September 1995
TOXAPHENE
Drinking Water Health Advisory
Office of, Water
U. S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Water (OW),
provides information on the health effects, analytical methodology and
treatment technology that would be useful in dealing with the contamination of
drinking water. Health Advisories describe nonregulatory concentrations of
drinking water contaminants at which adverse health effects would not be
anticipated to occur over specific exposure durations. Health Advisories
contain a margin of safety to protect sensitive members of the population.
Health Advisories serve as informal technical guidance to assist Federal,
State, and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The. HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10 percent of an individual's lifetime), and
lifetime exposures based on data describing noncarcinogenic endpoints of
toxicity. For those substances that are known or probable human carcinogens,
according to the Agency classification scheme (Group A or B), Lifetime HAs are
not recommended. The chemical concentration values for Group A or B
carcinogens are correlated with carcinogenic risk estimates by employing a
cancer potency.(unit risk) value together with assumptions for lifelong
exposure and the consumption of drinking water. The cancer unit risk is
usually derived from the linearized multistage model with 95 percent upper
confidence limits. This provides a low-dose estimate of cancer risk, to humans
chac is considered unlikely no pose a carcinogenic risk in excess of the
stated values. Excess cancer risk estimates may also be calculated using the
one-hit, Weibull, logit or probic models. There is no current understanding
of the biological mechanisms involved in cancer to suggest that any one of
these models is able co predict risk more accurately than another. Because
each model is based on differing assumptions, the estimates that are derived
can differ by several orders of magnitude.
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Toxaphene
September 1995
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 8001-35-2
Structural Formula
• Since the technical grade product is produced by free radical
reactions initiated by chlorine and ultraviolet light, toxaphene is a
complex mixture of polychlorinated camphenes and bornanes with an
average empirical formula of C^QHjQCLg and an average molecular weight
of 414. In fact, more than 177 incompletely characterized components
have been separated .(Holmstead et al., 1974).
• Agricide Maggot Killer (F); Alltex; Camphechlor; Chlorinated
Camphene; Crestoxo; Estonox; Geniphene; Hercules 3956; Milipax;
Motox; Octachlorocamphene; PCC; Penphene; Phenacide; Phenatox;
Polychlorocamphene; Polychlorocamthene; Strobane-T; Toxakil; Vertac
90Z (Budavari et al., 1989; Montgomery and Welkom, 1990; Sine et al.,
1989).
• In the U.S. , prior to being banned, toxaphene was used primarily as
an insecticide to combat cotton insects (such as the cotton boll
weevils; it was also used to control some ectoparasites on livestock,
poultry, as well as a few other field crop Insects (U.S. DHHS, 1994).
Properties (Budavari et al. , 1989; Howard et al., 1991; Montgomery and
Welkom, 1990; U.S. DHHS, 1995; U.S. EPA, 1987; Verschueren, 1983)
Synonyms
Uses
Partition Coefficient
Taste Threshold (Water)
Odor Threshold (Water)
Conversion Factor
Chemical Formula
Molecular Weight
Physical State (25*C)
Boiling Point
Specific Cravity (25'C)
Water Solubility (25*C)
Log Octanol/Water
Melting Point
Density (25*C)
Vapor Pressure (25*C)
C10H10C18 (average)
414 (average)
Amber, waxy solid
NA (begins to dehydrochlorinate at 120 to
155° C)
65 to 90°C
I.65 g/cm^
0.2 -to 0.4 mm Hg or 0.69 x 10"^ mm Hg
(calculated)
1.519 to 1.567
0.5, 0.74, 1.75, or -J ag/L
3.23, 3.30, 4.82 (calculated) or
5.50
0.14 mg/kg
(ppm air to mg/m3)
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Toxaphene
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Occurrence
*	The registrations for most uses of toxaphene were canceled and the
rest were restricted in 1982 by the EPA, then alL registered uses
were banned in 1990 (U.S. DHHS, 1995, 1994). Reported usage in the
United States prior to the 1982 restrictions has been estimated at
>3 x 10^ tons (Swackhamer et al., 1993).
*	There are very few reports of detectable levels of toxaphene in
drinking water supplies. Faust and Suffet (1966) reported that
between 1959 and 1963, treated water in Flint Creek, Alabama
contained toxaphene concentrations ranging from 5 to 410 ppt (Howard
et al., 1991; U.S. DHHS, 1995). In a study by Maddy ec al. (1982),
toxaphene was detected but not quantified in one or more California
drinking water wells (Howard et al., 1991).
*	Reports by Faust and Aly (1964), Gilliora et al. (1985), Granstrom et
al. (1984), Lichcenberg ec al. (1970), Mattraw, Jr. (1975) and
Schulze et al. (1973) suggest that toxaphene was only rarely found in
surface waters of most of the United'States from 1950 to
approximately 1980 (Howard et al., 1991). STORET data reported by
Staples et al. (1985) for 1980 to 1982 detected toxaphene in 32
.percent of ambient water samples tested, at a median concentration of
0.05 ppb (Howard et al., 1991). In two Mississippi watershed areas,
one studied during 1977 to 1979 and the other during 1982 to 1985,
toxaphene levels in surface waters ranged fron <0.01 ng/L (0.01 iig/L
- detection limit), to 0.40 or 1.07 jig/L (Cooper, 1991; Cooper ec al. ,
1987). Levels generally exceeded the detection limit only after
major run-off events.
*	In addition to Che Maddy ec al. study (1982) indicating the presence
Co toxaphene in one or more California drinking water wells, Cohen
(1986) reported its presence in 5 out of 2,963 California groundwater
samples (Howard ec al., 1991). The groundwater associated wich 479
waste disposal sices located throughout the United States was
examined for the presence of toxaphene and a variety of chemicals and
other pesticides (Plumb, Jr., 1991). Pesticides were analyzed for an
average of 4,100 times (range of L.600 to 9,000), and toxaphene was
detected 32 times at 13 sices in 3 different U.S. EPA Regions.
*	Anonymous data for the' United States during 1963 to 1969 iicated
chat 0 to 3.6X of sampled food composites tested positive r
toxaphene, with daily intakes ranging from 0 to 4.0 Mg (He *d et
al., 1991). Duggah et al. (1983) reported that between 1? ind
1976, positive food composites and daily intakes ranged £x. oc
detected to 0.8X and from not detected to O 5 uq, respecti\
(Howard et al., 1991). Johnson ec al. (1984) reported that :om
August, 1976 to September, 1977, 3.31 of food composites w
positive with toxaphene levels of 0.026 to 0.597 ppn; and rebarac
(1984) reported numbers of 1.7Z and 0.173 to 0.469 ppn for *..e period
from October 1977 to September 1978 (Howard et al., 1991). Cartrell
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et al. (1986) calculated an adult daily dietary average intake of
1.59 pg for 1980 to 1982, and Hundley et al. (1988) reported
toxaphene being found in 5 of 6,391 domestic agricultural commodity
samples at 0.1 to >2.0 ppm (Howard et al., 1991). More recently, of
thousands of food samples analyzed in 10 state laboratories, 0.143X
and 0.168Z tested positive for toxaphene in 1988 and 1989,
respectively (Minyard, Jr. and Roberts, 1991). Of 6,970 produce
samples taken during 1989 to 1991, only 1 cucumber sample had a
toxaphene level above the detection limit of 2.000 ppm (Schattenberg
and Hsu, 1992). Geometric mean residue concentrations of toxaphene
in fish at 112 stations throughout the United States declined from
0.34 ng/kg in 1976 to 77 to 0.14 mg/kg,in 1984, with the percentage
of stations having any detections falling from 882 in 1980 to 1981 to
69* in 1984 (Schoitt et al., 1990).
* Toxaphene has in the past (1967 to 1981) been detected in ambient air
in the United States at concentrations ranging ftfom <0.02 to
8,700 fxg/m^ (Howard et al., 1991; U.S. DHHS, 1995). More current data
were not located.
Environmental Fate
•	Toxaphene is apparently, resistant to physical-chemical and biological
transformation in water. Early EPA studies (1979, 1976) concluded
that*it was not likely to undergo direct photolysis or photo-
oxidation, and that its estimated hydrolytic half-life" at pH 5 to 8
(25*C) was >10 years .(U.S. DHHS. 1995).
