TECHNICAL REPORT DATA
fftette rttd Instructions on the revtne before completing)
1. REPORT NO.
EPA/600/8-88/056
2.
I. RECIPIENT'S ACCESSION NO
PB88-182886/AS
4 TITLE AND SUBTITLE .
Health Effects Assessment for Toxaphene
6. REPORT DATE
«. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qj*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. Of PAGES
20. SECURITY CLASS (This page/
Unclassified
22. PRICE
EPA F»tm 2220-1 (R«r. 4-77)
COITION is O«»OLCTC
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EPA/600/8-88/056
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR TOXAPHENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
-------
DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with toxaphene.
All estimates of acceptable Intakes and 'carcinogenic potency presented In
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on-Hne literature searches of the TOXLINE and the
CHEMFATE/DATALQG data bases. The basic literature searched supporting this
document 1s current up to May, 1986. Secondary sources of Information have
also been relied upon In the preparation of this report and represent large-
scale health assessment efforts that entail extensive peer and Agency
review. The following Office of Health and Environmental Assessment (OHEA)
sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Toxaphene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-076. NTIS PB81-117863.
U.S. EPA. 1986b. Evaluation of the Potential Carc1nogen1c1ty of
Toxaphene. Prepared by the Office of Health and Environmental
Assessment, Carcinogen Assessment Group, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
The Intent 1n these assessments Is to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available-. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the llfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$o)
exposures.
111
-------
The RfO (formerly AIC) 1s similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfO 1s route-specific and estimates acceptable exposure for either oral
(RfD(j) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The data base for toxaphene contained studies 1n rats and mice that
Indicated that toxaphene was carcinogenic, causing thyroid tumors 1n rats
and liver tumors In mice. Using data for combined Incidences of hepato-
cellular adenomas and carcinomas In male B6C3F1 mice from the Litton B1o-
netlcs. Inc. (1978) study, U.S. EPA (1980a) calculated a human carcinogenic
potency factor of 1.131 (mg/kg/day)'1.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
Page
. . . 1
. , , 4
. . . 4
. . . 4
. . . 5
... 5.'
. . . 5
, , 7
, , , 7
. . . 7
. . . 9
3.4.
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS. . .
4. CARCINOGENICITY . .
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
5. REGULATORY STANDARDS AND CRITERIA
-J 1C
12
13
13
....... 15
. . 15
15
15
15
15
17
17
18
19
V11
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TABLE OF CONTENTS
Page
6. RISK ASSESSMENT 23
6.1. SUBCHRONIC REFERENCE DOSE (RfOs) 23
6.2. REFERENCE DOSE (RfD) 23
6.3. CARCINOGENIC POTENCY (q-|*) 23
6.3.1. Oral 23
6.3.2. Inhalation 23
7. REFERENCES 25-
APPENDIX: Summary Table for Oral Toxldty of Toxaphene Using Male
B6C3F1 Mice 35
-------
LIST OF TABLES
No. TUIe Page
1-1 Selected Chemical and Physical Properties and Half-lives
for Toxaphene 2
3-1 Subchronlc Oral Toxlclty of Toxaphene 6
3-2 Chronic Toxlclty of Toxaphene to Laboratory Mammals at
Low Oral Levels 8
3-3 Chronic Toxlclty of Dietary Toxaphene In B6C3F1 Mice and
Osborne-Mendel Rats 10-
5-1 Tolerances for Toxaphene Residues 1n Various Agricultural
Products 21
5-2 Guideline Levels for Toxaphene In Foods 22
6-1 Cancer Data Sheet for Derivation of q-|* 24
1x
-------
LIST OF ABBREVIATIONS
CBI Confidential business Information
CNS Central nervous system
CS Composite score
EEG Electroencephalogram
HA Health advisory
MFO Mixed function oxldase
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfD Reference dose
RfOj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfO$I Subchronlc Inhalation reference dose
RfD-so Subchronlc oral reference dose
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
toxaphene are presented In Table 1-1.
Determination of the fate of toxaphene 1n the environment 1s complicated
because toxaphene 1s a complex mixture of polychlorlnated camphene
derivatives with different physical properties and environmental behavior
(Callahan et al., 1979). The half-life of toxaphene 1n the atmosphere could
not be located In the available literature. Data from monitoring studies
clearly suggest that toxaphene 1s a prevalent atmospheric contaminant 1n
areas where this pesticide 1s used, particularly 1n the southern United
States (U.S. EPA, 1980a). Toxaphene has been detected In rainfall and
levels of this compound In rainfall have been found to increase during
months of Increased usage of the chemical (HSOB, 1986). Toxaphene 1s very
stable to biological and chemical processess In aerobic systems, although It
does undergo partial reduction (loss of chlorine) In aerobic environments.
