry).
Salvellnua font!nail a

brook trout  (yearling),
Salvelinua fonttnalis

Fathead minnow.
Plmephalca promelaa

Channel catfish,
Ictalurua punctatus

Channel catfish (fry),
Ictalurua punctattia
Organism

Han


Domestic animals
Time
Bioconcentration Factor (days)
76,000
16,000
69,000
26,000
50.000
Maximum Permissible Tissue
Act ion- Level or Effect
15
161
98
100
30
Concentration
Concentration .
(mg/kg) •••;?
                                   edible fish and shellfish
                                   animal feed
5.0
0.5
                                                                           Ketetence
                                                                                    Mayer, et al., 1975
                                                                                    Mayer, et al.. 1975
                                                                                    Mayer, et al., 1977
                                                                                    Mayer, et al., 1977
                                                                                    Mayer, et al., 1977
 'Reference

 U.S. FDA Admin. Guideline
 7420.09

 U.S. FDA Admin. Guideline
. 7426.04
Geometric mean fish bioconcentration factor «? 44,000

Lowest maximum residue concentration - 0.5 mg/kg
                   1.00001.1
                          or 0.011 ng/1

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                            Table 6.  Other freshwater data for Coxaphene
        Oruani am
                                 Teat
                                                            Result
        Brook  trout.
        SalveHnus  fonttnalta

        Drook  trout .
                    fonttnalla
03

M
(J\
Brook trout,
Sal velinua fonttnalta

Brook trout,
Salvellmia fonttnalta

Brook trout (fry) .
Sal veil nua fontlnalia

Brook trout (fry) ,
Salvellnus fonttnalia

Fathead minnow,
Piincphalea prpmplaa

Fathead minnow (fry) ,
Piincphalea promclaa

Fathead minnow,
Flint! phales promelaa

Cliannel catfluh,
Ictaluriu) punctatua

Channel catfluh,
Tctalurua punctatua
                         90 daya  No effect on growth
                        166 daya  Growth inhibition
                                  11  daya   LTC-I.C50
                                 161  daya   Decreaaed
                                           reproduction

                                  60  daya   Growth  inhibition
                                  15  daya  Mortality
30 days  Growth inhibition
                                  30  daya  Growth  inhibition
                                   7  daya  LTC-LC50
                                  5 daya  LTC-LC50
                                 30 daya  Growth  inhibition
                                  <0.039    Mayer, et al.  1975
                                   0.27     Mayer, et al.  1975
                                   4.1      Mayer, et al.  1975
                                   0.075    Mayer, et al.  1975
                                   0.041    Mayer, et al.  1975
                                   0.041    Mayer, et al.  1975
0.097    Mayer, et al.  1977
                                   0.054    Mayer, et al.  1977
                                   5.3      Mayer, et al.  1977
                                  15.2      Mayer, et al.  1977
                                   0.299    Mayer, et al.  1977
        Channel catfish.
        Tctaluriis punctatua
                         30 daya  Backbone quality
                                   0.072    Mayer, et al.. 1977

-------
                       SALTWATER ORGANISMS
Introduction
     Toxaphene has been  used as  an  insecticide  for  many  years;  its
toxicity, persistence, and bioconcentration potential  has  been
well documented in studies using saltwater plants and  animals.
Its acute toxicity, particularly to  fishes, prompted  its use  to
control populations of undesirable  fishes.
     Chronic toxicity of  toxaphene  to saltwater  animals  has been
documented only recently, but  its toxicity to plants  and biocon-
centration by oysters and fishes has been known  since  the  1960's.
     Toxaphene is a mixture of numerous  chlorinated terpenes, but
which terpenes are most  toxic  to saltwater biota is unknown be-
cause they have not been  tested  individually.
Acute Toxicity
     In flow-through toxicity  tests  with five fish  species (Table
7) unadjusted 48- and 96-hour  LC50  values ranged from 0.5  ug/1  to
5.5 ug/1 (Butler, 1963;  1964;  Korn  and Earnest,  1974;  and
Schimmel, et al. 1977).   Katz  (1961) exposed the threespine
stickleback to toxaphene  in static  tests at 5 and 25°/oo
salinity and reported 96-hour  LC50  values of 8.6 and  7.8 ug/1/
respectively.  Freshwater fishes tested  were comparably  sensitive
(Table 1).
     The 12 saltwater invertebrate  species tested were highly
disparate in species sensitivity to  toxaphene (Table  8).
Crustaceans varied greatly in  species sensitivity.  Blue crabs
were relatively insensitive; the unadjusted 48-  and 96-hour LC50
values ranged from 330 ug/1 to 2,700 ug/1 (Butler,  1963; McKenzie,
1970).  Several life stages of the  pink  shrimp were nearly identi-
                              B-16

-------
cal in sensitivity to toxaphene with the 96-hour LC50 values



ranging from 1.4 to 2.2 ug/1 (Courtenay and Roberts, 1973;



Schimmel, et al. 1977).  However, sensitivity of individuals  of



five early life stages of the drift-line crab exposed to toxaphene



in 96-hour toxicity tests was inversely related to the age  of the



crabs tested.  For example, the 96-hour LC50 of stage I larvae was



0.054 ug/1; that for megalopa (the oldest stage tested) was 8.4



ug/1 (Table 8).  Other than stage I drift-line crab larvae, the



most sensitive crustacean tested was the copepod, Acartia tonsa,



the 96-hour LC50 being 0.11 ug/1 when recalculated by probit



analysis (Finney, 1971; Khattat and Farley, 1976).  The unadjusted



96-hour LC50 to mactrid clams, the least sensitive species, was



460,000 ug/1 (Chaiyarach, et al. 1975).  However, the data  from



toxicity tests such as this with molluscs which can close their



valves and avoid direct contact with exposure water for indefinite



periods of time may underestimate a chemical's toxicity.  In  a



more appropriate test with molluscs, embryos of Mercenaria



rnercenaria were also relatively insensitive with a 48-hour  EC50 of



1,120 ug/1 (Davis and Hidu, 1969).



Chronic Toxicity



     Chronic effects of toxaphene on saltwater fishes indicate



that concentrations that do not affect individuals in their early



stages differ little from 96-hour LC50 values.  Goodman, et al.



(1978) conducted an embryo-larval study with the sneepshead minnow



in which toxaphene was not lethal to embryos at concentrations as



high as 2.5 ug/1.  Combined embryo and larval mortality during a



28-day exposure to 2.5 ug/1 was significantly greater than  control



mortality, but at 1.1 ug/1 mortality was not greater.  Therefore,
                             B-17

-------
concentrations not affecting survival or growth of  sheepshead  min-
nows in an embryo-larval test were the same as the  96-hour  LC50  of
toxaphene to juvenile sheepshead minnows.  Schimmel,  et  al.  (1977)
exposed longnose killifish to toxaphene in a 28-day embryolarval
study.  Significant effects on survival were evident  at  1.3  ug/1/
but not at 0.6 ug/1.  No 96-hour LC50 data are available  for the
juvenile, of this species; however, it probably would  not  be
greater than 10 times the no-effect concentration in  an  embryo-
larval test (Schimmel, et al. 1977).
     The data for saltwater fishes contrast sharply with  chronic
test data for freshwater fishes  (Table 3).  The 96-hour  LC50 of
toxaphene for the channel catfish was nearly 100 times the  highest
concentration that produced no observable deleterious effects  in  a
chronic study; that for the fathead minnowr Pimephales promelas,
was nearly 200 times.  Data for  four other pesticides support  the
hypothesis that differences between acute- and chronic-effect
concentrations in freshwater and saltwater fishes are similar
(Parrish, et al. 1978).  Probably either saltwater  fishes differ
from freshwater fishes in chronic sensitivity to toxaphene  because
of the innate differences between salt water and fresh water,  or
theidifference in sensitivity may be due to phylogenetic  factors,
such as those reported by Macek  and McAllister (1970).   If  the
latter is true, then a criterion based on a saltwater cyprinodon-
tid fish, such as sheepshead minnow or longnose killifish in an
embryo-larval study may not provide adequate protection  for other
estuarine and marine fishes.
     The mysid shrimp is the only saltwater invertebrate  species
exposed to toxaphene in a lifecycle study (Table 10)  (Nimmo,
                              Fi-18

-------
1977).  Exposure to 0.14 ug/1 of salt water decreased  the  number



of young produced per female by 82 percent.  An  unmeasured  concen-



tration of 0.067 ug/1.did not adversely affect reproduction.   The



limits on the chronic values (0.07 to 0.12 ug/D  generated  using



the freshwater cladoceran, Daphnia magna  (Table  4),  are  comparable



to those for the saltwater mysid.



Plant Effects



      Ukeles (1962) found that five species of algae varied



greatly in sensitivity to toxaphene (Table 11).   The most  sensi-



tive organism was the dinoflagellate, Monochrysis lutheri,  its



growth b.eing inhibited at a concentration of 0.15 ug/1.  Data  from



Butler (1963) indicated that 1,000 ug/1 caused a 90.8  percent



decrease in productivity of natural phytoplankton communities.



Residues



     The bioconcentration of toxaphene into tissues  of saltwater



animals has been well studied (Butler, 1960; Goodman,  et al. 1978;



Lowe, 1964; Lowe, et al. 1970; 'and Schimmel, et  al.  1977)  (Table



12).  Lowe et al.  (1970) exposed eastern oysters, Crassostrea



virginica, to a concentration of 0.7 ug/1 for 36  weeks,  followed



by a 12-week depuration period.  . The maximum bioconcentration



factor (BCF), 32,800, was attained after  24 weeks.   No toxaphene



was found in oyster tissues after the 12-week depuration period.



     Goodman, et al.  (1978) exposed sheepshead minnow  embryos  and



fry to toxaphene for 28 days and reported an, average BCF of 9,800.



Schimmel, et al. (1977) exposed newly-hatched and juvenile  long-



nose killifish for 28 days and reported average  BCF's  of 27,900



and 29,450, respectively.
                             B-19

-------
     Therefore, the geometric mean BCF  for  saltwater  fishes  (ex-

cluding ova of the longnose killifish)  was  12,690  and  that  for


oysters exposed to toxaphene was  32,800.


Data Interpretation and Use of Guidelines


     The acute toxicity of toxaphene  to saltwater  organisms  may be


underestmated when LC50 values are based on unmeasured  concen-


trations, thereby . justifying the  use  of adjustment factors  for


this test condition.   For example, Schimmel,  et  al.  (1977)  re-


ported 96-hour LC50 values for five species based  on  unmeasured


and measured concentrations.  Four of the five measured  values


were lower and one was equal to the unmeasured value.   Only  the


test results with measured concentrations are listed  in  Tables  7


and 8.


     Variability  in species sensitivity of  fishes  exposed  to


toxaphene is approximately a factor of  10 (Table 7) compared with


that for invertebrate  species tested  (approximately a  factor of


105, not including data on the mactrid  clam;  Table 8).   There-


fore, use of the  greater species  sensitivity  factors  for inver-


tebrate species appears justified.  The use of adjustment  factors


contained in the  Guidelines for .species sensitivity produces a


Final Fish Acute  Value of 0.44 ug/1  (Table  7) which  is  only

                                                         1
slightly lower than the lowest adjusted LC50  values.   Since  the


Guidelines provide a  Final Fish Acute Value which  is  lower  than or


equal to 95 percent of the LC50 values, the sensitivity  adjustment


factor appears adequate.  For invertebrate  species, however, the


Final Invertebrate Acute Value of 0.12  ug/1 (Table 8)  is lower


than the adjusted LC50 values for nine  of eleven (82 percent)


species  tested.   Sesarma cinereum and Acartia tonsa,  (Table  8)
                              B-20

-------
would, therefore, not be protected from acute  effects  of  toxaphene
at the Final Invertebrate Acute Value.  Reasons  for  providing  a
less-than-adequate Final Acute Value for  the two species  above
probably lie in the extremely high range  (up to  100,000)  in LC50
values from species to species.  This  is  significant because these
two species are saltwater zooplankters which are especially impor-
tant as foods and larvae in saltwater  systems.
     Data from an embryo-larval test (Goodman, et al.  1978) and
information from the Guidelines were used  to obtain  a  saltwater
fish chronic value for toxaphene (Table 9).  No  reports of  entire
life-cycle exposures of saltwater fish were available  in  the
literature, but estimates of chronic values in these tests  can be
obtained by using procedures in the Guidelines with  data  on
embryo-larval tests.  Use of this procedure and  a species sensi-
tivity factor in the Guidelines appears to be  justified,  since the
sheepshead minnow has been shown to be generally less  sensitive  in
acute studies than are several other saltwater fishes.  No  other
saltwater fish can now be tested in life-cycle tests for  compari-
son of chronic sensitivity.  Therefore, 0.12 ug/1 is the  Final
Fish Chronic Value.
     One saltwater invertebrate species,  Mysidopsis  bahia,  has
been exposed to toxaphene in a chronic toxicity  test (Nimmo,
1977).  Using the procedures in the Guidelines,  a chronic value  of
0.097 ug/1 is derived from this test.  Using the species  sensi-
tivity factor of 5.1, a Final Invertebrate Chronic Value  of 0.019
ug/1 is derived (Table 10).   Since Mysidopsis bahia is a rela-
tively sensitive species, it is believed  that  this value  is
adequate to protect 95 percent of invertebrate species  exposed
chronically to toxaphene.
                             B-21

-------
     Data derived from plant  studies with  toxapene  (Table  11)  do
not generate a Final Plant Value  lower  than  the  Final  Invertebrate
Chronic Value of 0.019 ug/1.
     Saltwater residue data for toxaphene  (Table 12),  based on the*
average BCF's reported by Goodman, et al.  (1978)  and Schimmel,  et
al. (1977) and FDA maximum tissue concentration  of  toxaphene
allowable in animal feed  (0.5 mg/kg), produce a  Residue  Limited
Toxicant Concentration (RLTC) of  0.039  ug/1  in salt water.  siJse of:
the oyster BCF value of 32,800  (Lowe, et al. 1970)  and the FDA
maximum concentration of  toxaphene in edible shellfish (5.0 mg/kg)
provides a higher RLTC (0.15  ug/1).
Miscellaneous
     No data from Table 13 suggest any  more  sensitive  effects  than
those already discussed.
                              B-22

-------
CRITERION FORMULATION



                      Saltwater-Aquatic Life



Summary of Available Data



     The concentrations below have been rounded  to  two  significant



figures.