•	Analysis of toxaphene's aquatic fate and transport is complicated by
evolving analytical methodologies that render comparing earlier with
later monitoring data difficult, and by the potential production of
toxaphene-1ike materials by the paper and pulp industry (U.S., DHHS,
1995)
•	While a wide range of vapor pressure values has been reported (see
Properties, above), at lease the higher estimates suggest significant
volatility and ready partitioning from water to the atmosphere. The
various field dissipation, atmospheric monitoring and model ecosystem
studies reported by Seiber et al. (1979), Willis et al. (1983, 1980),
Nash et al. (1977) and Glotfelty et al. (1989) confirm this to be the
c»» (U.S DHHS, 1995)
•	Toxaphene's high soil organic carbon partition coefficient and field
studies,such as those of Seiber et al. (1979), Swoboda et al. (1971)
and McDowell et al. (1981) indicate that it strongly sorbs to soils
and sediments, with only minimal leaching to groundwater (U.S. DHHS,
1995) . This finding is reinforced by later studies of different
Mississippi watershed areas (Cooper et al., 1987; Cooper, 1991).
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•	A variety of studies have demonstrated that toxaphene is
bioconcentrated in the tissues of aquatic organisms (reviewed in U.S.
OHHS, 1995). In one of several studies describing the
biomagnification of toxaphene, its concentration increased by an
average factor of 4.7 from plankton to fish, through several trophic
levels (Evans et al., 1991).
•	Enhanced microbial degradation of toxaphene by natural microorganisms
was reported to occur in organically amended soils and sediments
under anaerobic (flooded) laboratory and field conditions (Mirsatari
et al., 1987). At 10 ppm of technical toxaphene, dissipation half-
life in the laboratory was approximately 3 weeks; the rate was slower
at 500 ppm. In the field, toxaphene residues were reduced from 63 to
23	ppm in 120 days. More than half of a toxaphene concentration was
degraded in 28 days by the combined action of 254 run UV light and a
UV-resistant strain of white rot fungus under laboratory conditions
(Katayama and Matsumura, 1991).
III. PHARMACOKINETICS
Absorption
•	No information was found in the available literature that provided
direct data on gastrointestinal (Gl) tract, respiratory system or
dermal absorption of toxaphene. However, the excretion studies
referred to below suggest that at least -45 to 652 of an oral dose is
absorbed (Chandurkar and Matsumura, 1979; Crcwder and Dindal, 1974;
Crowder and Whitson, 1980; Pollock and Kilgore, 1980).
Distribution
•	Croups of three 30-day-old albino racs were deprived of food for
24	hr prior to being dosed with 3®C1-toxaphene (20 tog/kg) in a peanut
oil-gum acacia solution via a stomach tube (Crowder and Dindal,
1974). Radioactivity was measured in various tissues after 3, 6, and
12 hr, and after 1, 2, 3, 5, 7, 9 and 20 days. Maximum and minimuoi
tissue radioactivity (expressed as a percentage of administered dose)
and the associated sampling times were reported as follows: kidney,
0 43 (12 hr) and 0 (7 and 20 days); muscle, 5.3 (12 hr) and 0 (2
days); fat. 3.65 (9 days) and 0.02 (7 days); testes, 0.28 (12 hr) and
0 <20 days); brain, 0.23 (12 hr) and 0 (3, 5, 7 and 20 days); blood
cells 3.1 (3 hr) and 0 (6 and 12 hr, 5 and 7 days); blood
supernatant, 2.35 (12 hr) and 0 (5 days); liver. 2.33 (12 hr) and 0
(3, 7 and 20 days); small intestine (first 2 cm), 0.34 (6 and 12 hr)
and 0 (3, 5 and 7 days); small intestine (last 2 cm), 0.34 (6 hr) and
0 (5, ,7, 9 and 20 days); large intestine, 1.20(12 hr) and 0 (9 and
20 days); esophagus, 0.04 (3 and 12 hr) and 0 (6 hr, 7 and 20 days);
spleen, 0.24 (7 days) and 0 (20 days); and stomach, 77.2 (12 hr) and
0 (20 days). Thus, with the exception of fat, blood cells and the
spleen, peak radioactivity was observed about 12 hr after dosing.
Disregarding the stomach, radioactivity was highest in muscle, blood
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ne
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Sepcember 1995
components, liver and Che large intestine during the first 12 hr
after exposure, but was highest In fat after 9 days and blood cells
after 20 days. Substantial metabolism of toxaphene occurred, and much
of the excreted radioactivity was water-soluble and ionic in form.
In female Sprague-Dawley rats dosed with 10 mg/kg of ,4C-toxaphene in
olive oil by gastric intubation, residual levels of toxaphene after 7
days were less than 0.2 ppm (0.2 mg/kg) in brain, heart, lung, liver,
kidney and spleen tissue (Pollock and Kilgore, 1980). However,
levels in abdominal and subcutaneous fat were similar and averaged
6.4 ppm (6.4 rag/kg).
Croups of four adult female Sprague-Dawley rats were injected ip with
90 MCi/0.0130 mmol/kg (90 jid/5.382 mg/kg) l4C-toxaphene. and blood
was drawn from two rats either 10 min or 2 hr later (Mohammed et al..
1990a). Of the radioactivity that was distributed to plasma,
approximately 41X and 36X were found after 10 min in the albumin-rich
bottom (BF) and cholesterol-rich high density lipoprotein (HLD2)
fractions, respectively. After 2 hr, total plasma radioactivity
dropped by 69X, with the principal fractions again being BF (52X) and
HLDj (30X). Percent radioactivity in other plasma fractions ranged
from about 4 to 9X.
Hale Swiss mice were dosed with 25 mg/kg ^Cl-toxaphene in corn oil by
gastric intubation (Crowder and Whitson, 1980). Retention of
radioactive chlorine (ppm, presumably expressed as ppm of toxaphene)
after 8 days in the tissues of ai single mouse was reported to be:
lipid (10.6), muscle (1.2), testes (0.8), kidney (0.7), liver (0.5)
and brain (0.2).
(formo lip identic, female NMRI mice (3/group) were injected iv with '*C-
Coxaphene in solutions of low density lipoprotein (LDL), high density
lipoprotein (HDL) or DMSO (Mohammed et al., 1990b). After 20 min,
relative radioactivity (dpra/g or ml tissue per dpm dose/g body
weight) was found to approximately range from 0.05 to 0.4 under all
conditions for the heart, spleen, muscle and plasma. Abdominal fat
was reported to be 0.2.to 0.3 (LDL, HDL) or about 1.1 (DMSO); kidneys
about 1.0 (LDL. DMSO) or 0.4 (HDL); adrenals about 2.6 (LDL), 1.4
(HDL), or 4.3 (DMSO); and liver 3.2 to 3.3 (LDL, DMSO) or about 2.2
(H0L). The principal changes after 4 hr were 2- to 4-fold reductions
In liver and adrenal levels, and an approximate 3- to, 10-fold
Increase in abdominal fat levels. In mice made hypolipidemic by.
pretreatment with 4-aminopyrazolo-(3,4-d)-pyrlmidine, relatively
lower levels accumulated initially in the liver and adrenals, while
more was seen in the kidneys and heart.
Mixed-breed heifer calves (6 to 7/group) were dosed with 50, 100 or
150 mg/kg of toxaphene in water via gastric intubation (Steele et
al., 1980). After 7 days, mean concentrations (ppm) found in the
liver, kidney and brain were 2.88, 3.45 and 2.67 (50 mg/kg dose);
7.66, 2.75 and 4.02 (100 mg/kg dose); and 22.26, 5.50 and 3.88 (150
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mg/kg dose). Liver residues were geometrically (logarithmically)
related to dose. Results from five field animals suspected of dying
as a result of being dipped in 0.5Z toxaphene solution were
qualitatively similar, with liver concentrations being two- to five-
fold higher than chose measured in kidney and brain.
fletabpUSTO
•	Groups of three 30-day-old albino' rats were deprived of food for
24 hr prior to being dosed with ^Cl-toxaphene (20 mg/kg) in a peanut
oil-gum acacia solution via a stomach tube (Crowder and Dindal,
1974). Extensive metabolism, including dechlorination, was suggested
by the partitioning patterns of excreted ^C1 radioactivity ineo
hexane, aqueous-nonionic and aqueous-ionic fractions: 10.5, 21.3 and
68.21 in feces, and 0.2, 23.3 and 76.22*in urine, respectively.