In water, a dominant fate process Is direct sorptlon onto sediments or
sorptlon onto partlculates followed by deposition Into sediments where
biological and possibly chemical reduction occurs under anaerobic condi-
tions. The tendency of toxaphene to bind to sediments usually results 1n
Its rapid removal from the water column. The rate of toxaphene loss from
water will then be partially determined by partlculate loading and quality
of the body of water; shallow, partlculate-laden eutrophU waters give
maximum transformation rates of toxaphene, with half-lives on the order of a
few months for some components. The physical properties and chlorinated
functionality of the Individual toxaphene structures win govern which
components will be sorbed and subsequently reduced.
OlOOh -1- 06/01/87
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TABLE 1-1
Selected Chemical and Physical Properties and Half-lives for Toxaphene
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure at 25°C:
Water solubility at 25°C:
Log octanol/water
partition coefficient:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives In
A1r:
Hater:
Soil:
8001-35-2
Polychlorlnated dHerpenes
414 (average)
0.2-0.4 mm Hg
0.4 to -3 mg/l
3.3*0.4
3400-10,000 brook trout
(Salvellnus fontlnalls)
52,000 fathead minnow
(Plmephales promelas)
7800-40,000 channel catfish
(Ictalurus punctatus)
9800 sheepshead minnow
(Cyprlnodon varleqatus)
2400-7200 (estimated)
NA
a few months
4 months to 16 years
IARC, 1979
Callahan
et al., 1979
Callahan
et al., 1979
Callahan
et al., 1979
U.S. EPA, 1980a
Lyman et al.,
1982
Callahan
et al., 1979
Sanborn
et al., 1977
NA = Not available
OlOOh
-2-
10/21/86
-------
The high bloconcentratlon factors 1n aquatic organisms Indicate that
bloaccumulatlon 1n aquatic food chains will occur (Callahan et al., 1979).
In soil, toxaphene 1s expected to be Immobile. Widely varying values for
the half-life of toxaphene In soil have been reported In the literature.
Values range from a half-life of 120 days for toxaphene applied to Dunbar
soil In a South Carolina field plot to 16 years for 51% loss of toxaphene
applied to Congaree sandy loam. Toxaphene 1n groundwater Is reported to
persist for at least 1 year (Sanborn et al., 1977).
OlOOh -3- 10/21/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative data regarding the oral absorption of toxaphene were
provided by Ohsawa et al. (1975), who administered single oral doses of
3SCl-toxaphene (H.2 mg/kg) or 14C-toxaphene (8.5-19.0 mg/kg) to rats
and measured the radioactivity excreted 1n the urine and feces over the
subsequent 14 days. Ohsawa et al. (1975) reported that 49-56% of the radio-
activity associated with an oral dose of 3«Cl-toxaphene was excreted In
the urine and -27% In feces of rats within 14 days. Following treatment
with 14C-toxaphene, fecal excretion accounted for -32% of the administered
dose of radioactivity. These data Indicate that absorption of toxaphene was
>68%. U.S. EPA (1980a) noted that cases of human poisoning Indicate that
humans absorb toxic doses following oral exposure. At least 13 deaths from
toxaphene poisoning have been recorded (Hayes, 1975). Most of the fatal
cases Involved Ingestlon of toxaphene by small children.
2.2. INHALATION
U.S. EPA (1980a) stated that Inhalation exposure to toxaphene probably
does not result In sufficient absorption by humans to cause quantifiable
levels 1n the blood. A study by U.S. EPA (1978) found no detectable levels
of toxaphene In the blood of 54 workers occupatlonally exposed to toxaphene;
however, no quantitative estimates of absorption were provided.
OlOOh -4- 06/01/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. The available Information concerning subchronlc oral
toxlclty of toxaphene Is summarized 1n Table 3-1. Generally, effects on
biochemical parameters (Baeumler, 1975; Grebenyuk, 1970), hlstopathologlcal
appearance of the liver (Ortega et al., 1957; Lackey, 1949, Sosnlerz et al.,
1972), hormone synthesis (Mohammed et al., 1985) and survival (NCI, 1979)
have been reported.