     Final Fish Acute Value = 0.44 ug/1



     Final Invertebrate Acute Value = 0.12 ug/1



          Final Acute Value = 0.12 ug/1



     Final Fish Chronic Value = 0.12 ug/1



     Final Invertebrate Chronic Value = 0.019 ug/1



     Final Plant Value =0.15 ug/1



     Residue Limited Toxicant Concentration = 0.039 ug/1



          Final Chronic Value = 0.019 ug/1



          0.44 x Final Acute Value = 0.053 ug/1



     The maximum concentration of toxaphene is the  Final  Acute



Value of 0.12 ug/1 and the 24-hour average concentration  is  the



Final Chronic Value of 0.019.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 toxaphene the criterion to  protect saltwater



aquatic life as derived using the Guidelines is  0.019 ug/1 as a



24-hour average and the concentration should not  exceed 0.12  ug/1



at any time.
                             B-23

-------
              Table  7.   Marine fish acute values for toxaphene
                                                                Adjusted
Bioauuay Tent
QiflSniSffl Method A- Cone. A*











CO
r
to


Sheepshead minnow.
Cypriiiodon yarict-atua
Tlireespine stickleback,
Gasterositetis aculeutua
Threespine stickleback,
Caaterosteus aculeatua
Striped bass.
Morone aaxutilla
I'infish,
I. a go don rhoinhnides
Spot,
Lelostomus xanthurus


White mullet,
Mu^ll curcrna
FT M

S U

S U

FT U

FT M

FT U


FT U

Time
fhra)
96

96

96

96

96

48


48

LC50
(uq/JL
1.1

8.6

7.8

4.4

0.5

1.0


5.5

LC50
(uq/lj
1.1

4.7

4.3

3.4

0.5

0.62


3.4


jiotertrnce
Schinuiiel, et al.

Katz, 1961

Katz. 1961

Korn & Earnest.

Schinunel , et al.

butler. 1964


butler, 1963



1977





1974

1977
•





*S = static, FT « flow-through
      measured. U " unmeasured
  Geometric mean of adjusted  values » 1.61 Mg/1   ~— " 0.44 Mg/1
  Lowest value from a flow-through test with measured concentrations ° 0.5 i'g/1

-------
Table- 8.   Marine Invertebrate acute values for toxaphene
                                                  Adjusted
B;
Eastern oyster,
Crasaoatrea vlrginlca
Eastern oyster,
Crasaoatreg vlrginlca
Eastern oyster,
Craasostrea ytr^lnicu
Hard clam (embryo),
Murcenarla inercenarla
Mactrld clam,
liS'lfitS. cuneata
Cope pod,
^ Acartia tonsa
IO
m Myeid ahrimp (juvenile),
Myaldopais baj»lj»
My a Id alirlmp (adult).
Mysidopals bah la
blue crab,
Calllnuctea sapldiis
•Blue crab,
Calllnectca sapldus
blue crab,
Culllnectes sapidiia
111 ue crab,
Ca 1 1 inactea aaplijua
Blue crab,
C.al linuctcs 221?iihi2-
Uluu crab,
Ci»l 1 1 nucteu aa|>ldua
blue crab,
Oil) 1 1 nectes tiapldu-j
FT
FT
FT
S
S

S
FT
FT
FT
S
S
S
S

S
S
T«iBt
Cone.**
M
U
U
U
U

U
M
M
U
U
U
U
U

U
U
Time
IfiLfi)
96
96
96
48
96

96
96
96
48
96
96
96
96

96
96
I£50
(IK1/U
16.***
63.***
57.***
LC!»0
mu/ii 	
16
48.
44
1.120**** 949
460, 000**** 309, 600

0.11*****
6.32
3.19 v
330.***
580
900
370
960

380
770

0.093
6.32
. 3.19
109
491
762
313
813

322
652
hcterf net
Schiounel
Butler,
Butler.
. et al. 1977
1963
1963
Davis & Illdu. 1969
Chaiyarach, et al. 1975


Khattac & Farley, 1976
Nlnuno, 1977
Nliiuno. 1977
Butler,
McKeiule
McKenzie
McKenzle
McKenzie

McKenzie
McKenzie
1963
. 1970
, 1970
, 1970
, 1970

. 1970
. 1970

-------
               Table 8.    (Continued)
Uioaeaay Test Tine
UllliiiiSS Method* Conc^** Jll£S)
Blue crab, S U 96
Calllncctea aapldua
03
1
to
Blue crab, S
Callinectea sapidua
Blue crab, S
Callinectea aapldus
Korean ahrimp, S
Palacroon macrodactylus
Korean shrimp, FT
Palaeroon macrodactylua
Grass ahrimp, FT
Palaemonetes puglo
Urown ahrimp. FT
Penaeua aztecua
Pink ahrimp. FT
Panaeua duorarum
Pink ahrimp (nauplius). S
Penaeua duorarum
Pink shrimp (protozoea). S
Penaeua duorarum
Pink uhrimp (uyala), S
Ponueus duorarum
Mud crab (atage I larva), S
Khithropanopltia harriail
Drift-line crab (atage S
1 larva) . .
Sesanuu clnereum
U
U
U
U
M
U
M
U
U
U
U
U
96
96
96
96
96
48
96
96
96
96
96
96
LC50
...lUfl/U
1,200 :
2.700 I
1,000
20.3
20.8
4.4
4.9***
1.4
2.2
1.8
1.4
43.75
0.054
Adjusted
LC50
1,016
2,287
847
17.2
16.0
4.4
1.6
1.9
1.5
1.2
37.1
0.046


McKenzle, 1970
McKenzie. 1970
McKenzle. 1970
Schoettger, 1970
Schoettger, 1970
Schlmmel. et al. 1977
Butler, 1963
Schlmuel. et al. 1977
Courtenay & Roberta,
1973
Courtenay & Roberta,
1973
Courtenay & Roberta,
1973
Courtenay & Roberta.
1973
Courtenay & Roberta,
1973
Drift-line crab (atage
II larva),
Sesurma cinereum
96
0.76
0.64    Courtenay &  Roberta,
        1973

-------
                              6.    (Continued)
               sin
                        Bioa&uay   Teat
Drift-line crab (stage     S
III larva).
Sesarma clnercum

Drift-line crab (stage     S
IV larva).
Sesanna cinereuro

Drift-line crab (inegalopa) ,S
Sosanna cinereum
                                                      Time
                                                       96
                                                       96
                                                       96
                                                       I.C50
0.74
6.8
8.4
         Adjusted
         I.C50
         Jiifl^lL _ MJL£E£!i£fi
                                                                  0.63     Courtenay & Roberta,
                                                                           1973
                                                                  5.8      Courtenay & Roberts,
                                                                           1973
                                                                  7.1      Courtenay & Roberts,
                                                                           1973
00
I
K)
-J
*    S M static. FT » flow through

**   M a measured, U » unmeasured

A*A  EC50:  Decreased growth of oysters, or  loss  of  equilibrium for brown shrimp or blue crabs.

**** |jO(_ uueil to calculate geometric mean because bivalve egg data and mortality data were not

     ubcd in calculation of variance.   In addition,  toxicity can be underestimated when molluscs

     close their valves and avoid direct exposure.

**-AA*i.c50 data recalculated using probic anaiyaeu Mettiod of Flnney (1971).
                                                       c  O£
     Geomiitrtc mean of adjusted values  = 5.86  ng/1    ~i"5~ " Q.12 iig/1

     Lowest value from a flow-through test with measured concentrations u 1.4 pg/1

-------
                   Table  9.   Marine  Invertebrate  chronic valued for toxaphene (Nliumo, 1970)


                                                           Chronic
                                                 Limits    Value
          Organism                     Ttat      (tig/H     
-------
to
I
                       Table 10.   Marine fluh chronic values  for  Coxaphene (Goodman, et al. 1978)




                                                           Chronic

                                                 LImito    Value

         Q£ilililiil!2                      !££.£.*      Jl
         Sheepbhcad minnow,             E-L     1.1-2.5     0.83

         Cyprjnodon yarjj
         * E-L *• embryo-larval

                                                            0 83
           Geometric monn of chronic  values  - 0.83 ng/1    5~T7~ * 0-12


           Lowest chronic value -  0.83

-------
              Table 11.   Marine plane effects for toxaphene
                                       Concentration

Organism
Alga,
Chi orel la op.
Dlnoflagellate.
Uunallella uuchlora
Etfect (u<]>
No growth
Lethal
Dinof lagellate, No growth
Monochryala luthcrl
Alga. irethal
Phaucodactyluin trlcornuturo
03
1
U)
o
Alga,
Pirotococcua ap.
Natural phytoplankton
communities

No growth
90. 8Z decrease in
productivity; **C

'11
70
150
0.15
40
150
1.000

peterfcnce
Ukelea. 1962
Ukelea. 1962
Ukelea. 1962
Ukelea. 1962
Ukelea, 1962
Butler. 1963


Lowest plant value ** 0.15 wg/1

-------
                       Table 12.  Marine reuiduea for toxaphene
DO
 I
U)
Lantern oyster.
Craaaoatrca vlr^lnlca

Sheepshead minnow.
Cyprinodon varietalua

Longnoae kllliflah (fry).
Fimilulus_ HJinilis

Longnoae ktllifiah (Juvenile),
FnmhiUis aim! Its

Longnoae killif iali (adult),
Fundulus almllia

Longnoae killiflah (ova of
exposed adult),
Funchilua aim 11 la

Lon^nose kllliflah (ova of
cxpoaed adult).
Fuiululua a i ml lia
Dloconcenti ation Factor
32,800
9,800.
27,900
29,450
5,400
1,270
Time
(days)
168
28
28
28
32
14
Hfeterenca
Lowe. 1970
Goodman, et al.
Schluunel, et al.
Schimmel. et al.
Schimmel, et al.
Schiuunei, et al.

1978
1977
1977
1977
1977
3,700
32
Scltltumel, et al.   1977
        OrganIam

        Man


        Domea tic animals
                           Maximum Permissible Tiastie Concentration


                          Action Level  or Effect
               Concentration
                 (gig/kg)	
                          edible  flah  and  shellfish
                          animal  feed
                     5.0
                     0.5
        Reference

        FDA Admin. Guideline
        7420.09

        FDA Admin. Guideline
        7426.04
         (Jeometrlc mean  sliellfLuh bioconcentratlon factor « 32,800

         Geometric mean  fish bioconcentratlon factor = 12,690

         l.owoat iiuxlmuni  residue concentration "0.5 rug/kg

         157590 " °-000039  "'E/kg or 0.039 tig/l

-------
                             Table  13.  Other marine  data  for toxuphene
03
 I
u>
to
Eastern oyster,
Crasaoatrea virglnLca

Eastern oyater,    .
Cruaaoatrea ylrglntca

Crass shrimp,
t'alaemonctea puglo

Fink ahrlini),
Ptiiiaeua duorarum

Sheepuheud minnow.
Cyprinudon varlegatua

Longnoae killlflah
(fry 48 hrs) ,
Fundulua a troll la

Longnose kllliflsli
(juvenile),
Fnndulus iilrollla

Longnose kllllflah
(udult) ,
Furidulua alml tla

Spot,
I.ciostomua xanthurua
  Test
  pu rat- ton.

 24 hra


  4 days


  4 days


 '4 days


  4 daya


 28 daya



 28 daya



 14 daya



144 lira
                                                                      Result
                                            Growth  Inhibition
                                            Bloconcentration
                                            factor  -  11,250

                                            Bloconcentration
                                            factor  -  960

                                            Bloconcentration
                                            factor  -  550

                                            Bloconcentration
                                            factor  -  7,620

                                            LC50
I.C50



95Z mortality



50% mortality
                         100
                           1.3
         Butler, 1960
                                    Schinunel,  et al.,  1977
                                    Schimmel,  et al.  1977
                                    Schlmmel, et al.  1977
                                    Schiuuiiel.  et al.  1977
         Suhiuunel, et al.   1977
0.9      Schinunel, et al.   1977
                                                                       1.7      Schimmel. et al,   1977
                                                                       0.5      Lowe. 1964

-------
                          TOXAPHENE
                          REFERENCES

Albaugh, D.W.  1972.  Insecticide tolerances of  two  crayfish
populations  (Procambarus acutus) in south-central Texas.
Bull. Environ. Contain. Toxicol.  8: 334.

Butler, P.A.  1960.  Effect of pesticides on oysters.  Natl.
Shellfish Assoc.• 51: 23.

Butler, P.A.  1963.  Commercial fisheries investigations,
pesticide-wildlife studies, a review of Fish and Wildlife
Service investigations during 1961 and 1962.  U.S. Dep.
Inter. Fish Wildl. Circ.  167: 11.                 *

Butler, P.A.  1964.  Pesticide-wildlife studies, 1963.
A review of Fish and wildlife Service investigations during
the calendar year.  U.S. Dep. Inter. Fish Wildl. Circ.
199: 5.              . .

Chaiyarach, S., et al.  1975.  Acute'toxicity of the insecti-
cides toxaphene and carbaryl and the herbicides propanil
and molinate to four species of aquatic organisms.   Bull.
Environ. Contain.  Toxicol.  14: 281.

Cohen, J.M., et al.  1960.  Effect of fish poisons on water
supplies.   Part 1, Removal of toxic materials.  Jour. Am.
Water Works Assoc.  52:  1551.
                              B-33

-------
Cope, O.B. 1965. Sport  fishery investigations.  Fish Wildl.
Serv. Bur. Sport Pish.  Wildl.  226: 51.

Courtenay, W.R., Jr., and M.H. Roberts, Jr.  1973.  Environ-
mental effect on toxaphene toxicity to selected fishes and
crustaceans.  EPA-R3-73-035. U.S. Environ. Prot. Agency.

Davis, H.C., and H. Hidu.'  1969.  Effects of pesticides
on.embryonic development of clams and oysters and on survival
and growth of the larvae.  U.S. Dep. Inter. Fish Wildl.
Fish. Bull.  67: 393.

Finney, D.J.  1971.  Probit analysis.  University Press,
Great Br*itain.

Goodman, L.R., et al.   .1978.  Effects of heptachlor and
toxaphene on laboratory-reared embryos and fry of the sheeps-
head minnow.  30th Ann. Conf. S.E. Assoc. Game Fish Comm.

Henderson, C.Q.H., et al.  1959.'  Relative toxicity of ten
chlorinated hydrocarbon insecticides to four species of
fish.  Trans. Am. Fish. Soc.  88: 23.