•	Croups of four male Sprague-Dawley rats were given a single dose of
^C-toxaphene (15 mg/kg) in corn oil via gastric intubation
(Chandurkar and Katsumura, 1979). Thin layer chromatography of
collected feces and urine indicated chat most of the toxaphene was
netabolized, largely to polar with some hexane-insoluble and
inextractable metabolites. Methylated, acidic and other hydroxylated
compounds were revealed, as were the presence of sulfate conjugates
(about 8.9 and 0.7X of total metabolites in the urine and feces,
respectively) and other acid-hydrolyzable metabolites (about 9.5 and
7.5X of total metabolites in urine and feces, respectively). These
results and those of associated in vitro experiments Indicate a
prominent role for hepatic NADPH-dependent mixed-function oxidases
and CSH S-transferases in the metabolism of toxaphene.
•	Female Sprague-Dawley rats were dosed with 10 rag/kg of toxaphene
Ln olive oil by gastric intubation (Pollock and Kilgore, 1980).
Analysis of urine and fat residues of toxaphene, as well as of polar
•nd nonpolar fractions of toxaphene that were similarly administered,
Indicated metabolism of a large percentage of the materials (>99X for
toxaphene as measured ln the urine). Residues of toxaphene and the
nonpolar fraction,were "more polar than the parent compounds, while
Chose idencified from the polar fraction were somewhat less polar in
nature.
¦ Metabolism of toxaphene (13 mg/kg) and one of Its major components
(K«ptachLorobornane I, 3 mg/kg) was examined in a comparative study
using male rabbits, male Swiss-Webster mice, male Sprague-Dawley
rats, male Hartley guinea pigs, male hamsters,, male long-tailed
monkeys and female white leghorn chickens (Saleh et al., 1979). The
chemicals were administered in soybean oil to mice, rats, monkeys and
chickens via gastric intubation; for che other species, treatment
solutions were applied to lettuce that was quickly consumed. After
72 hr,. the percentages of administered heptachlorobornane I excreted
in the feces were 17.7 (chicken), 2.8 (mouse), 2.5 (rabbit), 2.3
(guinea pig), 0.6 (hamster), 0.2 (rat) and 0.0 (monkey). Percentages
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of cwo dechlorinaced and one dehydrochlorinated metabolites that were
monitored ranged from 0.2 to 10.7X in the various species. Total
levels were highest in rabbits and monkeys, and lowest in mice and
hamsters. Seventy-two hours after toxaphene administration, the
chromatographic patterns of extracted fat samples from all tested
species were reported to be very similar to toxaphene. The patterns
of extracted liver and fecal samples, however, were species-specific
and contained significant differences from that of toxaphene.
Excretion
•	Groups of three 30-day-old albino rats were deprived of food for
24 hr prior to being dosed with 36C1-toxaphene (20 mg/kg) in a peanut
oil-gum acacia solution via a stomach tube (Crowder and Dindal,.
1974). Within 9 days, 52.62 of the administered radioactivity was
excreted, 37.32 in the feces and 15.32 in the urine. Upon
extraction, most of the radioactivity was found in the water
fractions as ionic chloride.
•	Groups of four male Sprague-Dawley rats were given a single dose of
l4C-toxaphene (15 mg/kg) in corn oil via gastric intubation
(Chandurkar and Matsumura, 1979). After 5 days, approximately 56.5X
and 9Z of the administered dose was excreted in the feces and urine,
respectively.
•	Female Sprague-Dawley rats were dosed with 10 mg/kg of toxaphene
in olive oil by gastric intubation (Pollock and Kilgore, 1980).
After 7 days, fecal, urinary and total excretion were 35.7, 22.5 and
S8.2X of the administered dose. Retention of toxaphene was less than
0.2 ppm in brain,, heart, lung, liver, kidney, and spleen, but
averaged 6.4 ppm in abdominal and subcutaneous fat.
•	Male Swiss mice were dosed with 25 mg/kg 36C1 - toxaphene in corn oil by
gastric intubation (Crowder and Uhitson, 1980). After 8 days, fecal,
urinary and total excretipn of radioactivity were 42.5, 18.2 and
60. 7X of the administered dose. Retention of	(ppm) in various
tissues was 10.6 (lipid), 1.2 (muscle), 0.8 (testes), .0. 7 (kidney),
'0.5 (liver) and 0.2 (brain).
•	When dairy cows were sprayed with a 0.5% solution of toxaphene, the
insecticide was detected in the cows milk for at lease 21 days
(Claborn et al., 1963). Detectedi levels (ppm) were 0.60 (1 day), 0.61
(2 days), 0.44 (3 days), 0.23 (5 days), 0.16 (7 days). 0.06 (14 days)
and 0.08 (21 days). Similarly, toxaphene was detected in the milk of
cows fed 20, 60, 100 and 140 ppm of toxaphene in the diet for 8 wk.
Using the conversion factor of 0.015 mg/kg/day per ppm in food for
maintenance feeding of cattle (Lehman, 1959), these doses would
correspond to 0.3, 0.9, 1.5 and 2.1 mg/kg/day. Average toxaphene
concentrations (ppm) in milk were fairly constant during the 8 wk of
exposure: 0.20 to 0.37 (20 ppm dose), 0.48 to 0.75 (60 ppm dose),
0.86 to 1.15 (100 ppm.dose) and 1.44 to 1.82 (140 ppm dose). Milk
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levels declined during the 3 wk. following termination of exposure,
with average levels (ppm) after 3 wk measured ac nondeteccable, 0.07,
0.12 and 0.20 for Che 20, 60, 100 and 140 ppm doses, respectively.
•	Toxaphene was excreted in the milk of cows fed 0 Co 20 ppm
(equivalent Co 0 to 0.3 mg/kg/day using Che 1959 Lehman conversion
described above) toxaphene in the diet for 77 days. Toxaphene levels
in milk ranged from 0.043 to 0.179 mg/L and were dependent on the
administered concentration (Zweig ec al., 1963). Following cessation
of exposure, residues in milk decreased to undetectable levels after
2 wk in cows given levels lower than 10 ppm (0.15 mg/kg/day). At the
20 ppm (0.3 mg/kg/day) level, residues were still detected 30 days
after administration of the test diet was terminated.
IV. HEAlTti EFFECTS
Hmnqilg
Short-term Exposure
•	Toxaphene poisoning in humans is characterized by diffuse stimulation
of che central nervous system (CNS) resulting in salivation,
restlessness, hyperexcitability, muscle tremors or spasms,
generalized convulsions and sometimes loss of consciousness. Nausea
and vomiting may follow ^ingestion. Clonic convulsions also may occur
and can be prevented by barbiturates (McGee et al., 1952).
•	The IUFAC (1979) has estimated an acute oral LD50 of 60 mg/kg for
toxaphene.
•	At lease thirteen deaths from toxaphene poisoning have been recorded
(Hayes, 1975). Most of the fatal cases involved ingestion of
toxaphene by small children.
•	A toxaphene aerosol (5X) at a maximum concentration of '500 mg/nP was
inhaled by 25 humans for 30 min/day over a period of 10 days
(Keplinger, 1963). Calculation by che author equates this exposure
to a maximum of 60 mg/person/day (or about 0.36 mg/kg/day for a 70 kg
adult). After an interval of 3 wk, the subjects received three more
of these daily doses. No adverse effects were reported by Che
subjects or noted by an examining dermatologist or Internist.
•	two men involved for approximately 2 months in spraying a coxaphene
solution (60 X toxaphene, 35% kerosine,. 3X xylol and 2* emulsifier)
suffered from acute pulmonary insufficiency and were diagnosed as
having extensive bilateral allergic bronchopneumonia (Warraki, 1963).
One or both men exhibited extensive miliary shadows and marked
bilateral hilar lymphadenopathy on their x-rays, as well as increased
sedimentation rates, blood eosinophilia and high serum globulin.
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Lone-term Exposure
•	Studies of human exposure to toxaphene in the workplace are
confounded because exposure to many chemicals occurred in all of the
reported studies. Two cases of acute aplastic anemia afcer dermal
exposure to a toxaphene/lindane mixture have been reported (1ARC,
1979).
Mutagenicity
•	Eight women occupationally exposed to toxaphene were reported to have
elevated levels of chromosomal aberrations (13.IX compared with 1.6 X
in controls) in cultures of peripheral lymphocytes from blood taken
8 days after exposure (Saoosh, 1974). The women had prematurely
entered a field that had been sprayed with 2 kg/ha of toxaphene.