Ortega et al. (1957) fed groups of six male and six female Sherman rats
diets containing 50 or 200 ppm toxaphene for 2-9 months. They found dose-
related hlstologlcal changes 1n the liver (hydropic accumulation); however,
no controls were examined for this effect.
Allen et al. (1983) fed 130 female Swiss-Webster mice diets containing
10, 100 or 200 ppm toxaphene for 8 weeks. Humoral antibody production was
suppressed 1n mice at 100 and 200 ppm.
NCI (1979) fed groups of five male and five female Osborne-Mendel rats
and 86C3F1 mice diets containing 160-5120 ppm (rats) or 40-1280 ppm (mice)
toxaphene In 2-fold Increasing concentrations for 6 weeks. Some rats died
at 2560 ppm, but no deaths or body weight effects occurred at 1280 ppm.
Some mice died at >320 ppm.
The dog studies by Lackey (1949) suggested a threshold for CNS stimula-
tion. Dogs given a single dose of 5 mg/mg toxaphene did not exhibit
convulsions. Dogs given 5 mg/kg/day for a few days experienced occasional
convulsions; however, dogs were able to tolerate large cumulative doses
(176-424 mg/kg) when administered at 4 mg/kg/day. Groups of two dogs
receiving 4 mg/kg/day for 44 or 106 days experienced changes In liver
histology and degener itlon of the renal tubular epithelium of the kidneys.
OlOOh -5- 06/01/87
-------
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-------
3.1.2. Inhalation. As reviewed by U.S. EPA (1985a), 50 volunteers who
Inhaled 0.4 mg/m3 toxaphene aerosol 10 minutes/day for 15 days had no
subjective or objective effects, and 25 humans who Inhaled a mist containing
250 mg/m3 toxaphene, 30 minutes/day for 13 days showed no toxic effects
(Shelanskl, 1947; Kepllnger, 1963).
U.S. EPA (1985a) reported that toxaphene aerosols In the form of dusts
are more toxic than mists to rats. M1st concentrations up to 500 rmj/m3
did not cause any mortality In rats and rabbits over a 3-week period;
however, all rats exposed to 250 mg/m3 dust for 1 week died. Rats, dogs
and guinea pigs exposed to dust at 12 mg/m3 for 3 months died, but no
deaths occurred at 4 mg/m3 (Boots Hercules Agrochemlcals, Inc., n.d.).
3.2. CHRONIC
3.2.1. Oral. The available Information concerning long-term toxldty of
toxaphene to laboratory animals 1s summarized In Table 3-2. The liver
appears to be a target organ; most adverse effects on this organ were
reported 1n studies that used dietary levels >100 ppm (Kennedy et al., 1973;
Lehman, 1952; Boots Hercules Agrochemlcals, Inc., n.d.). Lehman (1952)
found fatty degeneration of the liver 1n rats fed 100 ppm toxaphene.
FHzhugh and Nelson (1951) reported Increased liver weights and minimal
liver cell enlargement 1n rats fed 25 ppm for their lifetime. This Is the
lowest level for which liver effects were reported. U.S. EPA (1985a)
reported that unpublished studies with rats, dogs and monkeys by Boots
Hercules Agrochemlcals, Inc. (n.d.) were In general agreement with the
published studies.
The NCI (1979) conducted chronic bloassays with Osborne-Mendel rats and
B6C3F1 mice to determine possible cardnogenlclty of toxaphene. Treated
groups consisted of 50 rats and 50 mice/sex. Matched controls consisted of
10 untreated an1mals/sex/spedes and these were pooled with 40 untreated
OlOOh -7- 06/16/87
-------
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-------
mice/sex or 45 untreated rats/sex from other bloassays for statistical
comparisons. The dietary concentrations In both species are given In Table
3-3. TWA dietary concentrations were 99 and 198 ppm for mice, 558 and 1112
ppm for male rats, and 540 and 1080 ppm for female rats. Mice received
toxaphene for 80 weeks and were sacrificed at 90-91 weeks. Low-dose males
and females received 160 ppm 1n the diet for 19 weeks and then 80 ppm In the
diet for 61 weeks. High-dose males and females received 320 ppm In the diet
for 19 weeks and 160 ppm 1n the diet for 61 weeks. Doses were lowered
because of mortality 1n the high-dose mice. Clinical signs of toxldty
occurred 1n all treated mice and Included abdominal dlstentlon, alopecia,
diarrhea, rough coats and dyspnea. After1 75 weeks, there were dose-related
differences In survival.