Jdnnson, W.W., and A.M. Julin.  Acute toxicity of toxaphene
to fathead minnows, channel catfish, and bluegills.  (In
press).
                              B-34

-------
Katz, M.  1961.  Acute toxicity of some organic  insecticides
to three species of salmonids and to the threespine stickle-
back.  Trans. Am. Fish. Soc.  90: 264.
Khattat, F.H., and S. Farley.  1976.  Acute toxicity of
certain pesticides to Acartia tonsa Dana.  EPA 600/3-76-
003. U.S. Environ. Prot. Agency.

Korn, S.f and R. Earnest.  1974.  Acute toxicity of 20 insec-
ticides to striped bass, Morone saxatilis.  Calif. Fish
Game  60: 128.

Lowe, J.I.  1964.  Chronic exposure of spot, Leiostomus
xanthurus to sublethal concentrations of toxaphene in seawater
Trans. Am. Fish. Soc.  93: 396.

Lowe, J.I., et al.  1970.  Chronic exposure of oysters to
DDT, toxaphene and parathion.  Proc. Natl. Shellfish Assoc.
61: 71.

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

Macek, K.J., and W.A. McAllister.  1970.  Insecticide suscep-
tibility of some common fish family representatives.  Trans.
Am.  Fish. Soc.  99: 20.
                              B-35

-------
Mahdi, M.A.  1966.  Mortality of some species of  fish  to



toxaphene at three  temperatures.  U.S. Dep. Int.  Fish  Wildl.



Serv. 10: 1.







Mayer, F.L., et al.   1975.  Toxaphene Effects of  reproduction,



growth, and mortality of brook trout. EPA-600/3-75-013.



U.S. Environ. Prot. Agency.







Mayer, F.L., et al.   1977.  Toxaphene!  Chronic toxicity



to,fathead minnows  and channel catfish."  EPA 600/3-77-069.



U.S. Environ. Prot. Agency.







McKenzie, M.D.  1970.  Fluctuations  in abundance  of  the



blue crab and factors affecting mortalities.  South  Carolina



Wildl. Resour. Dep. Tech. Rep.  1: 27.







Naqvi, S.M., and D.E. Ferguson.  1970.  Levels of insecticide



resistance  in freshwater shrimp, Palaemonetes kadiakensis.



Trans. Am. Fish. Soc.  99: 696.







Nimmo, D.W.  1977.  Toxaphene: Its effects on mysids.  Memo



to Fred Hagman, U.S.  Environ. Prot.  Agency, Washington, D.C.







Pairrish, P.R., et al.  1978.  Chronic toxicity of chlordane,



trifluralin, and pentachlorophenol to sheepshead  minnows



(Gyprinodon variegatus).  EPA 600/3-78-010. U.S.  Environ.



Prot. Agency.
                              B-36

-------
Sanders, H.O.  1969.  Toxicity of pesticides to the crustacean
Ganunarus lacustris.  Tech. Pap. No. 25.  Bur. Sport Fish.
Wildl. January.

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

Sanders, H.O.  Sublethal effects of toxaphene on daphnids,
scuds, and midges.  (In Press).

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

Sanders, H.O.,  and O.B. Cope.  1968.  The relative toxicities
of several pesticides to naiads of three species of stoneflies.
Limnol. Oceanogr.  13: 112.

Schimmel, S.C., et al.  1977.  Uptake and toxicity of toxaphene
in several estuarine organisms.  Arch. Environ. Contam.
Toxicol.  5: 353.

Schoettger, R.A. 1970. Progress in sport fishery research.
Fish-Pesticide  Res. Lab. U.S. Dep. Inter. Bur. Sport Fish
and Wildl. Resour. Publ.  106.
                              B-37

-------
Ukeles, R.   1962.   Growth  of  pure cultures of marine phyto-
plankton in  the presence of  toxicants.   Appl. Microbiol.
10: 532.

U..S. Food and Drug  Administration.  1973-.   Administrative
Guidelines Manual 7420.09, Attachment P.

U.S. .Food and Drug  Administration.  1977.*   Administrative
Guidelines Manual 7-4.26:.04, Attachment M.             .
                              B-38

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Mammalian Toxicology and Human Health Effects
                           EXPOSURE
Ingestion from Water
     Several routine monitoring studies of United States
surface waters conducted prior to 1975 did not detect toxa-
phene  (Brown and Nishioka, 1967; Lichtenberg, et al. 1970;
Manigold and Schulze, 1969; Mattraw, 1975; Schafer, et al.
1969; Schulze, et al. 1973; Weaver,  et al. 1965).  Lichten-
berg (1971)  and Schulze, et al. (1973) placed the toxaphene
lower detection limit at 0.5 to 1.0  jug/1, whereas other
organochlorides can be detected at concentrations about
two orders of magnitude lower.  Nicholson, et al.  (1964,
1966) detected toxaphene in drinking water obtained from
Flint Creek, Ala. from 1959 to 1965.  Mean concentrations
of 0.05 to 0.10 /ig/1 were noted during the first four years
when toxaphene usage in the area was high, but dropped to
0.01 to 0.05 jug/1 in the last three  years.  A survey of
commercial drinking water samples conducted by the U.S.
Environmental Protection Agency (1976a) during 1975 and
1976 found no detectable levels of toxaphene in 58 samples;
the limit of detection was 0.05 jug/1.
     Toxaphene has been detected in water around areas where
it was applied to crops as an insecticide.  In California,
Johnston, et al. (1967) detected toxaphene residues in- 60
of 61 analyses of surface effluents in Panoche Drain Water
(average 2.009 pg/1 and range of 0.100 to 7.900/ig/l) and
in 13 of 66 analyses of San Joaquin Valley tile drainage
effluents (average 0.528 /ag/1 and range of 0.130 to 0.950

                              C-l

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/ag/1).   Also,  in California,  Bailey  and  Hannum (1967)  moni-
tored toxaphene  in 17  of 26  surface  water  samples (average
concentration  0.23/ag/l).  The  San Joaquin District,  California
Department  of  Water Resources (1963-1969)  detected toxaphene
in  51 of 422  (12 percent)  tile  drainage  effluents (0.02
to  0.5^ug/l);  in 216 of 447  (48 percent) of surface drains
in  Central  Valley (0.04 to 71.00 jug/1);  in 88  of  712  (12
percent)  of Central Valley surface waters  (0.02 to 0.93
/ag/1);  and  in  8  of 200 (4  percent) of  California  bays and
surface waters.
      In Alabama, the Flint Creek watershed was monitored
during  the  years 1959  to 1965 (Cohen,  et al.  1961; Grzenda
and Nicholson,  1965; Grzenda, et al.  1964; Nicholson,  1969;
Nicholson,  et  al. 1964; 1966).   This water-shed drains an
agricultural district  where  the major  pesticide source is
from small  cotton farms, major  users of  toxaphene (Nicholson,
et  al.  1964).   During  this study,  toxaphene was detected
 (carbon absorption followed  by  chloroform  extraction)  in
paired samples of raw  Flint  Creek water  and treated drinking
water obtained from Flint Creek.  Toxaphene concentrations
ranged from the limits of detection  to 0'.410 /ig/1, with
a mean of approximately 0.07 jug/1.   Since  the  recovery was
approximately  50 percent (i.e., 48 percent for the 1  ng/1
spiked samples and 42  percent for the  0.5  ng/1 samples),
actual residues may have averaged about  0.14jug/l.  The
toxaphene concentrations in  treated  and  untreated water
samples were not significantly  different,  indicating  that
treatment of drinking  water  does not reduce toxaphene concentra-
tions.
                              C-2

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     Although Mattraw (1975)  did not detect toxaphene in



surface water in an organochlorine residue survey in Flor-



ida, toxaphene was found in 3.2 percent of the sediment



samples (claimed lower detection limit of 0.05 jug/1).  Barthel,



et al. (1969) also found detectable toxaphene residues in



sediments at 11 sites on the lower Mississippi River.  Her-



ring and Cotton (1970) detected toxaphene in 11 of 20 Missis-



sippi Delta Lakes at a maximum concentration of 1.92 ;ug/l.



Sediments from 10 of these lakes had a maximum toxaphene



concentration of 2.46 ;jg/l.



     Toxaphene contamination also has been documented in



an area surrounding a toxaphene manufacturing plant.  The



University of Georgia Marine Institute (Reimold, 1974; Rei-



mold and Durant, 1972a, b, 1974; Durant and Reimold, 1972)



has monitored toxaphene contamination in surface waters,



sediment, and biota of waters receiving the effluent of



the Hercules, Inc. plant located on Terry Creek, Brunswick,



Ga, the largest producer of toxaphene in the United States.



The average monthly toxaphene concentration in the plant's



effluent has decreased from a high of 2332 pg/1 in August



1970 to a low of 6.4 jug/1 in June 1974.  Dye experiments



have shown that the effluent is diluted by a factor of 10



after it reaches Terry Creek (Reimold, 1974).  The Institute



(Reimold and Durant, 1972a, b; Durant and Reimold, 1972)



analyzed sediment at three locations downstream of the plant



outfall.  Samples were collected prior to a dredging operation



in June 1971 at three sites downstream:  0.2 miles from



the outfall at a location 50 yards from its intersection
                              C-3

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with another creek; 0.8 miles from the plant outfall; and
1.4 miles from the plant outfall and 50 yards from the end
of Terry Creek (junction with Back River).  Reimold and
Durant (1972b) measured 32.56 jug/1 as the average toxaphene
concentration in sediment cores within Terry Creek Marsh.
The highest residue concentration measured in the surrounding
water was 15 jug/1 before dredging.
Ingestion from Food
     Estimates of toxaphene exposure from dietary intake
can be made from the U.S. Food and Drug Administration (FDA)
market basket survey, the FDA survey of unprocessed food
and feed samples, and the U.S. Department of Agriculture
(USDA) survey of meat and poultry.  In the FDA market basket
survey, food samples are prepared for consumption (i.e.,
cooked, or otherwise processed)  prior to monitoring for
pesticide residues  (Duggan and McFarland, 1967).  The market
basket items are grouped by commodity class (e.g., dairy
products, leafy vegetables, legume vegetables) and are intended
to represent a 2-week diet for a 16- to 19-year-old male
(Duggan and Corneluissen, 1972) .  The results of these sur-
veys, from their inception to the most recently published
report, are summarized in Table 1.  From 1964 to 1972, food
samples were obtained from five cities:  Boston, Mass.,
Baltimore, Md., Los Angeles, Calif., Kansas City, Mo., and
Minneapolis, Minn.  Of the 26 positive samples encountered
during this period, 19 were in Los Angeles, four were in
Baltimore, and one was in Boston.  Based on the estimates
of daily intake made by Duggan and Corneluissen  (1972) ,

                              C-4

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                                                                   TALiLE  1
                                          Tuxaplicne Residues found in Food and Urug Administration
                                                    Market  Uasket  Survey,  1964  to  L975.
o
    Moni tor ing
    lv;r iod
  No. of      No. of        %      Commodities Contaminated
 Compos its   Composits Occurrence    (No. of Composits of
	1'psi t ive	Hach Commodity Contaminated
                               Range of     Daily  Reference
                                 Levels     Intake
                               	(mg/kg)	
June l!)G4-April 1965      216

June 1965-April 1966      312


June 1966-April 1967      360


June 1967-April 196U      360



June 1968-April 1969      360
                                             13
                           0.0

                           1.0


                           0.0


                           1.1



                           3.6
                                                              Leafy  vegetables(I)
                                                              and  garden  fruits(2)
                                            0      Duggan,  et  al.  1966

                               0.048-0.38   0.002  Duggan,  et  al.  1967
                                                                                                          0
                                                   Martin and  Duggan,
                                                      1968
Meat, fish, or poultry(l)
leafy vegetables(1),
garden fruits(2)

Garden fruits(6), meat,
fish, or poultry(l), legume
vegetables(2), root veget-
ables(l), leafy vegetables(3)
                                                                                             0.064-0.375  0.002  Corneliussen, 1969
0.022-0.33   0.004  Corneliussen, 1970
June J9G9-April 1970 360 4 1.1 Leafy vegetabl es (2) ,
garden fruits(2)
June 1970-April 1971 360 1 0.3 Root vegetables (1)

June 1971 -July 1972 420 1 0.2 Leafy vegetables (1)

Aug. 1972-July 1973 360 0(l)b 0.0

Aug. 1973-July 1974 360 3 0.8 Garden fruits(3)

Aug. 1.974-July l'J7b 240 1 0.4 Leafy vegetables (1 )

Ki'oiii Uu
-------
  and assuming  an  average  body  weight  of  70  kg,  the  estimated

  daily dose of  dietary  toxaphene  over  the period  of June
                                                     i
  1964 to April  1970  was 0.021pg  toxaphene/kg  body  weight/day.

  This estimate  is based on  food samples  from a  limited  number

  of cities, most  of  which are  not located in areas  of high

  toxaphene usage.  The  more recent (1972 to 1975) results

  of the market  basket  survey suggest  that the  current daily

  dietary dose may be substantially lower; however,  it is

  equally possible that  the  dietary doses for individuals

  located in the Mississippi Delta (an area  of  high  toxaphene

  usage) could  be  substantially higher.   The U.S.  EPA (1977)

  recently compiled the  results of the FDA survey  on unprocessed

  food and feed  samples.  As indicated in Table  2, the percent

  of occurence  of  toxaphene  contamination suggests significant

  potential exposures to field  workers.
                                TABLE  2
               Toxaphene Residues  Found  in  Food  and  Drug
             Administration Survey of  Unprocessed  Food  and
                      Feed Samples,  1972 to 1976
Year c
T97T
1973

1974
1975
1976
# of * of
commodities samples
:ontaminated checked
10
15

8
12
15
3516
2906

1919
2317
4228
# of
positive
samples
l"l8
150

109
118
257
% of
occurrence
3.3
4.8

4.6
5.0
6.0
Commodity most
frequently
contaminated
Leaf & Stem
Vegetables
Leaf & Stem
Vegetables
Fish
Fish
Fish
1U.S.  EPA,  1977.
                                C-6

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     The only published information encountered in the USDA

survey of meat and poultry is contained in the World Health

Organization (WHO) (1974a) monograph on toxaphene.  This

information is summarized in Table 3.