Unspecified mild-to-moderate symptoms were reported to have occurred
in the women beginning about 4 to 5 hr after' starting their field
work.
•	In a case-control study involving 622 white men from Iowa and
Minnesota with newly diagnosed non-Hodgkin's lymphoma (NHL) and 1,245
population based controls, an elevated risk for developing NHL (odds
ratio - 1.5, 95* confidence interval - 0.6 to 3.5) was found for
farmers who had ever handled toxaphene (Cantor et al., 1992). The
elevated risk was even more notable for those who had handled
toxaphene prior to 1965 (OR - 2.4, CI - 0.7 to 8.2). However,
because of the small numbers of farmers who had handled toxaphene (10
ever, 6 before 1965), these elevated risks were considered
nonsignificant.
AntntU
Shm-ttrm Emivp?
•	Toxaphene is a CNS stimulant in mammals. Effects of toxic exposures
in humans (hypersensitivity, tremors and convulsions) are similar to
those observed in both rats and dogs (Lehman, 1951).
•	Hale rats were given orally (via capsule) a single, one-half LD^q, 120
mg/kg dose of toxaphene and were sacrificed after 1, 5, or 15 days
(Peakall, 1979). Despite the presence of toxaphene In liver and
brain tissue, no alterations in blood plasma levels of pyruvic or
lactic acids were observed. The NOAEL for this effect after a single
exposure was thus 120 mg/kg. When exposures in a second experiment
were extended to 6 months at a,dose of 2.4 mg/kg/day, no alterations
after 1,3 or 6 months in these parameters were again observed. A
NOAEL for this effect after exposures of 1,3, and.6 months is
therefore 2.4 mg/kg/day.
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*	Groups of 10 male guinea pigs received either a single oral LDjq dose
of 300 mg/kg of toxaphene (99X pure) in groundnut oil, or daily oral
doses of 2 or 5 mg/kg/day for a period of 60 days (Chandra and
Durairaj, 1993, 1992). Within 72 hr of the acute dose, toxaphene was
observed to affect body weight'and the weights of brain (absolute),
liver (absolute and relative) and kidney (absolute and relative) . No
appreciable changes in the ultrastructures of these tissues were
observed. The treatment significantly reduced sodium potassium
ATPase activity in the liver and kidney, magnesium ATPase and total
ATPase activities in the brain, liver and kidney, and the specific
activity of acetyl cholinesterase in all three tissues. Furthermore,
the backbone's collagen content was lowered, while its calcium
content was elevated. After 60 days in the subacute experiment, both
2 and S mg/kg/day doses caused significant body weight loss, as well
as increased absolute and relative liver weight. Neuronal
disorganization and enlargement observed in the brain was attributed
to hypoxia and/or anoxia. Cerebral ollgodendrlal cells suffered
depletion of cytoplasmic organelles, and fluid accumulation in
myelinated axons resulted in abnormal myelin appearance. Chronic
venous congestion was observed in the liver, as was mononuclear
infiltration, hepatocytic hyperplasia, fatty changes and
proliferation of the endoplasmic reticulum. In the kidney, both
doses caused cellular vacuolation, degeneration and mitochondrial
proliferation. Both doses reduced acetyl cholinesterase and total
ATPase activities in the brain, liver and kidney, and elevated boch
cytochrome P^q content and aniline hydroxylase activity in the liver
and kidney.	values for the latter enzyme were lowered in a dose
dependent fashion. Finally, collagen reduction and calcium' elevation
in the backbone was observed at both doses. This study thus reflects
frank toxic effects at 2 mg/kg/day and above for a variety of adverse
effects in the brain, liver and kidney.
•	Hixed-breed heifer calves (6 to 7/group) were dosed once with 50, 100
or 150 af/kg of coxaphene in water via gastric intubation (Steele et
al., 1980). Within the first 7 days, treatment was lethal to 2/6,
6/7 and 5/6 animals at the 50, 100 and 150 mg/kg doses. Clinical
signs included apprehension, hyperexc itability., muscle fasiculacions
and generalized ewicching, clonic-conic convulsions, excessive
lalivaclon, licking and chewing movements, nystagmus, abnormal
posturing, belligerence and frenzied movements. Death occurred
between <• i hr and 5 days afcer treatment.
e Groups of 6 male Sprague-Dawley rats vere dosed by oral intubaCion
with 0, 25, 50 and 100 mg/kg/day of toxaphene in corn oil for. 3 days
(Moorthy et al., 1987; Rao et al., 1986). In these experiments, rats
demonstrated dose-dependent nervousness and mild tremors prior to
sacrifice at 24 hr. In brain tissue preparations, nuclear and ?2
fraction (synaptosomal) calmodulin levels were significantly reduced
at all doses, as were P2 fraction Ca^ + -ATPase accivity. 4*Ca^+ uptake
and calmodulin levels. The LOAEL for these effects following a 3 day
exposure is 25 mg/kg/day. A NOAEL could not be established.
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Toxaphene
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Septenber 1995
•	Groups of 40 co .50 male ICR mice were dosed via oral intubation with
0, 50, 100 or 200 mg/kg/day of coxaphene in com oil for up to 14
days prior to sacrifice or an additional 7 days of observation (Kuntz
et al., 1990). Dose-dependent decreases in body-weight gain were
observed at all three treatment levels, while increases were found
for relative liver weight and serum glutamic pyruvic transaminase
activity. Serum cholinesterase (ChE) activity was first depressed,
then elevated by all treatment levels, although no significant
effects on brain ChE activity were observed. Toxaphene produced 60X
<50 mg/kg/day dose) and 80% (100 mg/kg/day dose) decreases in
pentobarbital-induced sleep time, while 50 mg/kg/day (the only dose
examined) significantly lowered pentobarbital concentrations in
serum, brain, liver and kidneys. No structural changes were detected
by light microscopy in the brain or liver after 50 mg/kg/day (the
only dose examined), but electron microscopy revealed dilatation of
the endoplasmic reticulum in both tissues, and hydropic changes in
the liver. Based on a variety of observed effects, the LOAEL for
this study is 50 mg/kg/day.
•	Rats fed a protein-deficient diet were more susceptible to toxaphene
poisoning than were r*ts fed regular laboratory chow, with LDjq values
of 80 and 220 mg/kg by, respectively (Boyd and Taylor, 1971).
Clinical signs of depression and stimulation of the CNS were the same
in both groups; however, signs appeared earlier and at lower
toxaphene concentrations in protein-deficient rats. This suggests
that humans who ingest a protein-deficient diet may represent a
sensitive subpopulatlon.
•	Allen et al. (1983) reported that humoral antibody responses (IgG
antibody titers to bovine serum albumin) were depressed significantly
in young adult female Swiss-Vebster nice (10 animals/group) administ-
ered toxaphene for 8 wk at dietary concentrations of 100 ppm and
200 ppm, but not at 10 ppm (approximately 15, 30 and 1.5 mg/kg/day,
respectively, based on the dietary assumptions of Lehman (1959)).
Liver weights were increased in a dose-dependent manner at the 100
and 200 ppm doses (23-26 animals/group), as was abnormal variation in
hepatocyte size. Cell-mediated, delayed hypersensitivity responses
were not significantly affected at any dose. Based on these
immunologic and hepatic effects, the study established a NOAEL and
LOAEL of 10 and 100 ppm (1.5 and 15 mg/kg/day). respectively. In
young adult female mice.
•	In a study by Lackey (1949), fasted dogs (breed net Indicated, 3 to 8
per dosage group) were administered single doses toxaphene in corn
oil by gavage at 5, 10, 15, 20, 25, 30, 40 or 50 mg/kg. Deaths
occurred in all dosage groups except the two lowest (5 and
10 mg/kg/day), and were attributed to respiratory failure. Ho
convulsions'were induced after a single dose of S mg/kg, but were
observed in 4/5 animals receiving the 10 mg/kg dose. Therefore,
5 mg/kg and 10 mg/kg were the NOAEL and LOAEL, respectively, for
convulsions in fasted dogs after a single gavage exposure co
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Toxaphene
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Septeraber 1993
toxaphene in com oil. The author also reported that at dally
exposure of 5 mg/kg, convulsions were observed after a few days
(number not seated).