Rats were fed diets containing toxaphene for 80 weeks and then observed
until 108-110 weeks. Mean body weights of treated female rats were lower
than matched controls for most of the study. Because high-dose male rats
receiving 2560 ppm experienced tremors In the first 2 weeks, the doses for
males were lowered. At week 53, most of the high-dose males and females
(1280 ppm) experienced tremors and the doses were again lowered. Clinical
signs normally associated with aging were observed earlier In treated rats
than 1n controls. U.S. EPA (1985a) concluded that no valid NOAEL could be
determined for either rats or mice In the NCI (1979) bloassay.
3.2.2. Inhalation. There were many studies available Involving long-term
occupational exposures of workers to toxaphene. In most cases, however,
exposure levels were not quantified and workers were often exposed to mix-
tures of pesticides. Most of the useful Information relates to Incidences
of various types of cancer and therefore will be discussed 1n Chapter 4.
OlOOh -9- 01/26/87
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TABLE 3-3
Chronic Toxlclty of Dietary Toxaphene In B6C3F1 Mice
and Osborne-Mendel Rats*
Species/Sex
Duration
of Feeding
(weeks)
Toxaphene
Concentration
(ppm diet)
Response
High dose
19
61
19
61
160
80
320
160
Mean body weights unaffected
Mean body weights adversely
affected; several animals
died before week 19; dose-
related decrease 1n survival
Females
Lou dose
High dose
19
61
19
61
160
80
320
160
Mean body weights unaffected
Mean body weights unaffected;
several animals died before
week 19; dose-related decrease
1n survival
Rats/
Osborne-Mendel
High dose
2
53
25
2
53
25
1280
643
320
2560
1280
640
Mean body weights unaffected
HyperactlvHy (week 2); gener-
alized body tremors (week 53);
mean body weights unaffected;
no dose-related decrease 1n
survival
OlOOh
-10-
10/21/86
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TABLE 3-3 (cont.)
Species/Sex
Duration
of Feeding
(weeks)
Toxaphene
Concentration
(ppm diet)
Response
Rats/
Osborne-Mendel
Females
Low dose
High dose
55
25
55
25
640
320
1280
640
Mean body weights adversely
affected
Mean body weights adversely
affected; generalized body
tremors (week 53); no dose-
related decrease 1n survival
*Source: NCI, 1979
OlOOh
-11-
10/21/86
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3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Kennedy et al. (1973) conducted a 3-generat1on study In
which groups of 8 male and 16 female SO rats were fed diets containing 25 or
100 ppm toxaphene. Toxaphene at 100 ppm caused slight cytoplasmlc vacuoll-
zatlon 1n livers of parental animals. There were no effects on growth, mor-
tality, organ weights, litter size, pup survival or weanling body weights.
No treatment-related teratogenlc effects occurred.
Chernoff and Carver (1976) gave gavage doses of 15, 25 or 35 mg/kg
toxaphene 1n corn oil to groups of 16-39 pregnant CD rats on days 7-16 of
gestation. The highest dose was maternally toxic, causing 31/4 mortality.
The two lower doses caused dose-related reduction 1n weight gain of dams.
There were no treatment-related changes In fetal mortality or occurrence of
anomalies at these maternally toxic levels.
Kavlock et al. (1982) administered gavage doses of 12.5 or 25 mg/kg
toxaphene In corn oil to groups of five pregnant CD rats on days 7-16 of
gestation. There were no treatment-related effects on fetal mortality,
average number of Implants or fetal body weight. There was a significant
decrease In fetal kidney alkaline phosphatase activity at 25 mg/kg and In
total protein 1n fetal kidneys at both doses.
Behavioral effects of toxaphene may be the most sensitive Indicator of
perinatal toxldty In rats (U.S. EPA, 1985a). Olson et al. (1980) exposed
rats to 0.05 mg/kg body weight toxaphene through the diet from day 5 of
gestation to 3 months postpartum. Toxaphene caused retarded maturation, as
measured by swimming performance and righting reflex tested on days 7-17
postpartum. Crowder et al. (1980) also reported Impaired righting reflex In
offspring of rats receiving 6 mg/kg toxaphene 1n corn oil from day 7 of
gestation until parturition.
OlOOh -12- 06/16/87
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DIPasquale (1977) gave pregnant guinea pigs oral doses of 15 mg/kg/day
on days 21-35 of gestation. Treatment caused some adverse effects on
collagen-containing structures In the fetus, but this was thought to be
caused by a functional deficiency of vitamin C related to MFO induction.