                             TABLE 3
       Residues of Toxaphene in Meat and Poultry Products3
No. of tissues
analyzed
Species

Meat
Cattle
Calves
Swine
Sheep
Goats
TOTAL
Poultry
Young chickens
Mature chickens
Turkeys
Ducks
Geese
Other
TOTAL

1969

739
142
1964
312
12
3169

1909
78
169
42
1
-
2199
fworld Health Organization,

1970(6 mos)

583
67
1076
137
8
1871

1405
-
67
8 '
2
4
1486
1974a.
No. with a residue

1969

712
141
1741
303
10
2907

1898
77
164
41
1
-
2181
Q7n i «+•

1970 (6 mos)

NAb
NA
NA
NA
NA
1721

NA
NA
NA
. NA
NA
NA
1472

No. with
toxaphene

1969

2
0
0
0
0
2

2
0
0
0
0
0
2


1970

0
0
2
1
0
3

0
0
0
0
0
0
0

     Similar but unpublished information covering the years

1973 to 1978 has been obtained from the U.S. Department

of Agriculture (1978) and is summarized in Table 4.  These

data indicate that toxaphene is found consistently from

year to year in the fat of cattle, although the incidence

of contamination is extremely low.  During this survey period,

only six samples were in excess of the tolerance limit (7.0

ppm; see Existing Guidelines and Standards section).  Of


                              C-7

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                                                           TABLE 4
                              Residues of Toxaphene in Fat Samples of Meat and Poultry Products
                                             at Slaughter  in the United States9
Number of Positive Samples/Total Number of Samples (%)
Animal
Cattle
Calves
Sheep & Goats
Swine
Chicken
Turkeys
Ducks & Geese
Rabbits
Horses
TOTAL
1973
9/710 (1.27)
1/84 (1.19)
2/289 (0.69)
4/232 (1.72)
3/530 (0.57)
3/517 (0.58)
0/95 (0.0)
0/19 (0.0)
0/44 (0.0)
22/2520 (0.87)
[*U.S. Department of Agriculture,
first two quarters only
1974
2/1117
0/284
c 1/371
2/329
1/1138
0/735
0/148

3/266
9/4388
1978.
(0.18)
(0.0)
(0.27)
(0.61)
(0.09)
(0.0)
(0.0)

(1.13)
(0.21).

1975
3/1733
0/269
0/356
0/324
0/777
0/554
0/246
0/11
0/261
3/3971

(0.17)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.08)

1976
3/1785
0/327
0/250
1/442
0/927
0/456
0/267
0/65
0/217
4/4736

(0.17)
(0.0)
(0.0)
(0.23)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.08)

1977
4/880
0/124
0/100
0/215
1/375
0/303
0/18C
0/21
0/112
5/3216

(0.45)
(0.0)
(0.0)
(0.0)
(0.27)
(0.0)
(0.0)
(0.0)
(0.0)
(0.22)

1978b
1/432
0/62
0/36
0/179
0/191
0/64
0/39
0/14
0/20
1/1037

(0.23)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.0)
(0.10)

c]isted as lamb

-------
these six violations, five were in fat samples from cattle,

one of which occurred in the first quarter of 1978.  The


data summarized in Tables 3 and 4 indicate that toxaphene

is not a widespread contaminant in meat and poultry products.

     As detailed in the Ecological Effects section of this


criterion document, toxaphene in water can be bioconcentrated

in fish by factors of 50,000 and more, based on laboratory

studies and measurements of whole body residues.  However,

in assessing potential human dietary exposure, the .primary

concern is with residues bioconcentrated in the edible por-

tion or fillet.  Working with adult brook trout, Mayer,


et al.  (1975) found that toxaphene was bioconcentrated

in the fillet by a factor of 8,000 when fish were kept in

water containing toxaphene at 0.5 pg/1 for 161 days.  At

a nominal concentration of 0.041 ;ag/l - which is still greater

than the concentrations of toxaphene found in drinking water

(see Ingestion from Water section) - the bioconcentration

factor for the fillet was less than 2,400.  Toxaphene resi-

dues found in fish from toxaphene-treated lakes are gener-


ally consistent with levels obtained during laboratory studies

and indicate'that fish bioconcentrate toxaphene by a factor
                »
of several thousand.  For example, Terriere, et al. (1966)

found that total mean body residues in rainbow trout in


lakewater were several pg/g compared to approximatley 0.5

jug/1 in water (bioconcentration factor of 9,000 to 19,000),

which is comparable to the bioconcentration observed experi-

mentally by Mayer, et al. (1975) with total body residues


in brook trout.
                              C-9

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     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 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 comsumption is 18.7 g/day. From the data on the

19 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-10

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     The above approach have been used to estimate a biocon-



centration factor for toxaphene.  Measured steady-state



bioconcentration factors were obtained for toxaphene using



five species:
Organisms
Eastern oyster,
Crassostrea virginica
Sheepshead minnow,
Cyprinodon variegatus
Brook trout (fry) ,
Salvelinus fontinalis
Brook trout,
(yearling) ,
Salvelinus fontinalis
Fathead minnow,
Pimephales promelas
Channel catfish,
Ictalurus punctatus
Channel catfish
(fry),
Ictalurus punctatus
BCF
32,800
9,800
76,000
16,000
69,000
26,000
50,000
Percent
Lipids
1.5
5
4.5
4.5
8
3.2
3.2
Adjusted
BCF
50,293
4,508
38,844
8,178
19,838
18,688
35,938
Reference
Lowe, 1970
Goodman, et
al. 1978
Mayer, et
al. 1975
Mayer, et
al. 1975
Mayer, et
al. 1977
Mayer, et
al. 1977
Mayer, et
al. 1977
Each of these measured BCF's was adjusted from the percent



lipids of the test species to the'2.3 percent lipids that



is the weighted average for consumed fish and shellfish.



The geometric mean was obtained for each species, and then



for all species.  Thus, the weighted average bioconcentration



factor for toxaphene and the edible portion of all aquatic



organisms consumed by Americans is calculated to be 18,000.
                              C-ll

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Inhalation



     The highest toxaphene residues in air have been found



in areas where toxaphene is applied for agricultural purposes



(especially cotton production)  (Arthur, et al. 1976; Miss.



Agric. Exp.  Sta., 1976; Stanley, et al. 1971; Tabor, 1965



and 1966) .  Studies in cotton-growing areas demonstrate



that airborne residues are highest during the cotton growing



season and decrease to low levels after harvesting, but



spring tilling releases soil residues to the air.  The recent



identification of ng/m  levels over the Atlantic Ocean,



where toxaphene has not been applied, establishes that toxa-



phene residues move with air currents analagous to DDT (Bidleman,



et al.  1976; Bidleman and Olney, 1975).



     Arthur, et al. ,(1976) reported a 3-year  (January 1972



to December 1974) study of toxaphene air residues at Stone-



ville, Miss., which is located in the southern cotton belt.



Over this period, toxaphene concentrations were highest



in August  (1540.0, 268.8, and 903.6 ng/m ) and lowest in



January  (0.0, 0.0, 10.9 ng/m ).  The mean monthly concen-



tration was 167 ng/m  .  In a more recent unpublished survey



of the Mississippi area, conducted from January 1976 to



July 1976, the mean measured toxaphene concentration in



air was 18.7 ng/m , with the highest concentration found



during June and July  (42.09 ng/m )  (Miss. Agric.  Exp. Sta.,



1976).  Earlier studies  (Tabor, 1965, 1966) conducted in



seven southern agricultural communities, detected toxaphene



at only two sites:  Leland, Miss, where toxaphene levels
                               C-12

-------
ranging from 1.2 to 7.5 ng/m  were found in 6 of 15 samples



from July to September 1963; and Newellton, Tex., where



toxaphene levels ranging from 3.1 to 15 ng/m  were found



in 6 of 10 samples.  Both of these communities were cotton-



growing areas.



     Comparative geographic studies of toxaphene air concen-



trations suggest that toxaphene contamination is most perva-



sive in southern states.  From 1967 to 1968 Stanley, et



al. (1971) attempted to monitor toxaphene at nine locations:



Baltimore, Md.,  Buffalo, N.Y., Dothan, Ala., Fresno, Calif.,



Iowa City, Iowa, Orlando, Fla., Riverside,  Calif., Salt



Lake City, Utah, and Stoneville, Miss.  Toxaphene was found



in only three locations, all in the southern part of the



country:  Dothan (11 of 90 samples'at 27.3  to 79.0 ng/m ),



Orlando (9 of 79 samples at 20.0 to 2520 ng/m3), and Stoneville



(57 of 98 samples" at 16.0 to 111.0 ng/m ).   Similarly, Bidleman,



et al. (1976) monitored toxaphene at five sites in North



America.  As indicated in Table 5, the more southern sites



evidenced considerably higher concentrations of toxaphene.
                              C-13

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                                  TABLE 5
      Toxaphene Residues  in Air Samples at Five North American Sites3
                           (Bidleman, et al. 1976)

                                                   Number
                                                     of          Range
Location and Date	Samples	(ng/m )

Kingston, Rhode Island, 1975                         6      0.04  - 0.4

Sapelo Island, Georgia, 1975                         6      1.7   - 5.2

Organ Pipe Cactus National Park, Arizona, 1974       6      2.7   - 7.0

Hays, Kansas, 1974                                   3      0.083 - 2.6

Northwest Territories, Canada, 1974                  3      0.04  - 0.13
a
 Bidleman, et al. 1976.


         Toxaphene has also been monitored in the atmosphere

    over the east coast of the U.S., near Bermuda, and over

    the open ocean (Bidleman and Olney, 1975).  With respect

    to the above discussion of geographic distribution, it is

    not too surprising that a sample taken at Sapelo Island,

    Ga. is substantially greater  (mean of 2.8 ng/m ) than the

    samples taken at Bermuda  (mean of 0.79 ng/m )  or over the

    open ocean  (mean of 0.53 ng/m ), since substantial amounts

    of toxaphene are used in the south on cotton.

         These monitoring studies clearly suggest that toxaphene

    is a prevalent atmospheric contaminant in areas where this

    pesticide is used, particularly in the southern United States.

    Taking the mean monthly toxaphene concentration of 167 ng/m

    noted by Arthur, et al. (1976) over a 3-year period in Stone-

    ville, Miss., and assuming  (1) that the average human weighs

    70 kg and breathes 24 m  of air per day, and  (2) that all
                                  C-14

-------
of the toxaphene breathed into the lungs is absorbed,  the

average daily dose of toxaphene from air is approximately
            2
0.057/ig/kg.   This is approximately twice the estimated

daily intake of toxaphene from the diet (see Ingestion from

Food section) based on the FDA 1964 to 1970 market basket

survey.  An average national level of toxaphene exposure

from air cannot be estimated from the available data.  However,

taking the average concentration monitored by Bidleman and

Olney  (1975) over the open ocean (0.53 ng/m ), the.daily

intake of toxaphene from air would be 0.18 ng/kg.

Dermal

     No direct information is available on the importance

of dermal absorption in total human exposure to toxaphene.

Data from toxicity studies with laboratory mammals (see

Acute, Subacute, and Chronic Toxicity section) indicate

that toxaphene can be absorbed across the skin in  toxic

amounts by humans.  However, incidences of dermal  absorption

of toxaphene by humans are restricted to occupational or

accidental exposures to large amounts of toxaphene.  For

those exposed to only background levels of toxaphene, dermal

absorption is not likely to be a significant route of entry.


 Assuming 100 percent absorption is common EPA policy, but
in this case is very conservative since human studies of
occupationally exposed individuals suggest no absorption
(see Absorption section).
2
 It should be noted that 0.057 jug/kg is a maximum  or worst
case value due to (1) assumption of 100 percent absorption
and (2) use of a mean monthly toxaphene concentration from
a high toxaphene use area.
                              C-15

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                       PHARMACOKINETICS
Absorption
     The recently completed U.S. EPA (1978) study suggests
that inhalation exposures to toxaphene do not result in
sufficient absorption by humans to cause quantifiable levels
in the blood.  The study found no detectable levels of toxa-
phene in the blood of 54 workers occupationally exposed
to toxaphene.  However, of 53 personal air samples analyzed,
30 had quantifiable levels of toxaphene and 19 had trace
levels.  In the same study, one individual not occupation-
ally exposed to toxaphene was found to have elevated toxa-
phene blood levels associated with the consumption of toxa-
phene-contaminated fish (see Excretion section), indica-
ting significant absorption after oral exposure.
     Inferences on the absorption of toxaphene by laboratory
mammals can be made from some of the available toxicity
data.  Absorption across the alimentary tract, skin, and
respiratory tract is indicated by the adverse effects eli-
cited by toxaphene on oral, dermal, and inhalation exposures.
Based on toxicity studies detailed in the Acute, Subacute,
and Chronic Toxicity section, the vehicle used in the admini-
stration of toxaphene has a marked influence on lethality.
This effect is probably attributable to differences in the
extent and/or rate of absorption.  In oral exposures, toxa-
phene has a much lower LD50 when administered in a readily
absorbed vehicle - e.g. corn oil or peanut oil - than when
given in an indigestible vehicle such as kerosene.  Similarly,
dermal applications of toxaphene in solution with mineral

                              C-16

-------
oil, dimethyl phthalate, or water are much more toxic than



similar applications of toxaphene in powder preparations



(Lackey, 1949 a, b; Conley, 1952).   Documented cases of



human poisoning by toxaphene indicate that man may absorb



toxic levels following oral, dermal, or inhalation exposures



(McGee, et al. 1952; Pollock, 1958; Warraki, 1963).  When



administered or applied in comparable lipophilic solvents,



the ratio of oral LD50 to dermal LD50 is about 0.1 (Tables



6 and 8).  This suggests that toxaphene is absorbed more



completely and/or more rapidly from the alimentary tract



than from the skin.  The pronounced variability in time



to death after toxaphene ingestion indicates marked indivi-



dual differences in the rate of toxaphene absorption and/or



differences in susceptibility to toxaphene intoxication.



Distribution



     Toxaphene is readily distributed throughout the body,



with highest residues found in -fat tissue.  Three hours



after single intubations of Cl-36 labelled toxaphene in



peanut oil: acacia, rats had detectable levels of Cl-36



activity in all tissues examined (kidney, muscle, fat, testes,



brain, blood, liver, intestines, esophagus, spleen, and



stomach) with the highest levels being found in the stomach



and blood.  By nine days after dosing, 6.57 percent of the



administered dose  (measured as Cl-36 activity) remained



in the organism, with most of the activity found in the



fat, blood, liver, and intestines  (Crowder and Dindal, 1974).