Dermal-Ocular Effects
*	No information was found in the available literature regarding the
dermal-ocular effects of toxaphene.
Long-term Exposure
*	In a second part of the Lackey (19(t9) study discussed above, dogs
were, administered toxaphene by.oral gavage at large cumulative doses
(176 to 424*mg/kg), at 4 mg/kg/day for 44 to 106 days. At that level
there was widespread degeneration of the renal tubular epitheLium,
occasionally accompanied by pyelitis (inflammation of the renal
pelvis). Therefore, 4 mg/kg/day is identified as the LOAEL for renal
effects in this study.
*	Weanling Sprague-Davley rats (10/sex/group) were fed diets containing
0, 4, 20, 100 or 500 ppm toxaphene solubilized.in corn oil for 13 wk
(Chu et al. 1986). Based on measured food consumption, the authors
converted these intakes to dosages of 0, 0.35, 1.8, 8.6 and
45.9 mg/kg/day for males, and 0,0.50, 2.6, 12.6 and 63 mg/kg/day for
females. No significant dose*related clinical signs, gross pathology
findings or weight gain and food consumption effects were observed.
Increased liver weight, relative kidney weight (males) and hepatic
aniline hydroxylase and aminopyrine denethylase activities occurred
at the 500 ppm dose. Mild to moderate histological effects in the
liver, kidneys and thyroid were described by the authors to be
significant at doses of 20 ppm or more. These included mild focal
necrosis and Increased anisokaryosis of the liver, mild to severe
renal tubular injury and focal nec.rosiis (males), and mild to moderate
follicular abnormalities, papillary proliferation, cytoplasmic
vacuolation and reduced colloid density in the thyroid. This study
appears to define a NOAEL of U ppm (0.35 mg/kg/day for males, 0.50
mg/kg/day for females) and a LOAEL of 20 ppa (1.8 ng/kg/day for
males, 2.6 mg/kg/day for females) based on Che described histological
effects.
*	Groups of 7 to 8 month-old beagle dogs (6/aex/froup) were. illy
dosed via gel capsule with 0, 0.2, 2.0 or i to L0 ag/kg/d* f
toxaphene for 13 wk (Chu et al., 1986). Brtef convulsions,
salivation and vomiting were noted in several t>t|h-d0*e anlr ¦?
before the dose was lowered from 10 to 5 rag/kg/day. Slgnif: t
increases in relative liver weight were reported at the mid nales)
and high doses, and in alkaline phosphatase activity at the h ;h
dose. Mild histopathological effects noted to be slgnificar n one
or both sexes ac the aid and/or high .doses included Increase,
relative liver weight, hepatocyte vacuolation and Increased
cytoplasmic density, and follicle abnormalities, interstitial-cell
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Toxaphene
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September 1995
hyperplasia and reduced colloid density in che thyroid. Based on
these histopathological effects in the liver and thyroid, the NOAEL
and LOAEL were established at 0.2 arid 2.0 mg/kg/day, respectively.
*	Male and female dogs of nixed breed were fed toxaphene at levels of
0, 10 or 50 pptn for 2 years (Treon et al., 1952). Using the
equivalency factors of Lehman (1959), these doses were approximately
0, 0..25 and 1.25 mg/kg/day. At 50 ppm (1.25 mg/kg/day), a slight
degeneration of the liver was observed that was characterized by
granularity and nonsudanophilic vacuolation of hepatocyte cytoplasm.
No pathological changes in other viscera were reported. Based on
slight, hepatic degeneration, the NOAEL and LOAEL for this study are
0.25 and 1.25 mg/kg/day.
*	In a lifetime feeding study, Fitzhugh and Nelson ,(1951) observed
increased liver weights with minimal liver cell enlargement in rats
fed a diet containing toxaphene at 25 ppm . (approximately
1.25 mg/kg/day based on the dietary assumptions of Lehman (1959)).
In a lifetime study in racs by Lehman (1952), this level' resulted in
no effects, whereas 100 ppm'(approximately 5 mg/kg/day based on
Lehman (1959)) resulted in fatty degeneration of the liver. Boots.
Hercules Agrochemicals, Inc. (not. dated) reported liver necrosis in
racs fed toxaphene at 200 ppm (author's conversion: approximately
5 mg/kg/day) for 3.7 years. Clapp et al. (1971), however, observed
no adverse effects on liver histology even at doses up to 189. ppm
(approximately 9.45 mg/kg/day, based on Lehman (1959)). Based on
these combined observations, the LOAEL for liver effects is
determined to be 1.25 mg/kg/day, as reported in the Fitzhugh and
Nelson (1951) study.
Reproductive Effects
*	Groups of weanling Sprague-Dawley rats (15 males, 30 females) were
fad diets containing 0, 4, 20, 100 or 500 ppm toxaphene (Chu et al.,
1981). Corn oil was used as a solubilizing agent (42 w/w of the
diet, including controls). Based on measured food consumption, the
authors calculated corresponding dose levels of 0, 0.36, 1.8, 9.2 and
45 ng/kg/day for males, and 0, 0.36, 1.9, 8.5 and 46 mg/kg/day for
females. The iduration of parental exposure was 26 wk, with matings
at 14 and 21 wk. With respect to systemic effects, higher level
exposures were reported to depress weight gain, elevate serum
cholesterol and hepatic aminopyrine demethylase activity, and
Increase liver and kidney weights. More subtle Indications of
toxicity in the form of various histological changes in the liver,
kidney and thyroid were significant at exposures as low as 20 ppm
(1.8 to 1.9 mg/kg/day). These effects included increased weight and
cytoplasmic density in the livers of females, mild renal tubular
injury in the kidneys of females, and increased anisokaryosis in the
livers and kidneys of males. A NOAEL of 4 ppm, or 0.36 mg/kg/day,
can be identified for these parental systemic effects. The
corresponding LOAEL for this study is 20 ppm, or 1.8 mg/kg/day for
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Toxaphene	September 1995
-15-
raales and 1.9 rag/kg/day for females. Toxaphene had no significant,
treatment-related effects at any dose on mating behavior, or on
fertility, gestation and survival indices. Calculated dose levels
were similar for the Fja and generations, which were fed toxaphene
diets upon weaning. Treatment had no significant effect on litter
size, pup weight, or pup survival index, and no other development-
specific effects were noced. Therefore, based on the examined
parameters, this study established NOAELs of 500 ppm, or
approximately 6.5 mg/kg/day, for both reproductive and developmental
effects.
Developmental Effects
•	Pregnant CD rats received 0, 15, 25 or 35 rag/kg/day of toxaphene in
corn oil during the period of organogenesis, i.e., gestation days 7
to 16 (Chernoff and Carver, 1976). The numbers of dams in the
respective groups were 33, 39 , 39 and' 16. There were dose-related
decreases in number of maternal animals reaching term, maternal
mortality (0, 5, 8 and 31*, respectively) and average maternal weight
gain.. Average fetal weight was lower In toxaphene-treated fetuses,
and dose-related reductions in sternal and caudal ossification
centers were noted. No dose-related changes in fetal mortality or
other anomalies were observed. Based on a reduction in average
number of sternal ossification centers, the developmental LOAEL for
this study is 15 mg/kg/day.
•	Approximately 25 pregnant Sprague-Dawley rats were dosed by oral
gavage with 32 mg/kg/day of toxaphene in corn'oil from gestation days
6 to 15 (Chernoff et al., 1990). This dose depressed maternal weight
gain, altered maternal thymus, spleen and adrenal weights, and was
lethal to half the treated dans. While mean fetus weight was
reduced, the only statistically significant developmental effect
rioted was an increase in supernumerary ribs. Concomitant results
with other chemicals tested suggests that the fetal effects were ,not
simply a result of maternal toxicity. The study's LOAEL was the only
dose tested, 32 rag/kg/day.
•	Croups of five pregnant CR rats were dosed orally (details not
provided) with 0, 12.5 or 25 mg/kg/day of toxaphene during days 7
through 16 of gestation (Kavlock et al., 1982). No external
malformations were identified and fetal weight was not reduced. As
measured by various biochemical parameters, brain, lung and liver
development was normal, whereas kidney development was abnormal in
terms of tptal protein (both doses) and alkaline phosphatase activity
(high dose). Based on a composite kidney index, toxaphene in this
study exerted a weak developmental effect at a LOAEL of 12.5
mg/kg/day, the lowest dose tested.