Chernoff and Carver (1976) exposed groups 26-90 CD-I mice to 0, 15, 25
or 35 mg/kg toxaphene by gavage In corn oil on days 7-16 of gestation.
There were no dose-related effects on fetal mortality, fetal weight, number
of caudal or sternal ossification centers, or Incidence of supernumerary
ribs. Five litters from the high-dose group had one or more fetuses with
encephaloceles, but none were observed 1n other groups. There was a dose-
related reduction In maternal weight gain and Increase In relative liver
weight 1n treated dams. Chernoff and Kavlock (1982) reported that adminis-
tration of 75 mg/kg toxaphene In corn oil to pregnant CD-I mice on days 8-12
of gestation caused reduced maternal weight gain and reduced fetal body
weights.
KepHnger et al. (1970) conducted a 5- to 6-generat1on study In which
groups of 4 male and 14 female Swiss white mice were exposed to 25 ppm toxa-
phene In the diet. There were no adverse effects on Utter size, survival,
fetal mortality, body weight or Indices of viability, lactation or reproduc-
tion; however, treated rats did have hlstologlcal changes 1n the liver.
3.3.2. Inhalation. Pertinent data regarding reproductive effects of
Inhalation exposures to toxaphene could not be located In the available
literature.
3.4. TOXICANT INTERACTIONS
There were several studies available concerning Interaction of toxaphene
with other pesticides. U.S. EPA (1980a) concluded that Induction of hepatic
mlcrosomal enzymes appeared to account for most of these Interactions. In
OlOOh -13- 06/16/87
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rats pretreated with aldrln or dleldMn, toxaphene toxldty was decreased
2-fold and toxaphene toxldty was decreased 3-fold In rats pretreated with
DOT (Delchmann and KepHnger, 1970). KepHnger and Delchmann (1967) report-
ed that toxaphene showed some degree of antagonism (I.e., toxldtles were
less than additive) with parathlon, dlazlnon and Tr1th1on«. Toxldtles of
toxaphene and De1nav«, VC-13 or malathlon were essentially additive.
Crowder (1980) reported that toxaphene did not potentiate the toxldty .of
methyl parathlon.
Toxldty from toxaphene/Hndane combinations 1s unusual In that the
symptoms of toxldty associated with the mixture differed from those seen
when animals or humans were exposed to either pesticide alone. Symptoms of
the combination Include aplastlc anemia, mild hyperthermla and decreased
response to stimuli (U.S. EPA, 1980a).
OlOOh -14- 06/16/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data concerning cardnogenldty of toxaphene 1n
humans orally exposed could not be located 1n the available literature.
4.1.2. Inhalation. There were several studies available concerning
occupational exposure to toxaphene and cancer Incidence. Barthel (1976)
reported an Increased Incidence of lung cancer among 285 pesticide appU-
cators (10 observed vs. 0.54 expected). Barthel (1981) found a significant
excess of bronchial carcinomas among 1658 male plant protection workers
exposed to pesticides Including toxaphene. U.S. EPA (1985a) reported
results of other studies, but In no case was a clear association between
toxaphene exposure and Incidence of any type of cancer demonstrated, and
toxaphene exposures were not well quantified.
4.2. BIOASSAYS
4.2.1. Oral. The most complete carclnogenldty bloassays with toxaphene
were performed by NCI (1979) (see Chapter 3). Both Osborne-Mendel rats and
B6C3F1 mice were fed diets containing toxaphene for 80 weeks, followed by an
observation period of 10-11 weeks (mice) or 28-30 weeks (rats). TWA doses
were 558 and 1112 ppm diet for male rats, 540 and 1080 ppm for female rats,
and 99 and 198 ppm for male and female mice. In male rats, there was a
dose-related Increased combined Incidence of thyroid folUcular cell
adenomas or carcinomas (1/7 matched controls, 2/44 pooled controls, 7/41 low
dose and 9/35 high dose). In female rats, the Incidence of thyroid
folUcular cell adenomas was dose-related (0/6 matched controls, 1/46 pooled
controls, 1/43 low dose and 7/42 high dose). The Incidences of folUcular
cell adenomas or carcinomas 1n the high-dose male rats and folllcular cell
adenomas In high-dose female rats were significantly higher than pooled
OlOOh -15- 10/21/86
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controls (p<0..05, Fisher Exact test) and the Incidences were significantly
dose-related In both cases (p<0.05, Cochran-Armltage test). The authors
concluded that toxaphene treatment was associated with an Increased Inci-
dence of thyroid tumors, suggesting that 1t was carcinogenic for male and
female Osborne-Mendel rats. Reuber (1979) conducted an Independent evalua-
tion of the hlstologlcal slides from this study and agreed qualitatively
with the thyroid tumor conclusions. He also found carcinogenic effects In
other organs; however, U.S. EPA (1985a) concluded that his criteria for
cardnogenlcHy were different from those commonly accepted by others and,
therefore, his conclusions were questionable.