In a similar single dose study using rats with corn oil



as the vehicle (Ohsawa, et al. 1975), both C-14 labelled
                              C-17

-------
toxaphene  (8.5 mg/kg) and C-14 labelled 2,2,5-endo, 6-exo,



8,9,10-heptachloroborane  (2.6 mg/kg)  (a component of toxa-



phene) were found primarily in the fat, liver, kidneys,



and blood after 14 and 9 days, respectively.  These patterns



are consistent with  toxaphene redistribution from the fat



via the circulatory  system to kidneys and liver prior to



urinary and fecal elimination (see Metabolism and Excretion



sections).



     The predominance of fat storage has also been demon-



strated in 12-week feeding studies with rats (Clapp, et



al. 1971) and 2-year feeding studies with rats and dogs



(Lehman, 1952a; Hercules, Inc.,  undated).  In all these



studies, toxaphene residues were highest in fat tissue but '



remained below the levels administered in the diet.  This



suggests that toxaphene is not likely to be biomagnified



in terrestrial organisms, and is consistent with.the relatively



rapid elimination of toxaphene by mammals (see Excretion



section).



Metabolism



     Toxaphene undergoes reductive dechlorination, dehydro-



chlorination, and hydroxylation in mammalian systems.



     In the study by Crowder and Dindal (1974).using Cl-



36 labelled toxaphene, about 68 percent of the activity



was recovered as ionic chloride.  Similarly, Ohsawa, et



al. (1975) found that of seven Cl-36 labelled toxaphene



fractions administered by intubation to rats, all were de-



chlorinated by about 50 percent.  Based on the recovery



of both C-14 and Cl-36 labelled toxaphene, these investi-





                              C-18

-------
gators concluded that only three percent of the original
dose is excreted unchanged and only two percent is eliminated
as carbon dioxide.
     For technical (i.e., commercial grade) toxaphene, both
reductive dechlorination and dehydrochlorination occur in
reduced bovine blood hematin solutions, and 50 percent de-
chlorination has been noted in toxaphene incubated with
rat liver microsomes and reduced nicotinamide adenine dinu-
cleotide phosphate (NADPH) under anaerobic conditions (Khalifa,
et al.  1976).  Reductive dechlorination has also been demon-
strated for heptachloroborane, a component of toxaphene,
(Saleh, et al. 1977; Chandurkar, 1977; Pollock, 1978).
     Toxaphene has been shown to yield a type I binding
spectra with hepatic cytochrome P-450 of rats, mice, and
rabbits which suggests that toxaphene may serve as a sub-
strate for the hepatic microsomal mixed-function oxidase
system (Kulkarni, et al. 1975). , Type II binding has not
been observed.  Metabolism by the hepatic microsomal mixed
function oxidase system is further suggested by the potentia-
tion of toxaphene by piperonyl butoxide  (Saleh, et al. 1977)
and the demonstrated NADPH dependance for the in vitro hy-
droxylation of nonachloroborane (a toxaphene component)
by" rat liver microsomes (Chandurkar, 1977).
     In comparing the chromatographic patterns of toxaphene
residues found in the liver, feces, and fats, both Pollock
(1973) and Saleh, et al.  (1977) have noted that only fat
residues approximate those of whole toxaphene, while resi-
dues in both the liver and feces are consistently more polar.
                              C-19

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  Excretion
     The half-life of C-14 or Cl-36 labelled toxaphene in
rats after single oral doses appears to be from one to three
days, with most of the elimination occurring via the urine
and feces  (Crowder and Dindal, 1974; Ohsawa, et al. 1975).
Only a small portion of the urine and fecal metabolites
are eliminated as glucuronide or sulfate conjugates (Chan-
durkar, 1977) .
     As mentioned in the Absorption section, elevated toxaphene
blood levels in one individual in the U.S. EPA (1978)  study
were associated with the consumption of toxaphene-contaminated
fish (catfish fillet with a toxaphene residue of 52 ;ug/g
wet weight).  On the first day that blood samples were taken,
toxaphene was found in the blood of this individual at a
concentration of 142 ppb.  Eleven days after this measurement,
the concentration of toxaphene in the blood had fallen to
47 ppb.  By 14 days after the initial measurement, toxaphene
blood levels were below the limit of detection (30 ppb).
                           EFFECTS
Acute, Sub-acute, and Chronic Toxicity
     Information on the acute oral toxicity of toxaphene
to laboratory animals is summarized in Table 6.  In cases
of acute intoxication, toxaphene, like most chlorinated
hydrocarbon insecticides, appears to act as a central ner-
vous system stimulant.  However, unlike DDT, toxaphene does
not significantly affect conduction in the rat superior
cervical ganglion (Whitcomb and Santolucito, et al. 1976).
Published reports of human cases of acute toxaphene poisoning
                              C-20

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                                     TABLE 6
        Acute Oral Toxicity of Technical  Toxaphene  to  Laboratory Mammals
   Organism
Vehicle
 LD50
(mg/kg)
Reference
Rats

  Unspecified strain   Unspecified

  Wistar, male,
  3-4 weeks, 50-60 g,
  fasted               Cottonseed oil

  Sherman, male,
    90 days,   175 g,
 • fasted               Peanut oil

  Sherman, female,
     90 days,   175 g,
  fasted               Peanut oil

                       Peanut oil


                       Peanut oil

                       Corn oil
Mice
Cats
Dogs
Rabbits

Guinea Pigs
Corn oil

Corn oil

Unspecified oil

Peanut oil

Unspecified oil

Peanut oil

Corn oil

Unspecified oil

Peanut oil

Corn oil

Unspecified oil
                           69
            Lehman, 1951
 220 + 33a  Boyd and Taylor, 1971



90(67-122)b Gaines, 1960



 80(70-91)b Gaines, 1960

       40   Shelanski and Gellhorn,
              undated

       90   Hercules Inc. , undated

  120-125   Shelanski and Gellhorn,
              undated

       60   Hercules Inc., undated

      112   Hercules Inc., undated

       80   Rico, 1961

    25-40   Hercules Inc., undated

      100   Rico, 1961

     ^25   Lackey, 1949a

       49   Hercules Inc., undated

      100   Rico, 1961

   75-100   Hercules Inc., undated

      270   Hercules Inc., undated

       80   Rico, 1961
,4- standard error.
 95 percent confidence interval,
                                     C-21

-------
by ingestion are summarized in Table 7.  In these cases,

convulsions are the mo.st consistent clinical signs of intoxi-

cation.  Similar effects have been observed in both rats

and dogs (Lehman, 1951).  Along with convulsions, hyperreflexia

has been noted in dogs  (Lackey, 1949a, b) , rats  (Boyd and

Taylor, 1971), and humans  (Kaun and Cueto, 1967).  Addi-

tional unpublished reports  (U.S. EPA, 1976e) of poisoning

in humans describe the major symptoms of oral intoxication

as vomiting, convulsions, cyanosis, and coma.  Based on

a review of the acute toxicity of toxaphene to experimental

mammals and cases of human poisoning, Conley (1952) has

estimated the minimum lethal oral dose of toxaphene for

man to be between 30 and 103 mg/kg body weight.  In rats,

pathological effects of toxaphene include cloudy swelling

and congestion of the kidneys, fatty degeneration and necrosis

of the liver, and decreased spermatogenesis (Boyd and Taylor,

1971).  Mehendale (1978) has reported that toxaphene (100

mg/kg in the diet for eight days)  inhibits hepatobiliary

function in rats.

     The acute dermal toxicity of toxaphene is summarized
                                v
in Table 8.  Toxaphene appears to be somewhat less toxic

when administered dermally.  In rats the ratios of dermal

to oral LDSO's range from 10 to 12 (Gaines, 1960; 1969;

Hercules Inc. , undated).  Without providing documentation,

Hayes (1963) estimates the hazardous dermal dose for humans

at 46 grams.  For a 70 kg man, this is approximately 660

mg/kg.  Dermal LDSO's for rats range from 780 to 1075 mg/kg

(Gaines, 1960; 1969; Hercules Inc., undated).


                               C-22

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                                                             TABLE  7
                                      Case  Studies of Toxapliene Poisoning in Humans in which
                                             Ingestion  is  the  Primary Route  of  Entry
Case No. la
Subject(s) Male
2 yr 8 mo
Nature of
toxaphene Wax
Dose Unknown
Ci Time to react
^j to onset of
\«Li symptoms -~7 hours
Symptoms Convulsions
Outcome Death
Time to death
or recovery 9.5 hours
2a
Male, 4 yrs
Emulsion in
water
Unknown
2 hours
Convulsions
2-5 minute
intervals
Death
6 hours
3a 4a
Male, Male, 2 yrs
1 yr 5 mo
60% in 20% in solution
solvents
— 100 mg/kg Unknown
N.S. N.S.
5a
Female, 20 yrs
Female, 16 yrs
Female, 12 yrs
Residue of spray
in food
9.5-47 mg/kg
1.5-4 hours
Convulsio.ns Convulsions, inter- Nausea; vomiting;
intermittent mittent; mild convulsions
cerebral excite-
ment; aimless
jerking motion and
excessive muscular
tensions of extremities,
marked pharyngeal and
laryngeal spasms;
labored respiration;
cyanosis
Death Recovery
11 hours 12 hours
Recovery
~12 hours
6a 7b
Male, adult Female, 9 mo
Male, young
Female, adult
Residue of Powder, .13. 8%
spray in food toxaphene,
7.04% DDT
Unknown Unknown
4 hours A few hours
No nausea; Vomiting;
spontaneous diarrhea; convulsions;
vomiting; hyperreflexia; tachycar-
convulsions dia; b. p. 140/100; labored
jerking and respiration; respira-
transitory tory failure
movements; muscular
rigidity; periods
of unconscious-
ness; amnesia(?)
Recovery Death
<.! day(?) ~9 hours
"McGee,  et al.  1952
 Ilaun and Cueto,  1967

-------
                         TABLE  8
Acute Dermal Tpxicity of Toxaphene to Laboratory Mammals
Organism
Rats
Sherman, male,
>90 days, 7 175 g,
unfasted
Rats
t Sherman, female,
£ 790 days, > 175 g,
. unfasted
Rats
Rabbits
Rabbits
Vehicle
Xylene
Xylene
Xylene
Dust
Peanut
oil
Dose
(mg/kg)
1075
(717^1613)
780
(600-1014)
930
>4000
^ 250
Response
LD50 (95%
Confidence
Interval)
LD50 (95%
Confidence
Interval)
LD50
LD50
LD50
Reference
Gaines, 1960 and 1969
Gaines, 1960 and 1969
Hercules Inc. , undated
Hercules Inc. , undated
Hercules Inc. , undated

-------
     Table.9 summarizes the effects of subacute oral admini-



stration of toxaphene to laboratory mammals.  Except for



convulsions observed in dogs given 5 mg/kg/day, none of



the exposures detailed in Table 9 resulted in clinical signs



of toxaphene poisoning.  The ability of dogs to tolerate



large cumulative doses (176 to 424 mg/kg)  when given at



4 mg/kg/day suggests a rather sharp threshold level for



central nervous system stimulation.  This is consistent



with information discussed in the Excretion section, showing



that toxaphene is eliminated relatively rapidly.  A similar



pattern is seen in rats on intraperitoneal injection.  Ohsawa



and coworkers (1975) have found that male rats injected



with 50 mg toxaphene (approximately 300 mg/kg) every 48



hours tolerated cumulative doses of 700 to 2,000 mg/kg  (over



10 times the single oral LD50 dose) before marked lethality



occurred.



     In subacute exposures, which do not cause apparent



central nervous system stimulation, no increases in morta-



lity are noted.  However, pathological changes of the kid-



neys and liver, as well as changes in blood chemistry, seem



to be common features of subclinical toxaphene intoxication.



     Ortega, et al.  (1951) (using rats) and Lackey  (1949a)



 (using dogs) have noted similar changes in liver histology.



Morphologically, these changes appear as vacuoles of plasma



with occasional red blood cells found within hepatic cells.



This condition, referred to as hydropic accumulation, is



distinct from fatty degeneration.  In neither rats  nor dogs



was hydropic accumulation associated with the destruction
                              C-25

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                                                                TABLE 9
                                                  Subacute Oral  Toxicity of  Toxaphene
I
N)


Organism Vehicle
Mice, both albino and Diet
wild strains

Hats Diet


Duration
Several weeks
• or months

12 weeks

Dose
mg/kg/day or
ppm in diet)
50. mg/kg/day
(250-480 ppm)

189 ppm
Estimated
cumulative
dose
(mg/kg) Response3
300 Changes in blood
chemistry and
urine protein
No apparent adverse
effects


Reference
Baeumler ,

Clapp, et
1971



1975

al.
       Uats
                                N.S.
                                             7 months
                1.2-4.8 mg/kg/day    250-1000
       Uats,  Sherman,  male
         and  Comale,    100 q    Diet
       Kats and guinea pigs     Diet
2-9 months      50 and 200 ppm
                                                 Temporary change in
                                                   blood chemistry
                                                 Questionable liver
                                                   pathology
                      Grebenyuk, 1970
                      Ortega, ot al.
                        1957
6 month
                100-800 ppm
No significant effect Shelanski and
                        Gellhorn, undated
       At,
ocja Corn oi 1
Corn oil
Corn oil
"A few days"
44 days
106 days
5 mg/kg/day
4 mg/kg/day
4 mg/kg/day
^15-35
176
424
Convulsion Lackey,
Questionable liver Lackey,
pathology: renal
tubular degeneration
Questionable liver Lackey,
pathology: renal
tubular degeneration
1949a
1949a
1949a
        Sec text for  details.
         .S.  - not specified.

-------
of hepatic cells.  However, Ortega, et al. (1957) also noted



occasional masses of red blood cells invading the cytoplasm



of liver cells in areas of hypertrophy and margination.



In addition to liver damage, Lackey (1949a) also noted wide-



spread degeneration of the tubular epithelium, occasionally



accompanied by inflammation of the pelvis of the kidney.



Identical pathological changes were seen in dogs surviving



prolonged dermal exposures to toxaphene  (Lackey, 1949b).



     As noted in Table 9, alterations in clinical chemistry



have also been seen in subacute oral toxaphene exposures.