•	Behavioral effects were studied in albino rats exposed prenatally
(from gestation day 5 on, 3 dams/group) and postnatally (4 male and 4
female pups/group) through days 70 to 90, to either 0 or
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Toxaphene
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September 1995
O.OS mg/kg/day of toxaphene in the disc (Olson et al., 1980).
Although this study is deficient with respect to standard protocols
in terms of the number of animals treated, statistically significant
deficits in,righting ability and retarded development of swimming
ability were noted in treated offspring. Similar deficits at
0.002 mg/kg/day were observed for two toxic fractions of toxaphene
(toxicants "A" and "B"). The LOAEL for the behavioral developmental
endpoints examined in this study is the only dose tested,
O.OS mg/kg/day. However, because of statistical limitations arising
from the use of small numbers of animals in this study, the
significance of these data is uncertain.
•	Croups of pregnant CD-I albino mice (26 to 90/group) were
administered 0, IS, 25 or 35 mg/kg/day of toxaphene in corn oil via
gastric intubation from gestation days 7 through 16 (Cheznoff and
Carver, 1976). At thei highest dose, maternal mortality was 8Z, and
there were dose-related reductions in maternal weight gains and
increases in maternal relative liver weights. There were no
significant dose-related responses in fetal mortality or weight,
number of caudal or sternal ossification centers, or Incidence of
supernumerary ribs. At the high dose, however, five litters had one
or more pups displaying encephaloceles (none were observed at lower
doses or in the controls)-. Based on this effect, the study's N0AEL
and LOAEL for .developmental effects are 25 and 35 mg/kg/day,
respectively.
•	In a study separate from che one discussed under Short-terra Exposure.
Allen et al. (1983) exposed adult female Swiss-tfebster mice (36
cotal, 3/cage, apparently 9/dose level) co 0, 10, 100 or 200 ppm
toxaphene in che diet (0, 1.5, IS or 30 mg/kg/day using the 1959
Lehman conversion), from 3 wk prior co mating through gestation and
lactation. Offspring (11 to 40/dose/endpoint) were weaned at 3 wk,
put on toxaphene-free control diet and tested 5 weeks later (at 8 wk)
for cell-mediated, delayed-type hypersensitivity response, humoral
iaaune response (antibody titers to bovine serum albumin), and
macrophage phagocytic activity. Effects on cell-mediated immune
response and antibody formation were noted at che raid and/or high
doses, while a dose-dependent decrease in macrophage phagocytic
ability was observed even ac the 1.5 mg/kg/day dose (p<0.05). Based
on this decreased phagocytosis, the study's LOAEL Is 10 ppm (1.5
mg/kg/day) for developmental inununocoxlc effects.
itamtnltUY
•	Toxaphene has been reported to be mutagenic in tester strains TA98
and TA100 of the Salmonella tvphimurlura reverse mutation assay, both
with and without activation by exogenous rat liver microsomal
preparations (Hill, 1977, summarizing assays performed by Litton
Bionetics, Inc., 197B; Hooper et al., 1979; Mortelmans et al., 1986;
NTP,. 1983).
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Toxaphene
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September 1995
•	Sobti et al. (1983) reported that toxaphene induced sister chromatid
exchanges (SCEs) in the cultured human lymphoid cell line of B cell
origin, LAZ-007. Positive responses were obtained at molar
concentrations of 10"4 and 10"^, but not at 10*^ (41.4, 4.14 and 0.414
mg/L, respectively). The response was slightly less in the presence
of rat liver microsomal preparations used to simulate ijj vivo liver
metabolism^
•	Epstein et al. (1972) used a modified dominant lethal assay in ICR/Ha
Swiss mice to examine toxaphene's it} vivo potential to induce major
genotoxicity in mammalian germ cells. The assay is most sensitive to
structural and chromosomal anomalies. Male mice either were injected
ip once with 36 or 180 mg/kg of toxaphene, or received 40 or
80 mg/kg/day of the insecticide by gavage for S consecutive days.
They were then continually mated with untreated females for B
consecutive weeks. Lethality ratios (number of deaths/number of
treated males) were 0/7, 2/9, 2/12 and 9/12, respectively. Results
were negative, as the numbers of early fetal deaths arid
preimplantation losses were within control limits for all toxaphene
treatments.
Cftrqlnpftgntailty
•	The most definitive study of toxaphene carcinogenicity was conducted
by the.Tracor Jitco Co. under contract to the National Cancer
Institute (NCI, 1979), despite the fact that the study was not
conducted in strict accordance with NCI guidelines (control groups
contained only 10 animals each and paired-feeding was not done).
Osborne-Mendel rats and B6C3Fj. mice (50/sex/treatment group;
10/sex/control group) were used. Diets fed to male rats initially
contained toxaphene at 2,560 and 1,280 ppm, and the females received
1,280 and 640 ppm. For mice of both sexes, the doses were 320 and
160 ppm. Because of overt toxicity,.these concentrations were
lowered later.' For male rats, the high dose was lowered to 1,280 ppm
at 2 wk. and to 640 ppm at 53 wk after initiation of the study for an
average dose of 1,112 ppm. The low dose was similarly lowered Co
640 ppm after 2 wk and 320 ppm 53 vk after feeding had begun for an
average does of 556 ppm. For female rats, both dose levels were
halved after 55 wk, and average doses were calculated to be 540 and
1.080 pps. For both sexes, toxaphene treatment was discontinued
after 80 wV, and the animals were fed control diets without corn oil
for 20 wk and then with corn oil for an additional 3 vk. In male and
female mice, both doses were halved 19 wk after treataent was
initiated and average doses were 99 and 198 ppm. Toxaphene treatment
was discontinued after 80 wk, and animals were fed control diets
without corn oil for 7 wk then diets with com oil for an additional
3 to 4 wk.
Although none of the tumors observed in the animals was uncommon for
the animal strain used, certain tumors and hyperplastic lesions were
present with higher incidence in the treated aninals. In rats these
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Tcxaphene
-18-
Sepcember 1995
included thyroid follicular cell adenomas and carcinomas 7/41 (17%)
ac the low dose; 9/35 (26X) at the high dose; and 1/7 (14X) in
control males). Taking thyroid follicular cell adenomas and
carcinomas together, a statistically significant increase was found
for the high-dose group compared with the matched controls for both
male arid female rats. Increased incidence of these lesions was also
significant in comparison with historical controls from the same
laboratory. In the female rats, there was also an elevated
cumulative incidence of tumors of the pituitary (chromophobe
adenomas, chromophobe carcinomas) in the high dose group, when
compared with the control group.
In the mice, toxaphene was reported to be more toxic. Hepatocellular
carcinomas were observed with incidences of 69X and 981 in males at
the low and high doses, respectively, and at 10X and 69X in females
at the low and high doses, respectively. These neoplasms were
observed in 20Z of matched-control males, but: not in females. On the
basis of these findings, toxaphene was carcinogenic in B6C3F| mice and
caused an increased incidence of thyroid tumors in Osborne-Mendel
rats.
• Litton Bionetics (1978) reported a long-term carcinogenicity bioassay
in which groups of B6C3F1 mice (54/sex/group) were administered 0, 7,
20 or 50 ppm of toxaphene in the diet for 18 mon (U.S. EPA, 1995).
Using the conversion factor of 1 ppm in the diet per 0.15 mg/kg/day
(Lehman, 1959), these doses were equivalent to approximately 0, 1.05,
3 or 7.5 mg/kg/day. Animals were observed for up to 6 mon after
treatment was stopped. The incidence of hepatocellular carcinomas
and neoplastic nodules (adenomas) was increased in both sexes, and
was statistically significant in males at the high dose.
v. ooamtificatton of toxicological effects
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-tara and lifetime exposures if adequate data are available that
identify a sensitive noncarcinogenic end point of toxicity. The HAs for
nonearcinogenic toxicants are derived using the following formula:
" '""(in " (^V/day'"' "	"g/L < r°u"ded " 	 *8/U
NOAEL or L0AEL - No- or Lowest-Observed-Adverse-Effect-Level in
mg/kg bw/day.
BW - assumed body weight of a child (10 kg) or an adult
(70 kg).
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Toxaphene
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September 1995
UF - uncertainty factor (10, 100, 1,000 or 10,000), in
accordance with EPA or National Academy of
Sciences/Office of Water (NAS/0W) guidelines.