In the NCI (1979) mouse study, the Incidence of hepatocellular carci-
nomas was significantly Increased 1n treated mice. Incidences were 0/10
matched controls, 4/48 pooled controls, 34/39 low-dose and 45/46 high-dose
males, and 0/9 matched controls, 0/48 pooled controls, 5/49 low-dose and
34/39 high-dose females. Incidences of hepatocellular carcinomas In low and
high-dose males and 1n high-dose females were significantly higher than
pooled or matched control groups (p<0.001, Fisher Exact test). Incidences
were significantly dose-related (p<0.001, Cochran-Armltage test). The
authors concluded that toxaphene was carcinogenic In B6C3F1 mice. Reuber
(1979) reviewed the hlstologlcal slides from this study and came to qualita-
tively similar conclusions regarding liver tumors, but also reported tumors
at sites where NCI (1979) did not. It 1s difficult to draw conclusions from
his findings because of the differences between his criteria and others.
Litton Blonetlcs, Inc. (1978) fed groups of 53-54 86C3F1 mice 0, 7, 20
or 50 ppm toxaphene 1n the diet for 18 months, followed by a 6-month obser-
vation period. Incidences of hepatocellular carcinomas were 13, 20, 33 and
23% 1n matched controls, low, middle- and high-dose male mice, respectively,
OlOOh -16- 10/21/86
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and 2, 2, 6 and 6% In matched controls, low, middle- and high-dose female
mice, respectively. Incidences of hepatocellular adenomas were 6, 0, 4 and
22% 1n males and 2, 2, 2 and 6?4 In females 1n the matched control, low,
middle- and high-dose groups, respectively. The only statistically signifi-
cant tumoMgenlc effect was an Increased combined Incidence of hepatocellu-
lar adenomas and carcinomas 1n high-dose male mice.
There have been other less complete studies of toxaphene carclnogenlc-
Hy. Nelson (1949) fed groups of 12 male and 12 female rats diets contain-
ing 0, 25, 100, 400 or 1600 ppm toxaphene for 107 weeks. Hlstologlcal exam-
inations were Incomplete, but liver and thyroid hyperplasla were reported 1n
treated animals. Four of five high-dose rats developed hepatic carcinomas
that were not observed 1n any other group.
4.2.2. Inhalation. Cardnogenlclty bloassays of toxaphene administered
by Inhalation exposure could not be located In the available literature.
4.3. OTHER RELEVANT DATA
Oldenko et al. (1978) administered twice weekly Injections of 50 mg/kg
toxaphene In sunflower oil to mice for "10 weeks. Toxaphene treatment did
not cause an Increase 1n the Incidence of any type of tumor.
Samosh (1974) reported an Increased frequency of chromosomal aberrations
In lymphocyte cultures obtained from eight women occupatlonally exposed to
toxaphene. In contrast, U.S. EPA (1978) found no Increased rates of chromo-
somal aberrations In leukocytes from people occupational"^ exposed to
toxaphene. Epstein et al. (1972) reported negative results for toxaphene In
a mouse dominant lethal assay.
OlOOh -17- 06/01/87
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4.4. WEIGHT OF EVIDENCE
Toxaphene has been placed In EPA Group B2, based on positive test
results 1n rats and mice (U.S. EPA, 1986b). Chemicals In this group are
those for which there Is Inadequate evidence of carc1nogen1dty from human
studies and adequate evidence from animal studies (U.S. EPA, 1986a). IARC
(1979) reported that toxaphene 1s classified 1n IARC Group 28, chemicals for
which there 1s Inadequate evidence of cardnogenldty In humans and adequate
evidence of carclnogenldty 1n animals (mice and rats).