Mice with no clinical signs of intoxication evidenced consist-



ent increases in serum acid phosphatase, glutamicpyruvic



transaminase, and gamma-glutyamyl transpeptidase activities,



along with increased neutrophil counts and changes in urine



protein (Baeumler, 1975). . At a much lower daily dose, rats



had only a transient increase in serum alkaline phosphatase



during the 5th month of intoxication and showed no variation



in urine hippuric acid (Grebenyuk, 1970) .  Increases in



all of the above enzyme activities are consistent with the



mild liver pathology associated with subacute toxaphene



exposure.



     Lehman  (1952b) states that the 90-day dermal LD50 of



toxaphene  (as a dry wax) is 40 mg/kg in  rabbits.  No details



of symptoms or pathology are provided.



     Hercules Inc.  (undated) has conducted experimental



dermal and inhalation exposures of human volunteers to toxa-



phene.  Toxaphene doses of 300 mg/day applied to the skin



of 50 volunteers for 30 days produced no observable toxic





                              C-27

-------
effects.  Similarily, cotton patches treated with toxaphene



produced neither sensitization nor primary skin irritation



when applied to the skin of 200 subjects.  Shelanski (1974)



indicates that humans exposed to toxaphene mists of 500



mg/m  of air for 30 minutes daily for ten consecutive days



followed by three daily exposures three weeks later showed



no adverse effects, based on physical examinations as well



as blood and urine tests.



     However, Warraki (1963) has attributed two cases of



acute bronchitis with miliary lung shadows to inhalation



of toxaphene during applications of toxaphene formulation



spray.  Warraki does not specify the carriers used during



the toxaphene spray applications of the cases that he sum-



marized.  However, he did indicate that toxaphene is usually



applied as an emulsifiable concentrate containing 60 percent



toxaphene, 35 percent kerosene, 3 percent xylol, and 2 per-



cent emulsifier.  Both individuals, male adults, had been



exposed to toxaphene sprays from 1-1/2 to 2 months before



the onset of pulmonary insufficiency.  Maximum breathing



capacity was between 19 and 22 percent of normal.  Both



adverse affects observed (pulmonary insufficiency and lung



lesions) were reversible within 3 months after toxaphene



exposure was discontinued.  No central nervous system effects



were noted.  One case of allergic rhinitis in a worker exposed



to toxaphene by inhalation has been reported.  However,



details on the duration of exposures were not given (U.S.



EPA, 1976e).
                              028

-------
     Long-term exposures to low dietary levels of toxaphene



are summarized in Table 10.  All studies note some form



of liver pathology in rats at dietary levels of 100 mg/kg



or above.  At 100 mg/kg, cytoplasmic vacuolization similar



to 'that' seen on subacute oral exposure was noted by Kennedy,



et al. (1973).  Lehman  (1952)  noted both cytoplasmic vacuo-



lization and fatty degeneration of the liver in rats fed



100 mg/kg.  At 25 mg/kg diet,  Fitzhugh and Nelson (1951)



did observe increased liver weight with minimal liver cell



enlargement.  Unpublished studies on rats, dogs, and monkeys



by Hercules Inc. (undated) are in general agreement with



the above published reports.  The lowest dietary level of



toxaphene producing unequivocal liver damage over a two-



year feeding period is 20 mg/kg diet.  Only at relatively



high concentrations -i.e., 1,000 mg/kg diet - does chronic



toxaphene, exposure elicit central nervous system effects.



characteristic of .acute intoxication.



     No cases of chronic human intoxication have been encoun-



tered in the literature.



Synergism and Antagonism



     Induction of hepatic microsomal mixed-function oxidase



appears to account for most of the. interactions of toxaphene



with other compounds.  In rats pretreated.with aldrin or



dieldrin and evidencing increased liver O-dealkylase and



0-demethylase activities, toxaphene 96-hour LD50 values



were approximately two times higher  (indicating decreased



toxicity) than those of rats given no pretreatment.  Similarly,



pretreatment with DDT, a known inducer of hepatic microsomal
                              C-29

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                                    TABLE 10
                        Chronic Toxicity of Toxaphene at
                    Low Dietary Levels to Laboratory Mammals
Organism
Duration
of feeding
Toxaphene
concentration
in diet
Response3
Reference
Rats,
  Sprague Dawley   3  generations
                       25  mg/kg   No effect
                                    Kennedy, et
                                      al. 1973P
Rats
Rats
Rats
Dogs


Dogs
Lifetime



Lifetime


2 years

2 years



2 years


2 years
      100  mg/kg

       25  mg/kg

      100  mg/kg

       25  mg/kg


       25  mg/kg

      100  mg/kg

1000-1600  mg/kg

     5-20  mg/kg


       40  mg/kg


      200  mg/kg
Liver pathology

No effect        Lehman, 1952a

Liver pathology

Liver pathology  Fitzhugh and
                 Nelson, 1951

No effect        Hercules Inc.
                   undated
Slight liver damage
CNS stimulation

No effect
Slight liver
  degeneration

Moderate liver
  degeneration
Hercules Inc.
  undated
Dogs
Monkeys
1360 days
( 3.7 years)
2 years
5mg/kg/day Liver necrosis
10-15 mg/kg No clinical or
( 0.64-0.78 . histological
rng/kg/day) effects
Hercules Inc.
undated
Hercules Inc.
undated
         Administered  in capsules containing, toxaphene dose  in  corn
        oil;  5 mg/kg/day equivalent  to  200 mg/kg  in diet.
         Diets prepared fresh weekly.   (The other  studies  in  this
        table did not  specify frequency).
                                     C-30

-------
mixed-function oxidase, resulted in a threefold increase
in the 96-hour LD50 of toxaphene in rats (Deichmann and
Keplinger, 1970).  Piperonyl butoxide, which inhibits the
metabolism of many toxicants by mixed-function oxidase,
has been shown to potentiate the toxicity of toxaphene in
house flies  (Saleh, et al. 1977).
     When administered by intubation to rats, equitoxic
combinations of toxaphene with parathion, diazinon, or tri-
thion were less toxic than would be expected based on the
assumption of simple similar action (Keplinger and Deich-
mann, 1967) .
     Cases of acute human intoxication by toxaphene-lindane
mixtures have been reported.  In one instance, (Pollock,
1958) a 70-year-old male had his hands in contact with a
toxaphene-lindane solution for two hours.  After ten hours,
the following symptoms developed:  headache, poor coordina-
tion, lassitude, severe nausea, and vomiting.  Over the
next week, this individual exhibited mild hyperthermia,
flaccid musculature, and decreased response to stimuli.
Only after nine days did the individual become semicomatose.
At no time were convulsions or hyperreflexia noted.  These
signs and symptoms are not characteristic of toxaphene or
lindane poisoning  (Matsumura, 1975) and differ markedly
from the previously described cases of acute oral toxaphene
poisoning in humans.  While clinical signs of intoxication
may be expected to show some variation with different routes
of entry, such profound variation  is uncommon with the chlori-
nated insecticides.  Gaines  (1960, 1969) noted no difference
                               C--31

-------
between signs of intoxication in rats orally and dermally



exposed to a variety of pesticides.  Lackey (1949 a, b)



similarly notes no remarkable differences in the response



of dogs to subacute oral and dermal doses of toxaphene.



     Two cases of acute plastic anemia associated with dermal



exposure to toxaphene/lindane mixtures have been reported



(U.S. EPA, 1976e).  One of these cases resulted in death



due to acute myelomonocytic leukemia which was presumed



to be secondary to the development of plastic anemia.  Thus,



while toxic anemia has not been reported in laboratory mammals



in acute toxaphene poisoning, such an effect may be hazardous



in man in instances also involving lindane exposure.



Teratogenicity



     In a study by Kennedy, et al. (1973), male and female



rats were fed dietary levels of 25 mg/kg diet and 100 mg/kg



toxaphene.  Gross and microscopic pathology of F3 weanlings



revealed no indication of teratogenic effects.  Further,



no statistically signficiant variations from controls were



noted in either dose group for any of the following parame-



ters:  mating index, fertility index, pregnancy index, par-



turition index, mean viable litter size, live birth index,



five-day survival index, lactation index, or weaning body



weights of offspring.  One of 16 females from each dose



group resorbed an entire litter.  This was not seen in any



of the 32 control females but did occur in tests with another



pesticide, delnav.
                               C-32

-------
     In multigeneration studies of mice given toxaphene



at 25 mg/kg diet, no effects on fertility, gestation, via-



bility, lactation, or survival indices were observed (Kep-



linger, et al. 1970).



     In addition to these long-term dietary studies, one



study (Chernoff and Carver, 1976)  has been conducted in



which toxaphene in corn oil was administered to pregnant



female rats and mice from days 7 to 16 of gestation at doses



of 15, 25, and 35 mg/kg/day.  All doses produced signs of



maternal and fetal toxicity but no teratogenic effects.



     DiPasquale  (1977)  has examined the effects of toxaphene



on fetal guinea pig development.  In this study, toxaphene



was administered to pregnant females at a dose of 15 mg/kg



body weight orally from day 21 to day 35 of gestation.



No effects were noted on anatomical development of the fetus.



The only sign of fetotoxicity was a decrease in collagen-



containing structures.   This was attributed to a functional



deficiency of vitamin C related to mixed-function oxidase



induction.  Maternal guinea pigs showed a slight loss of



body weight but no effects were seen on maternal liver weight



or mortality.



Mutagenicity



     Epstein, et al. (1972) have used a modified dominant



lethal assay  in mice to evaluate the mutagenic potential



of a variety of chemical agents including toxaphene.  In



this study, four groups of male ICR/Ha Swiss mice were given



toxaphene  intraperitoneally - single doses of 36 mg/kg and



180 mg/kg  - and  orally - five doses of 8 mg/kg/dose and
                               C-33

-------
16 mg/kg/dose.  After dosing, the treated males were mated



to groups of untreated females over an eight-week period.



Based on measurements of early fetal deaths per pregnancy



and the percent of females with early fetal deaths, the



toxaphene-treated groups did not differ significantly from



controls.  Thus, in this strain of mice, toxaphene apparently



does not produce chromosomal abnormalities that preclude



zygote development.



     Hill (1977) has summarized information on the mutageni-



city testing of toxaphene in bacterial systems.  Ames tests



have been conducted on Salmonella typhimurium strains TA-



1535, TA-1537, TA-1538, TA-98, and TA-100 with and without



metabolic activation by non-induced mammalian liver frac-



tions.  Positive results were obtained for strains TA-98



(frameshift mutation) and TA-100 (base pair substitution)



only in tests without metabolic activation.  All other tests



were negative.  A "high temperature" toxaphene has elicited



positive dose response increases in strains TA-98 and TA-



100 only with metabolic activation.  All the above tests



were conducted by Litton Bionetics Inc. for Hercules, Inc.



     In addition to these studies,  work has been conducted



on the mutagenicity of toxaphene in the Salmonella system



by Dr. Kim Hooper of Bruce Ames1 group in Berkeley, Calif.



(Hill, 1977) .  His results indicate that toxaphene and toxa-



phene subtractions are mutagenic to strain TA-100 with and



without activation by Aroclor-induced rat microsomes.  Mutagenic



activity was decreased in those tests using microsomal activation.
                              C-34

-------
     A recently completed study by U.S.  EPA (1978)  found

no significant differences in the rates  of chromosomal aber-

rations in leukocytes between groups of  individuals occupa-

tionally exposed to toxaphene and groups with no occupational

exposures to toxaphene.

Carcinogenicity

     Under contract to the Natl. Cancer  Inst., Gulf South

Research Institute has recently completed a carcinogeni-

city bioassay of toxaphene (Natl. Cancer Inst. 1979) .   It

should be noted that this study, which was conducted from

1971 to 1973, did not follow current NCI protocols (Natl.

Cancer Inst. 1977).  Specifically, only  ten animals were

used in each matched control group, and  matched-fed control

groups were not utilized.  In this study, groups of Osborne-

Mendel rats and B6C3F1 hybrid mice were  exposed to technical-

grade toxaphene in the diet for 80 weeks.  Details of the
                                                 -j
dose schedule and number of animals used are provided in

Tables 11 and 12.

     Toxaphene was added to the feed in  acetone.  In addi-

tion, 2 percent corn oil was added to the diet as a dust
            *
suppressant.  Actual dietary toxaphene concentrations, which

were confirmed by gas-liquid chromotography, did not deviate

from the nominal concentration by more than '6.9 percent.

In addition to the matched control groups indicated in these

tables, pooled control groups were used  in the statistical

analyses.  For rats, pooled controls consisted of matched

controls from similar bioassays on captan, chloraben,  lin-

dane, malathion, and picloram, as well as the matched con-
                              C-35

-------
                                  TABLE 11
                                  i.ridJ-iJj J-j.
                 Toxaphene Chronic Feeding Studies in Rats
Sex and
Test
Group

Male

Matched-Control

Low-Dose
High-Dose
Female
Matched-Control
  Initial  Toxaphene
  No. of   in  Diet(c)
Animals(b)   (mg/kg
              Time on Study    Time-Weighted
         Dosed(d)  Observed(e)Average Dose(f)
          (weeks)     (weeks)       (mg/kg)
    10

    50
    50
1,280
  640
  320
    0

2,560
1,280
  640
    0
 2
53
25
 2
53
25
    10
                     108-109
                                                            28
  556
1,112
                                                            28
                     108-109
Low-Dose


High-Dose


^National Cancer
50


50


Institute,
640
320
0
1,280
640
0
1979.
55
25

55
25


540

30
1,080

30
j_ . _ ^2 . .
     Initial doses shown  were  toxic;  therefore,  doses were lowered
     - after 2 weeks and again  at  53 or  55  weeks,  as  shown.
     All animals were  started  on  study  on  the  same day.  ,
     When diets containing  toxaphene  were  discontinued,  dosed rats
      and their matched controls  were fed  control diets  without
      corn oil for 20  weeks, then control  diets  (2 percent corn
    c oil added) for an additional ,8  weeks.            ,-     ,    .  ..  .  ,   .
    fTime-weighted average  dose =% a°se ™ ?Pm x no"  of  weeks at that dose)
                                  g(no.  of  weeks  receiving each dose)
                                 C-36

-------
                                  TABLE 12
                 Toxaphene  Chronic Feeding  Studies in Micea
Sex and
Test
Grou;
Male

Matched-Control

Low-Dose



High-Dose



Female

Matched-Control

Low-Dose



high-Dose
  Initial   Toxaphene       Time on Study    Time-Weighted
  No. of   in  Diet(c)  Dosed(d)  Observed(e)Average Dose(f)
Animals(b)  (mg/kg)    (weeks)      (weeks)       (mg/kg)
10

50



50
10

50



50
  0

160
 80
  0

320
160
  0
160
 80
  0

320
160
  0
                                             19
                                             61
                                             19
                                             61
                                             19
                                             61
                                             19
                                             61
                                                        90-91
                                                            11
                                                            10
                                                         90-91
                                                            11
                                                            10
                                                    99
                                                   198
                                                    99
                                                   198
    ^National Cancer Institute, 1979.
     All animals were 5 weeks of age when placed on study.
    clnitial doses shown were toxic;  therefore, doses were
    , lowered at 19 weeks, as shown.
     All animals were started on study on the same day.
     When diets containing toxaphene were discontinued,  dosed mice
      and their matched controls were fed control diets  without
      corn oil for 7 weeks, then control diets  (2 percent corn oil
                                 C-37

-------
trols from the toxaphene bioassay.  For mice, pooled con-



trols consisted of matched controls from similar bioassays



on lindane, malathion, phosphamidon, and tetrachlorvinphos,



as well as the matched controls from the toxaphene study.