	; L/day - assumed daily water consumption of a child (1 L/day) or
an adult (2 L/day).
One-dav Health Advisory
No suitable information was found in the available literature for
determining the One-day HA for toxaphene. The Ten-day HA of 4./ig/L,
calculated below, is recommended for use as a conservative estimate for a 1-
day exposure.
Ten-dav Health Advisory
Several studies were considered for deriving the Ten-day HA. The study
by Lackey (1949) provides evidence of well-documented effects potentially
occurring ac the lowest reported dose for this exposure duration. The study
reports that dogs orally exposed to 4 mg/kg/day of toxaphene for 44 to 106
days suffered from degeneration of the renal tubular epithelium and
inflammation of the renal pelvis (pyelitis), as well as from occasional
convulsions. Because it may be that idogs are somewhat more sensitive than
rodents to the short-term effects of toxaphene, and because the dog study is
unclear as to whether any or all of the reported effects occurred during the
first 10 to 30 days of exposure (although it appears likely that at least
sporadic convulsions did), 4 mg/kg/day has been taken as the LOAEL for these
effects after subacute exposure to toxaphene.
Croups of weanling Sprague-Dawley rats (15 males, 30 females) were fed
diets containing 0, 4, 20, 100 or 500 ppm toxaphene (Chu et al. , 1988). Corn
oil was used as a solubilizing agent (4%kw/w of the diet, including controls).
Bated on measured food consuoption, the authors calculated corresponding dose
levslft ef 0, 0.36, 1.8, 9.2 and 45 mg/kg/day for males, and 0, 0.36, 1.9, 8.5
and 46.Bg/kg/day for females. The duration of parental exposure was 26 vk,
with macings at 14 and 21 wk. With respect to systemic effects, higher level
exposures were reported to depress weight gain, elevate serum cholesterol and
hepatic aminopyrine demethylase activity, and increase liver and kidney
weLghcs. More subtle indications of toxicity in the form of various
histological changes in the liver, kidney and thyroid were significant it
exposures as low as 20 ppm (1.8 to 1.9 mg/kg/day). These effects inclt. ed
increased weight and cytoplasmic density in che livers of females, mild enal
tubular Injury in the kidneys of females, and increased anisokaryosis ii. he
livers and kidneys of males. A NOAEL of 4 ppm, or 0. 36, mg/kg/day, can bt-
identlfied for these parental systemic effects, and. was selected for use
the calculation below to derive the Ten-day HA,
It should be noted that while a Ten-day HA based on this NOAEL is 11 .-ly
to be protective against the commonly studied adverse fetal effects of de -h,
retarded growth and malformations, there is suggestive, but unconfirmed
preliminary evidence that toxaphene could cause itnmunocompetence (Allen et
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Toxaphene
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Sepcember 1995
al., 1983) and functional developmental deficits in behavior (Olson et al.,
1980) at low levels of exposure (at least as low as 1.5 and 0.05 nig/kg/day,
respectively).
The Ten-day HA for the 10-kg child is calculated as follows:
Ten-day HA -	" 0 0036 rag/L (rounded to 4 fig/L)
where:
0.36 mg/kg/day - NOAEL for maternal kidney, liver and thyroid effects in
the rat.
10 kg - assumed weight of child.
100 - uncertainty factor; this uncertainty factor was chosen
in accordance with EPA or NAS/Ctf guidelines in which a
NOAEL from an animal study is employed.
10 - modifying factor; this modifying factor was chosen to
account for data gaps relevant to potential
developmental behavioral and immunological effects.
1 L/day - assumed water consumption by a 10-kg child.
The subchronic rat study by Chu et al. (1986) has been selected to serve
as the basis for the Longer-term HA because it provides both a NOAEL and a
LOAEL for relatively mild effects in three of the principal target organs of
toxaphene--the liver, kidney and thyroid. Rats were exposed for 13 wk to 0,
U, 20, 100 or 500 ppm of toxaphene in the diet (equivalent to 0, 0.35 or 0.50,
1.8 or 2.6, I.6.or 12.6, or 45.9 or 63 mg/kg/day for males and females,
respectively). Baaed on mild to moderate histological effects (focal
necrosis',, anisokaryosis, cytoplasmic vacuolation, etc.) in the liver, kidney
and thyroid, the study defined a NOAEL of U ppm (0.3S mg/kg/day for males) and
a LOAEL of 20 ppm (1.8 mg/kg/day for males). ,These results are supported by
findings in a subchronic dog described in the same publication (Chu et al.,
1986), and in a rat reproduction study using the same doses (Chu eC al. 1988).
The sybchronlc dog study (Chu et al. , 1986), which supported a slightly
lower NOAEL of 0.2 mg/kg/day, was not selected as the principal basis for the
Longer-term HA primarily because the gel capsule dosing methodology was
considered less relevant to likely human exposure conditions than the more
continuous feeding exposure of the rat study. Furthermore, there may be some
degree of uncertainty as to' whether these studies firmly establish a NOAEL or
OAEL for the described critical effects, which were often reported in such a
way (e.g., as being minimal to mild, moderate to severe, etc.) as to make
difficult the precise determination of. the relationship between severity of
effect and dose.
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As noted above for Che Ten-day HA, although a Longer-term HA based on
this NOAEL Is likely to be protective against the commonly studied adverse
fetal effects of death, retarded growth and malformations, there is
suggestive, but unconfirmed preliminary evidence that toxaphene could cause
imnunocoapetence (Allen et al., 1983) and functional developmental deficits in
behavior (Olson et al., 1980) at low levels of exposure (at least as low as
1.5 and 0.05 mg/kg/day. respectively).
The Longer-terra HA for the 10-kg child is calculated as follows:
Longer-term HA - (°('Loo) VloV?* L/day^ " 0,0035 mg/L 
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Toxaphene
-22-
September 1995
10 - modifying factor; this modifying factor was chosen to
account for data gaps relevant to potential
developmental behavioral and immunological effects.
2 L/day - assumed water consumption by a 70-kg adult.
Lifetime Health Advisory and DUEL
The Lifetime HA represents that'portion of an individual's total
exposure that is attributed to drinking water and is considered protective of
noncarcinogenic adverse health effects over a lifetime exposure. The Lifetime
HA is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (AD1). The RfD is. an
estimate of a daily exposure to the human population that is likely to be
without appreciable risk of deleterious effects over a lifetime, and is
derived from the NOAEL (or LOAEL), identified from a chronic (or subchronic)
study, divided by an uncertainty factor(s). From the RfD, a Drinking Water
Equivalent Level (DWEL) can be determined (Step 2). A DUEL is a medium-
specific (i.e., drinking water) lifetime exposure level, assuming 100X
exposure from that medium, at which adverse, noncarcinogenic health effects
would not be expected to occur. The DWEL is derived from the multiplication
of the RfD by the assumed body weight of an adult and divided by the assumed
daily water consumption of an adult. The Lifetime HA is determined in Step 3
by factoring in other sources of exposure, the relative source contribution

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Toxaphene
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nonsudanophilic vacuolation of hepatocyce cytoplasm. No pathological changes
in other viscera were reported. Based on slight hepatic degeneration, the
NOAEL and LOAEL for Chis study are 0.25 and 1.25 mg/kg/day, respectively.
While such values are supported by comparable values in the Chu et al. (1.988)
reproduction study, the 2-year dog study by Treon et al. (1952) could not
serve as the basis of the RfD calculation because only summary documentation
of the study is available, apparently only a United number of animals were
exposed per dose level and the strain of dogs was undetermined. As a result
of these deficiencies, Treon et al. (1952) was considered inadequate for use
as the critical study for the calculation of the RfD.
Collectively, these chronic and subchronic studies identify certain
relatively subtle histopathological effects in the liver, kidney and thyroid
of two species as being critical indicators of toxicity resulting from longer-
term oral exposure to toxaphene. Although they agree remarkably well in
defining NOAEL and LOAEL levels, two concerns remain regarding their use in
establishing the chronic oral RfD. Firstly, there may be some degree of
uncertainty as to whether these studies firaly established a NOAEL or LOAEL
for the reported critical effects, largely due to imprecise toxicity grading,
levels as discussed previously in the Longer-term HA section. Secondly, there
is some preliminary evidence thac suggests certain neurological, developmental
behavioral and/or immunological effects may turn out to be more sensitive
Indicators of toxaphene toxicity. These concerns have been accounted for in
the derivation of the chronic oral RfD by including a 10-fold modifying factor
to account for the data deficiencies.