OlOOh -18- 02/13/87
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5. REGULATORY STANDARDS AND CRITERIA
The U.S. EPA (1980a) recommended ambient water quality criteria for the
protection of human health based on the results of the Litton 81onet1cs,
Inc. (1978) cancer bloassay. This study was selected because 1t allowed
derivation of slightly more conservative criteria than the NCI (1979)
study. These criteria were derived based on data concerning Incidences of
hepatocellular carcinomas and neoplatlc nodules In male B6C3F1 mice. Using
these data, U.S. EPA (1980a) calculated a human carcinogenic potency factor
(q *) of 1.131 (mg/kg/day)'1. The levels of toxaphene resulting In
Incremental Increases 1n lifetime cancer risk of 10~5, 10"6 and 10"7
are 7.1, 0.71 and 0.07 ng/l, respectively, based on 1ngest1on of 2 a
water and 6.5 g aquatic organisms/day. Estimates for the consumption of
aquatic organisms only are 7.3, 0.73 and 0.07 ng/i; however, U.S. EPA
(1982) corrected these values to 5.1, 0.51 and 0.05 ng/l for consumption
of water and contaminated aquatic organisms, and 5.2, 0.52 and 0.05 ng/i
for consumption of aquatic organisms only.
NAS (1977) calculated a human ADI of 1.25 yg/kg toxaphene based on the
Fltzhugh and Nelson (1951) study In which rats receiving 25 ppm 1n the diet
for 2 years had Increased liver weights and liver cell enlargement. NAS
(1977) assumed that the dosage at this level was 1.25 mg/kg/day and divided
by an uncertainty factor of 1000 to derive the ADI.
The national Interim primary drinking water standard for toxaphene Is 5
ug/l (U.S. EPA, 1976), and 1s based on organoleptlc effects (Slgworth,
1965). U.S. EPA (1976) calculated a safe level of 25 yg/l based on
slight effects or no effects 1n rats fed toxaphene at 10 ppm In the diet,
OlOOh -19- 06/01/87
-------
calculated to be equivalent to 1 mg/kg/day (Lehman, 1965). U.S. EPA (1976)
calculated a maximum safe dose for humans of 3.4 pg/kg/day. The FOA also
established a standard of 5 wg/i for bottled water (U.S. FOA, 1979).
Tolerances and guidelines for toxaphene 1n various food products are
summarized 1n Tables 5-1 and 5-2.
A TWA of 0.5 mg/m3 and a STEL of 1 mg/m3 have been proposed by ACGIH
(1984).
OlOOh -20- 06/01/87
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TABLE 5-1
Tolerances for Toxaphene Residues In Various Agricultural Products3
Residue
Level
(mg/kg)
Product
Reference
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
aSource: U.S. EPA, 1980a
U.S. FDA, 1957
U.S. FDA, 1959
U.S. FDA, 1962a
U.S. FDA, 1957
U.S. FDA, 1962a
6
5
3
2
0.1
Crude soybean
Barley, oats,
Sorghum grain
Cottonseed
Pineapple and
Soybeans, dry
011
rice, rye and wheat
bananas^
form
Sunflower seeds
U
U
U
U
U
U
U
.s.
.s.
.s.
.s.
.s.
.s.
.s.
FDA.
FDA,
FDA,
FDA,
FDA
FDA,
EPA,
1968
1958
1960
1961
1962b
1966
1977
which not >0.3 mg/kg will be 1n pulp after the peel 1s removed and
discarded.
OlOOh
-21-
10/21/86
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TABLE 5-2
Guideline Levels for Toxaphene In Foods*
Food Level
(mg/kg)
Fat of meat of cattle, sheep, goats and pigs 5
Broccoli, brussels sprouts, cabbage, celery, collards, eggplant, 2
kale, kohlrabi, lettuce, okra, peppers, pimentos, spinach,
tomatoes, barley, rice (rough), rye, sorghum, bananas (whole),
pineapple, beans (snap, dry, Uma), peas, cauliflower, oats,
wheat, shelled nuts, carrots, onions, parsnips, radishes, rutabagas
Soybeans, peanuts (ground-nut), cotton-seed oil (refined), rape- 0.5
seed oil (refined), soybean oil (refined), peanut oil (refined),
maize, rice (finished)
Milk and milk products (fat basis) 0.5
'Source: U.S. EPA, 1980a; WHO, 1974
OlOOh -22- 10/21/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO.)
O
Because toxaphene is considered a carcinogen, no RfOSQ or
values will be calculated.