Organisms used in all pooled control groups were of the



same strains, from the same suppliers, and examined by the



same pathologists.



     During the course of this study, both rats and mice



evidenced signs of general toxic effects.  Both male and



female rats in the high-dose group developed body tremors



at week 53.  From week 52 to week 80, other clinical signs,



which occurred primarily in toxaphene-dosed rats, included



diarrhea, dyspnea, pale mucous membranes, alopecia, rough



hair coats, dermatitis, ataxia, leg paralysis, epistaxis,



hematuria, abdominal distention, and vaginal bleeding.



Female rats in both dose groups had lower mean body weights



than the matched controls.  No dose-related effect on mor-



tality was noted in any of the rat test groups.  In mice,



males and females in each dose group displayed a significant



increase in mortality when compared to the matched controls.



In high-dose male mice, mean body weights were generally



lower than those in the matched control group.  Clinical



signs of toxicity in mice included abdominal distention,



diarrhea, alopecia, rough hair coats, and dyspnea.



     The effects of dietary toxaphene on tumor incidence



in male rats, female rats, male mice, and female mice are



summarized in Tables 13, 14, 15, and 16, respectively.
                              C-38

-------
                        TABLE  13
Analyses of the Incidence of Primary Tumors in Male Rats
             Fed Toxaphene in the Diet  (a,L>)
Topography; Morphology
Liver: Neoplastic Nodule (c)
P Values (d)
Weeks to First Observed Tumor
Pituitary: Chromophobe Adenoma,
Carcinoma, NOS, or Adenoma,
NOS(c)
0 P Values (d)
i
£ Weeks to First Observed Tumor
Adrenal: Adenoma, NOS, Cortical
Adenoma, or Carcinoma
P Values (d,e)
Weeks to First Observed Tumor
Spleen : Hemang ioma ( c )
P Values (d)
Weeks to First Observed Tumor
Thyroid: Follicular-cell
Carcinoma or Adenoma (c)
P Values (d)
Weeks to First Observed Tumor
Matched
Control
1/9 (ID
N.S.
I0y
3/7 (43)
N.S.
102
4/9 (44)
P = 0.019 (N)

0/9 (0.)
N.S.
—
1/7 (14)
N.S.
109
Pooled
Control
1/52 (2)
N.S.
—
8/46 (17)
N.S.
5/52 (10)
N.S.

0/49 (0)
N.S.
—
2/44 (5)
P - 0.007
—
Low
Dose
6/44 (14)
P = 0.034**
108
13/42 (31)
N.S.
85
5/41 (12)
P - 0.043 (N)*
85
3/45 (7)
N.S.
83
7/41 (17)
N.S.
104
High
Dose
4/45 (9)
N.S.
94
5/31 (16)
N.S.
95
3/37 (8)
P - 0.020 (N) *
85
3/42 (7)
N.S.
85
9/35 (26)
P - 0.008**
56

-------
n
i
       ^A National Cancer  Institute,  1979.
        Dosed  groups received time-weighted average doses of 556 or 1,112 ppm.
       ^Number of  tumor-bearing animals/number of animals examined at site (percent).
        Beneath the incidence of tumors in  a control group is the probability level for the Cochran-
       Armitage test when  P less than 0.05;  otherwise,  not significant (N.S.) is indicated.  Be-   .
       neath the incidence of tumors  in a dosed group is the probability level for the Fisher exact
       test for the comparisons of that dosed group with the matched-control group  (*) or with the
       pooled-control group (**) when P less than 0.05 for either control group; otherwise, not
       significant (N.S.)  is indicated.
        A negative trend (N) indicates a lower incidence in a dosed group than in a control group.

-------
                                              TABLE 14
                     Analyses of the Incidence of Primary Tumors in Female Rats
                                   Fed Toxaphene in the Diet(a,b)
Topography ; Morphology
Integumentary System: Malignant
Fibrous Histiocytoma of the
Subcutaneous Tissue (c)
P Values (d)
Weeks to First Observed Tumor
Mammary Gland: Fibroadenoma (c)
P Values (d)
Weeks to First Observed Tumor
i
*-
M
Liver: Hepatocellular Carcinoma
or Neoplastic Nodule (c)
P Values (d)
Weeks to First Observed Tumor
Pituitary: Chromophobe Adenoma/
Carcinoma, or Adenoma, NOS(c)
P Values (d)
Weeks to First Observed Tumor
Thyroid: Follicular-celle
Adenoma (c)
P Values (d)
Matched
Control
0/10 (0)
N.S.
1/10 (10)
N.S.
87
1/10 (10)
N.S.
109
3/8 (38)
P = 0.046
85
0/6 (0)
P = 0.022
Pooled Low
Control Dose
0/55 (0) 1/50 (2)
N.S. N.S.
105
6/55 (11) 10/50 (20)
N.S. N.S.
— . ~ 19
1/55 (2) 5/42 (12)
N.S. N.S.
108
17/51 (33) 15/41 (37)
P = 0.012 N.S.
75
1/46 (2) 1/43 (2)
P = 0.008 N.S.
High
Dose
3/49 (6)
N.S.
83
10/49 (20)
N.S.
67
4/40 (10)
N.S.
109
23/39 (59)
P = 0.013**
79
7/42 (17)
P = 0.021**
W^eks to First Observed Tumor
102
105

-------
n
i
                                                  TABLE 14
                         Analyses of the Incidence of Primary Tumors  in  Female  Rats
                                       Fed Toxaphene in the Diet(a,b)
Topography: Morphology
Adrenal: Cortical Adenoma or
Carcinoma (c)
P Values (d)
Weeks to First Observed Tumor
Uterus: Endometrial Stromal
Polyp (b)
P Values (c)
Weeks to First Observed Tumor
Matched Pooled
Control Control
0/8 (0) 3/50 (6)
N.S. N.S.
0/9 (0) 5/53 (9)
N.S. N.S.
^National Cancer Institute, 1979.
Dosed groups received time-weighted average doses of 540 or I/
^Number of tumor-bearing animals/number of animals examined at
Low
Dose
3/44 (7)
N.S.
104
9/41 (22)
N.S.
87
080 mg/kg.
site (percent) .
High
Dose
6/43 (14)
N.S.
87
5/45 (11)
N.S.
109
«-Kn
         Cochran-Armitage test when P less than 0.05;  otherwise not significant (N.S.) is indicated.
         Beneath the incidence of tumors in a dosed group is the probability level for the Fisher
         exact  test for  the comparison of that dosed group with the matched-control group  (*) or with
         the  pooled-control group (**) when P less than 0.05 for either control group;  otherwise, not
         significant (N.S.)  is indicated.

-------
                                                  TABLE 15
                          Anaylses of the Incidence of Primary Tumors  in Male  Mice
                                       Fed Toxaphene  in the Diet(a,b)
o
i
    Topography;  Morphology

    Liver:     Hepatocellular
      Carcinoma(c)

    P Values(d)
Matched
Control
 0/10 (0)

P less
than 0.001
  Pooled
 Control
  4/48 (8)

P less
than 0.001
    Week.-5  to  First Observed 'Tumor
    Low
   Dose
 34/49 (69)

P less
than 0.001*

P less
than 0.001**

        73
   High
   Dose
45/46  (98)

P less
than 0.001*

P less
than 0.001**

       59
    Liver:    Hepatocellular  Carcinoma
      or Neoplastic  Nodule(c)

    P Values(d)
2/10 (20)

P less than
0.001
 7/48 (15)

P less than
0.001
 40/49 (82)

P less than
0.001* .

P less than
0.001**
45/46 (98)

P less than
0.001*

P less than
0.001**
    Weeks  to First Observed  Tumor
      90
                        73
                        59
        j~A National Cancer  Institute,  1979.
         Dosed groups  received  time-weighted  average doses of 99 or 198 mg/kg.
         .Number of tumor-bearing  animals/number  of  animals examined at site (percent).
         Beaneath the  incidence of  tumors  in  a control group is the probability level for the
        Cochran-Armitage  test when  P  less  than 0.05;  otherwise not signficant (N.S.) is indicated.
        Beneath the incidence of  tumors  in a  dosed  group is the probability level for the Fisher
        exact test for  the  comparison  of that dosed group with the matched-control group (*) or with
        the pooled-control  group  (**)  when P  less than 0.05 for either control group; otherwise, not
        significant (N.S.)  is indicated.

-------
                                                  TABLE 16
                         Analyses  of  the  Incidence of  Primary Tumors in Female Mice
                                      Fed Toxaphene in the Diet  (a,b)
                                                             Pooled
                                                            Control
                                                             0/48  (0)

                                                           P less  than
                                                           0.001
Topography;  Morphology

Liver:  Hepatocellular
  Carcinoma(c)

P Values(d)
Matched
Control
  0/9 (0)

P less than
0.001
   Low
   Dose
  5/49 (10)

P = 0.030**
  High
  Dose
34/49 (69)

P less than
0.001*
o
i
    Weeks to First Observed Tumor
                                                                                89
                                                P less  than
                                                0.001**

                                                        72
    Liver:   Hepatocellular
      Carcinoma or Neoplastic
      Nodule(c)

    P Values (d)
                                          0/9  (0)

                                        P less than
                                        0.001
                 0/48 (0)

               P less than
               0.001
    Weeks to First Observed Tumor
 18/49 (37)

P = 0.026*
                                                                       P  less  than
                                                                       0.001**

                                                                                89
40/49 (82)

P less than
0.001*

P less than
0.001**

       72
        ^National Cancer Institute, 1979.
         Dosed groups received time-weighted average doses of 99 or 198 rag/kg.
        ^Number of tumor-bearing animals/number of animals examined at site  (percent).
         Beneath the incidence of tumors in a control group is the probability  level  for  the Cochran-
          Armitage test when P less than 0.05;  otherwise not significant  (N.S.)  is indicated.  Be-
          neath the incidence of tumors in a dosed group is the probability  level  for  the Fisher
          exact test for the comparison of that dosed group with the matched-control  group  (*)  or
          with the pooled-control group (**) when P less than 0.05 for either control  group; other-
          wise, not significant (N.S.) is indicated.

-------
     In male rats in the high dose group, a significant



increase was noted in the incidence of follicular-cell carcin-



omas or adenomas of the thyroid.  Of the nine thyroid tumors



which were found in this group, two were carcinomas.  A



significant increase of follicular-cell adenomas of the



thyroid was also noted in the high-dose group of female



rats.  No carcinomas of the thyroid were found in this group.



In both of these groups, the development of thyroid tumors



was dose-related.  A significant increase was also noted



in the incidence of chromophobes, adenomas, chromophobe



carcinomas, and adenomas of the pituitary in the high-dose



group female rats.  However, an examination of historical



control data on the incidence of pituitary tumors in female



rats suggested that an association between the administra-



tion of toxaphene and the development of pituitary tumors



could not be maintained based on the results of this study.



     In both male and female mice, significant increases



were noted in the incidence hepatocellular carcinomas and



in the incidence of hepatocellular carcinomas combined with



neoplastic nodules of the liver.



     Based on the results of this study, the National Cancer



Institute has concluded that "Toxaphene was carcinogenic



in male and female B6C3F1 mice, causing increased incidences



of hepatocellular carcinomas.  The test results also suggest



carcinogenicity of toxaphene for the thyroid of male and



female Osborne-Mendel rats"  (Natl. Cancer Inst. 1979).
                              C-45

-------
     Litton Bionetics, Inc.  (1978) reported a study in the
B6C3F1 strain of male and  female mice fed at doses of 7, 20,
and 50 ppm toxaphene  in the diet which showed a statistically
significant excess of hepatocellular tumors (hepatocellular
adenoma plus hepatocellular carcinoma)  in male mice, but
only at the 50 ppm dose.
     Strobane, a chlorinated terpene pesticide related to
toxaphene, has been shown  to cause an increase in liver
tumor in male but not female mice (Innes, et al.  1969).
                              C-46

-------
                    CRITERION FORMULATION


Existing Guidelines and Standards


     Standards for toxaphene in air, water, and food have


been established or recommended by groups within the United


States, international agencies, and agencies of other govern-


ments.  All these standards were set before the results


of the National Cancer Institute bioassay of toxaphene for


carcinogenicity were available.


     Both the Occupational Safety and Health Administration


(39 FR 23540)  and the American Conference of Governmental


Industrial Hygienists (1977a) have established a time-weighted

                         3
average value of 500 jug/m  for toxaphene in the air of the


working environment.  The American Conference of Governmen-


tal Industrial Hygienists (1977b) based this standard on


unpublished acute and chronic toxicity studies conducted


in the 1950's and on comparisons of the toxicity of toxa-


phene with DDT and Lindane.  A tentative short-term exposure


limit for toxaphene has been set at 1.0 mg/m  (Am. Conf.


Gov. Ind. Hyg., 1977a).


     The national interim primary-drinking water standard


for toxaphene is 5 pg/1 (40 FR 11990; U.S. EPA 1976b, 1976c).


This standard is based on the reported organoleptic effects


of toxaphene at concentrations above 5 pg/1 (Cohen, et al.


