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
-------
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
-------
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
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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
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B-35
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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
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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
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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.
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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
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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
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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
-------
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
-------
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
-------
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
-------
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
-------
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
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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
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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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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
-------
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.
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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.
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GPO 913-1 '8
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