Therefore, the RfD for toxaphene is based on the reproduction study by
Chu et al. (1988). Ic should be noted thac the 2-year dog study (Treon et
al., 1952) does In fact provide support for the NOAEL/LOAEL values determined
from the more rigorously performed rat scudies (Chu et al., 1988, 1986), which
were selected as the basis for derivation of the chronic oral RfD..
Step I; Determination of Reference Dose (RfD)
Based upon the study cited above (Chu et al., 1988), the RfD may be
calculated as shown below:
RfD - (0.36 rag/kg/dav^ - 0.00036 mg/kg/day (rounded to 0.0004 rag/kg/day)
(100) (10)
where:
0.36 mg/kg/day
100
NOAEL, based on absence of liver, kidney ai thyroid
effects in the rat exposed to toxaphene vie he oral
route for 2I> weeks.
uncertainty factor; this uncertaincy factor as chosen
in accordance with EPA or NAS/0W guidelines a which a
NOAEL from an animal reproduction study is tnployed,
and which is supported by a 2-year dog study.
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Toxaphene
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September '1995
10 = modifying factor; this modifying factor was chosen to
account for data gaps relevant to potential
developmental, behavioral and immunological effects.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
(0.0004 ma/ka/dav) 170 kal ....
DWEL = 	' , '	 —	= 0.014 mg/L (rounded to 10 pg/L)
(2 L/day)
where:
0.0004 mg/kg/day = RfD
70 kg = assumed weight of adult;
2 L/day = assumed water consumption by 70-kg adult.
Step 3: Determination of the Lifetime HA
Toxaphene has been classified in Group B: Probable human carcinogen,
thus a Lifetime HA is not recommended. The estimated excess cancer risk
associated with lifetime exposure to drinking water containing toxaphene at
0.003 mg/L is 1 x 10"4. This estimate represents the upper 95% confidence
limit from extrapolations prepared by EPA's Carcinogen Assessment Group using
the linearized multistage model. The actual risk is unlikely to exceed this
value.
Evaluation of Carcinogenic Potential
•	The results of,two bioassays (NCI, 1979; Litton Bionetics, Inc.,
1978)	were positive for cancer induction, thus estimated risk levels
for toxaphene in drinking water can be calculated using the
linearized multistage model as discussed in the appendices to the
Federal Register notice regarding the availability of Water Quality
Criteria Documents (U.S. EPA, 1980a). Data from human studies are
inadequate to determine toxaphene carcinogenicity.
•	Applying the criteria described in EPA's guidelines for assessment of
carcinogenic, risk (U.S. EPA, 1986), toxaphene may be classified
Group B2: Probable Human Carcinogen. This category is for agents
for which there is inadequate evidence from human studies and
sufficient evidence from animal, studies.
•	Additionally, the International Agency for Research on Cancer (IARC,
1979)	has placed toxaphene in Category 2B, meaning that toxaphene is
probably carcinogenic in humans.
•	Drinking water concentrations- estimated to result in lifetime excess
cancer risks of 10"4, 10'3 and 10"® for a 70 kg adult drinking 2 liters
of water per day over a 70 year lifespan are 3 pg/L, 0.3 yig/l> and
0.03 fjg/h, respectively (upper 95% confidence limit).
• 'DRAFT - DO NOT CTO OR QUOTE - September 23. 1995"

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xaphsne
-25-
Sept^mber
VI.	C.HER CRITERIA. GUIDANCE AND STANDARDS
•	A Time Weighted Average (TWA) of 500 pg/m3 and a short-term exposure
limit of 1.0 mg/m3 have been set for toxaphene by ACGIH (1986).
•	The National Interim Primary Drinking Water Standard of 5	(U.S.
EPA, 1980b) is superseded by the 1991 MCL of 3 ug/L.
•	The NAS (1977) estimated the ADI of toxaphene for humans at
1.25 pg/kg.
•	A Permissible Exposure Limit (PEL) (TWA) of 0.5 mg/m3 has been set by
Occupational Safety and Health Administration (OSHA) for
occupationally exposed workers over an 8-hour workday (OSHA 1989).
VII.	ANALYTICAL METHODS
Toxaphene can be analyzed by EPA Methods 505, 508 and 525.2.
•	Determination of toxaphene using EPA Method 505 — sample is
extracted with hexane, and an aliquot of the extract is injected into
a gas chromatograph equipped with an electron capture detector for
separation and analysis (U.S. EPA, 1991).
•	Determination of toxaphene using EPA Method 508 — sample is
extracted with methylene chloride. The methylene chloride extract is
then dried and concentrated during a solvent exchange to methyl tert-
butyl ether. An aliquot of the extract is injected into a gas
chromatograph equipped with a nitrogen-phosphorous detector for
separation and analysis. Confirmation of the compound's identity may
be obtained using a dissimilar column or by the use of GC-MS (U.S.
EPA, 1991).
•	Determination of toxaphene using EPA Method 525.2 — sample is passed
through a cartridge or disk containing a solid matrix with a
chemically bonded C18 organic phase (liquid-solid extraction, LSE).
The organic compounds are eluted from the LSE cartridge or disk with
ethyl acetate followed by methylene chloride and the extract is
concentrated. An aliquot of the concentrated extract is injected
into a high-resolution fused-silica capillary column of a gas
chromatography/mass spectrometry system for separation and
identification (U.S. EPA, 1994).
VIII.	TREATMENT TECHNOLOGIES
.• Treatment technologies with limited data for removal of toxaphene
from drinking water are adsorption by granular activated carbon (GAC)
and powdered activated carbon (PAC), air stripping and coagulation/
filtration. Other technologies adaptable to drinking water systems
might be able to remove toxaphene; however, such data are not readily
available.
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September 1995
•	GAC columns mounted in a mobile unit have been used for the treatment
of hazardous waste spills. This unit proved to be 97X effective in
removing toxaphene from pond water in Virginia from an initial
concentration of 36 fig/L. The CAC columns, with a contact time of
26 minutes, treated the water at a rate of 70,000 gallons per day.
•	Another study examined the effectiveness of PAC for the removal of
several fish poisons, including toxaphene. PAC was added to water
containing^0.3 mg/L of toxaphene. Toxaphene removals of 95X were
achLeved at a carbon dosage of 9 mg/L. The results of this
experiment Indicate that PAC Is effective for toxaphene removal (U.S.
EPA, 1985).
•	A theoretical model of an air stripping column was developed and
applied to the removal of some synthetic organic chemicals (S0C)
Including toxaphene. The mass transfer coefficients for each SOC
were developed according to Perry and Chilton (1973). The results
show that toxaphene was 99X theoretically removed at an air-to-water
ratio of 30. Actual air stripping performance data for removal of
toxaphene are not readily available.
•	Air stripping is a simple and relatively inexpensive process for
removing organics from water. However, use of this process then
transfers the contaminant directly to the air stream. Uhen
considering use of air stripping as a treatment process, It is
suggested that careful consideration be given to the overall
environmental occurrence, fate, route,of exposure, and various
hazards associated with the chemical.
•	A conventional water treatment plant consisting of, coagulation,
sedimentation and filtration reportedly had little effect on reducing
toxaphene from water. The influent toxaphene concentrations did not
exceed 0.41 yjg/L (U.S. EPA, 1985).
•	Treatment technologies for the removal of toxaphene from drinking
water have not been extensively evaluated except on an experimental
level. Individual or combinations of technologies selected for
toxaphene reduction must be based on a case-by-case technical
evaluation, and an assessment of the economics involved.
* * * DRAFT -¦ 00 NOT CITE OB QUOTE •• Saptemlw 23. 1995"*

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Toxaphene
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September 1995
IX. MmBTCES
ACCIH. 1986. American Conference of Governmental Industrial Hygienists.
Documentation of Che threshold limit values and biological exposure indices.
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Allen, A.L., L.D. Koller and G.A. Pollock. 1983. Effect of toxaphene
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Chandurkar, P.S. and F. Matsumura. 1979. Metabolism of toxaphene components
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Septeaber 1995
Claborn, H.V., H.D. Mann, M.C. Ivey, R.D. Radeleff and G.T. Woodward. 1963.'
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September 1995
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