1961; Sigworth, 1965) .  A standard of 25 jag/1 was also calcu-


lated based on a concentration of 10 mg/kg in the diet,


which was estimated to give an average daily dose of 1 mg/kg


body weight, as the lowest long-term level with minimal


or no effects in rats (Lehman, 1965).  This standard was


calculated using the following assumptions:
                               '—4"

-------
     weight of rat =  300  g
     daily food consumption of rat = 50 g
     weight of average  human adult = 70 kg
     average daily water  intake for man = 2 liters
     safety factor -  1/500
     dietary intake = trace  (assume zero)


From these assumptions, the maximum safe daily dose for

human was estimated to  be 3.4 jug/kg body weight  (U.S. EPA,

1976b).  It should be noted, however, that the assumption

of 50 g daily food consumption for a 300'g rat is probably

excessively high.

     Based on a study by  Fitzhugh and Nelson  (1951) summar-

ized in Table 10, in which rats evidenced increased liver

weight and hepatic cell enlargement after exposure to toxa-

phene at 25 mg/kg diet  for two years, the acceptable daily

intake for man has been estimated at 1.25 jug/kg  (Natl.

Acad. Sci., 1977).  This  is based on (1) the  estimate that

the daily dose in rats  during the Fitzhugh. and Nelson study

was equivalent to 1.25  mg/kg body weight and  (2) the applica-

tion of a safety factor of 1,000.  Assuming a human body

weight of 70 kg and a daily water consumption of 2 liters,

the suggested no-adverse  effect level from water was set

at 8.75 jag/1 (assigning 20 percent of the total ADI to water)

or 0.44 pg/1 (assigning 1 percent of the total ADI to water)

(Natl.  Acad. Sci., 1977).

     Effluent standards for toxaphene manufacturers have

been set at 1.5 jug/1 for  existing facilities  and 0.1 jug/1

for new facilities (U.S.  EPA, 1976d).
                              048

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      Tolerances established by the U.S. Food and Drug Admini-

 stration for toxaphene residues in various agricultural

 products are as follows:
Residue
level    Product                                          Reference
(mg/kg)	
6

5



3

2

0.1
Fat of meat from cattle, goats, and sheep
Fat of meat from hogs
Fat of meat from horses
Cranberries, hazelnuts, hickory nuts, horse-
  radish, parsnips, pecans, peppers, pimentos,
  rutabagas, walnuts
Collards, kale, spinach
Crude soybean oil

Barley, oats, rice, rye, and wheat
Sorghum grain
Cottonseed

Pineapple and bananas

Soybeans, dry form

Sunflower seeds
                                                          22 FR 4615
                                                          24 FR 4727
                                                          27 FR 7492
22 FR 4615
27 FR 7492
31 FR 12435

23 FR 477
25 FR 5335
26 FR 11799

27 FR 4913

31 FR 9453

U.S. EPA, 1977
  of which not more than 0.3 mg/kg shall be in pulp after the peel
 is removed and discarded.
      In Canada, the tolerance for toxaphene in citrus fruits

 is 7.0 mg/kg.  In both the Netherlands and West Germany,

 the corresponding standard is 0.4 mg/kg (Gunther, 1969).

      The World Health Organization has not yet established

 an acceptable daily intake level for toxaphene (WHO, 1974a,

 1974b, 1976).  The following information is considered neces-

 sary by WHO  (1974b) before an acceptable daily intake can

 be established:

      1.   Adequate toxicological information on camphechlor
           (toxaphene) as currently marketed, including a
           carcinogenicity study.
                               C-49

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     2.   Comparative  studies evaluating  the  toxicological
          hazard associated with polychlorinated camphene
          of different manufacture used in worldwide agricul-
          ture.

     3.   Before recommendations can be made  concerning
          residues  from the use of camphechlor, other  than
          that conforming to FAO specifications, information
          is needed on the composition, uses, and  residues
          arising from such products.
The following guideline levels for toxaphene  in the  speci-

fied foods have been  recommended  (WHO, 1974a) :•

          Fat of meat of cattle,  sheep,
          goats, and  pigs                               5 mg/kg

          Broccoli, brussels sprouts, cabbage, celery,
          collards, eggplant, kale,  kohlrabi, lettuce,
          okra, peppers, pimentos, spinach, tomatoes,
          barley,  rice  (rough), rye, sorghum, bananas
           (whole), pineapple, beans  (snap, dry, lima),
          peas, cauliflower, oats, wheat, shelled nuts,
          carrots, onions, parsnips, radishes,
          rutabagas                                     2 mg/kg

          Soybeans, peanuts  (ground-nut), cotton-seed
          oil  (refined), rape-seed oil (refined),
          soybean  oil (refined).,  peanut oil  (refined),
          maize, rice (finished)                        0.5 mg/kg

          Milk and milk products  (fat basis)            0.5 mg/kg


These recommendations are based on levels which might be

expected  if good application practices are followed  and

do not reflect a judgement concerning potential human hazard.

     The  International Joint Commission of the United States

and Canada (1977)  has recommended a  water standard of 0.008

;ug/l for  the protection of aquatic life.  This standard

is based  on the study by Mayer, et al. (1975) which  found

that toxaphene at  0.039jug/l caused  a significant increase

in mortality and a significant decrease in growth in brook
                              C-50

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 trout  fry  over  a  90-day period.  The  standard of  0.008 jjg/1

 is obtained by  applying a safety factor of 0.2.

 Current  Levels  of Exposure

     Quantitative estimates of  human  exposure to  toxaphene

 are  extremely difficult to make based on  the data presented

 in the Exposure section.  The three major obstacles  are:

     1.    The wide  variation  in toxaphene concentrations
           noted in  food, water, and air.

     2.    Conflicting  information  concerning the  trend of
           toxaphene residues  in food.              !

     3.    The marked seasonal and  geographic difference
           in toxaphene concentrations found  in  air and food.

 Given  these problems,  a conservative  approach in  estimating

 exposure to toxaphene  is necessary.                :

     The best available estimate of dietary  intake;is 0.021

 jug/kg/day, based  on the U.S.  Food  and Drug Administration

 market basket surveys  between 1964 and  1970  (Duggan  and

 Corneliussen, 1972).   Although  more recent market basket

 surveys  indicate  a;decrease in  the incidence of toxaphene

 contamination  (Table 1) and the U.S.  Department of Agricul-

 ture survey suggests that the incidence of toxaphene contam-

 ination  of raw  meat has remained relatively  stable since

 1969 (Tables 2  and  3), the U.S. Food  and  Drug Administration

 survey of  unprocessed  food samples shows  an  almost:two-fold

 increase in the incidence of  toxaphene  contamination between

 1972 and 1976  (Table 2).  Given this  conflicting  informa-

 tion,  the  current dietary intake is estimated to  be  0.042

/jg/kg/day, twice  that  noted by  Duggan and Corneliussen  (1972)
                               C-51

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     No satisfactory estimate can be made of average national

inhalation exposures.  In areas where toxaphene is not used,

inhalation exposure may; be negligible.  Even in areas of

high use, the apparent low absorption of toxaphene across

the lungs suggests that inhalation may not be a significant

source of exposure.

     These admittedly tenuous exposure estimates are summar-

ized as follows:

          Source    Estimate Intake
          Water     no estimate
          Food      0.042 ug/kg/day
          Air       0

Special Groups at Risk

     Individuals working with toxaphene or living in areas

where toxaphene is used or produced would seem to be at

higher risk than the general population.  However, as indicat-

ed previously  (see Mutagenicity section), an increased incidence

of chromosomal aberration has not been noted in groups with

occupational exposure to toxaphene  (U.S. EPA, 1978).  Further,

of 32 samples of human adipose tissue obtained from autopsy

or surgery cases in areas of high toxaphene usage, only

one sample contained detectable levels of toxaphene (0.13

ppm).  This sample was from an individual who lived in the

Mississippi Delta, an area of high toxaphene use, and who

therefore potentially was exposed to toxaphene through agri-

cultural use (U.S. EPA, 1978).  Thus, there is no firm data

to support the assumption that individuals living in high

use areas or individuals with occupational exposure to toxa-

phene are at greater risk than the general population.
                              C-52

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Basis and Derivation of Criterion

     Various water concentrations have already been recommended

for tpxaphene  (see Existing Guidelines and Standards section

in the Criterion Document).  These concentrations,;with

the rationale, are summarized below:

     Standard       Rationale                Source

     5.0 jug/1       Organoleptic effects     U.S. EPA, 1976b
     8.75 >ug/l      Non-carcinogenic         Natl. Acad. Sci., 1977
                    mammalian toxicity
     0.44 jug/1      Non-carcinogenic         Natl. Acad. Sci., 1977
                    mammalian toxicity             :          '
     0.008 jag/1   ,  Aquatic toxicity data    Int. Joint
                                               Comm., 1977

     Estimated risk levels for toxaphene in water can be

calculated using the linear, non-threshold model described

in.'-Federal Register FR 15296, 1979.  The results of the

National Cancer Institute bioassay of toxaphene for carcino-

genicity is presented in Appendix I.  This model assumes

a risk of 1 in 100,000 of developing cancer as a result

of drinking 2 liters of water per day containing toxaphene

at the concentrations used in the bioassay.  Allowances

are also made for consuming fish from toxaphene-contaminated

waters.   The results of these calculations are summarized

in Table 17.  Taking the results of these calculations from

the lowest dose shown to cause a significant increase in

tumor incidence, a toxaphene criterion of 0.467 ng/1 can

be calculated.
                             C-53

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                                  TABLE 17
      Concentrations of Toxaph.ene in Water Estimated to Induce No More
       than One Excess Cancer per 100,000  Individuals  Exposed  over  a~
     Lifetime based on Data  from National  Cancer  Institute  Bioassay of
                      Toxaphene for  Carcinogenicity '

                                          Estimated concentration (ng/1)
                                        	by tumor type '	
                                         H & N         H             T

Mice

Male, high dose, matched controls        0.417®        0.393*;
                 pooled controls         0.409         0.402e

Male, low dose, matched controls         0.502®        0.623e
                 pooled controls         0.467e        1.673e
                                             £           o
Female, high dose, matched  controls      1.996      .   1.43_
                   pooled controls       1.996s        1.43e

Female, low dose, matched controls       1-84®         7.84  (N.S.)
                  pooled control         1.84          7.84

Rats

Male, high dose, matched controls                                 108
                 pooled controls                                   61.6

Male, low dose, matched controls                                  237 (N.S.)
                pooled controls                                    55.7  (N.S.)

Female, high dose, matched  controls  •                              70.2  (N.S.)
                   pooled controls                                 79.9e

Female, low dose, matched controls.                               277 (N.S.)
                  pooled controls                                 421 (N.S.)


   ^National Cancer  Institute, 1979.
    The worksheets and computer output  sheets are  included  in  Appendix
     III of this report.
    H & N, hepatocellur carcinoma or  neoplastic  nodule
    H, hepatocellular carcinoma
    ,T, thyroid  tumor
    N.S. - not  significant
    tumor incidence  significantly greater  than controls at p 0.05.
                                C-54

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                         APPENDIX  I



    Summary and Conclusions Regarding the Carcinogenicity



                        of Toxaphene*



     Toxaphene is a mixture of polychlorinated camphenes.



It is obtained from camphene by photochemical chlorination



which produces a heterogeneous mixture of chemicals  (177)



containing 67 to 69 percent chlorine.  It is structurally



related to strobane (polychlorinated terpene), an insecticide



(currently not in use)  known to induce hepatomas in.mice.



Toxaphene was found to be mutagenic for Salmonella typhimurium



strains TA-98 and TA-100 without metabolic activation.



     Two studies, (1)  the National Cancer Institute bioassay



(dietary study)  on toxaphene in mice and rats, and  (2) the



Bionetics Research Laboratory dietary study  (sponsored by



Hercules) in mice, have demonstrated that toxaphene is carcino-



genic to both mice and rats.



     The National Cancer Institu'te (NCI) dietary study using



male and female B6C3F1 mice at doses of 99 and 198 ppm revealed



a statistically- significant excess of hepatocellular carci-



nomas in male and female mice at both dose levels.



     The Bionetics Research Laboratory study in the same



strain (B6C3F1)  of male and female mice fed at doses of



7, 20, and 50 ppm in the diet showed a statistically signi-



ficant excess of hepatocellular tumors  (hepatocellular adenoma



plus hepatocellular carcinoma) in male mice, but only at



the 50 ppm dose.
                              C-55

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     The National Cancer Institue bioassay  study  also
showed a carcinogenic response  induced by toxaphene  in  both
male and female Osborne-Mendel  rats only at the high dose
level  (1,08.0 ppm) , consisting of a statistically  significant
excess of follicular-cell carcinomas and adenomas of the
thyroid.
     ;In summary, carcinogenic responses have been .induced
in mice and rats by toxaphene.  These results., together
with the positive mutagenic response,.constitute  substantial
evidence that toxaphene is likely to be a human carcinogen.
     The water quality criterion for toxaphene is based
on incidence of hepatqcellular  carcinoma and neoplastic
nodules from the low dose BgC^F^ male mice  bioassay.  It
is concluded that the water concentration of toxaphene  should
be less than 4.7 x 10   micro.grams per liter: in qrder to
keep the lifetime cancer risk below 1.6~" .
*This s.ummary  has  been prepared by  the Carcinogens Assessment
 Group, .EPA, on June  15, 1979.
                               C-56

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Derivation of the Water Quality Criterion for Toxaphene
     The water quality criterion for toxaphene is derived
from the development of hepatocellular carcinomas and neo-
plastic nodules in the 8^3?^ male mice given the low dose
of toxaphene in the NCI bioassay study.  In that group,
a time-weighted average dose of 99 ppm was administered
in the diet for 80 weeks and the animals were observed for
an additional 10 weeks before terminal sacrifice.  The in-
cidence of hepatocellular carcinomas and neoplastic nodules
was 7/48 and 40/49 in the pooled control and treated groups,
respectively.  Assuming a fish bioconcentration factor of
18,000, the criterion is calculated from the following para-
meters:
     nfc = 40            d = 99 ppm x 0.136 = 13.50 mg/kg/day
     Nfc = 49            w = 0.033 kg
     n  = 7             L = 900 days
      c
     Nc = 48            R = 18,000
     Le = 900 days      F = 0.0187 kg/day
     le = 665 days
     Based on these parameters, the one-hit slope BH is
4.42 (mg/kg/day)~ .  The resulting water concentration of
toxaphene calculated to keep the individual risk below 10
is 4.7 x 10~4 ng/1.
                              C-57

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