6.2. REFERENCE DOSE (RfO)
Because toxaphene Is considered a carcinogen, no RfD- or RfOT values
or CSs will be calculated.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The U.S. EPA (1980a) has performed a quantitative
cardnogenlcHy risk assessment for toxaphene using data for Increased
combined Incidences of hepatocellular adenomas or carcinomas In male B6C3F1
mice from the Litton B1onet1cs, Inc. (1978) study. Data used 1n these
calculations are presented 1n Table 6-1. Dosages of 0, 0.91, 2.6 and 6.5
mg/kg/day resulted 1n Incidences of 10/53, 11/54, 12/53 and 18/51, respec-
tively. Using these data and a linearized multistage model as described by
U.S. EPA (1980a, 1985), a human q * of 1.131 (mg/kg/day)'1 was calculated.
An examination of the CBI file for toxaphene did not reveal any Informa-
tion that would modify this assessment.
6.3.2. Inhalation. Inhalation data were Insufficient for performing a
cardnogenlcHy risk assessment for toxaphene.
OlOOh -23- 06/01/87
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TABLE 6-1
Cancer Data Sheet for Derivation of q-|*
Compound: toxaphene
Reference: Litton Blonetlcs, Inc., 1978; U.S. EPA, 1980a
Specles/straln/sex: mice, B6C3F1, male
Route/vehicle: diet
Length of exposure (le) = 540 days
Length of experiment (Le) = 735 days
Llfespan of animal (L) = 735 days
Body weight = 0.03 kg assumed
Tumor site and type: hepatocellular carcinomas and neoplastlc nodules
Exposure
(ppm diet)
0
7
20
50
Transformed Dose
(mg/kg/day)
0
0.91
2.6
6.5
Incidence
No. Responding/No.
10/53
11/54
12/53
18/51
Tested
Human q-|* = 1.131 (mq/kg/day)'1
OlOOh -24- 10/21/86
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1984.
TLVS: Threshold Limit values for chemical substances and physical agents In
the work environment and biological exposure Indices with Intended changes
for 1984-1985.
Allen, A.L., L.O. Koller and G.A. Pollock. 1983. Effect of toxaphene
exposure on Immune responses 1n mice. J. Toxlcol. Environ. Health. 11:
61-69.
Baeumler, W. 1975. Nebenwerkungen von Toxaphene auf Mause. Anz. Schaed-
Ungsk. Pflanzenschutz. Umweltschutz. 48: 65-71.
Barthel, E. 1976. High Incidence of 'lung cancer In persons with chronic
professional exposure to pesticides 1n agriculture. Z. Erkr. Asn.-Ory.
146: 266-274.
Barthel, E. 1981. Increased risk of lung cancer on pesticide-exposed male
agricultural workers. J. Toxlcol. Environ. Health. 8: 1027-1040.
Boots Hercules Agrochemlcals, Inc. n.d. Boots Hercules Toxaphene Insecti-
cide Summary of Toxlcologlcal Investigations. Bulletin T-1050.
Callahan, M.A., M.U. Sllmak, N.W. Gabel, et al. 1979. Water-related
Environmental Fate of 129 Priority P-llutants. U.S. EPA, Washington, DC.
EPA 440/4-79-029A.
OlOOh -25- 06/16/87
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Cheroff N. and B.O. Carver. 1976. Fetal toxlclty of toxaphene In rats and
mice. Bull. Environ. Contam. Toxlcol. 15(6): 660-664.
Chernoff, N. and R.J. Kavlock. 1982. An In vivo teratology screen utiliz-
ing pregnant mice. J. Toxlcol. Environ. Health. 10(4-5): 541-550.
Clapp, K.L., D.M. Nelson, J.T. Bell, et al. 1971. A study of the effects
of toxaphene on the hepatic cells of rats. JJK Proc. Ann. Meet. Western
Section, Am. Soc. Anlm. Sc1. 22: 313-323.
Crowder, L.A. 1980. Mode of action of cyclodlence Insecticides; the
nervous system Influenced by toxaphene. NTIS PB80-186 042. Ill p. (Taken
from PESTAB/81/1767)
Crowder, L.A., G.C. LAnzaro and R.S. UhUson. 1980. Behavioral effects of
methyl parathlon and toxaphene exposure In rats. 3. Environ. Sd. Health
Part B. 15: 365-378.
Delchmann, W.B. and M.L. KepHnger. 1970. Protection against the acute
effects of certain pesticides by pretreatment with aldrln, dleldrln and DOT.
JJK Collection of Papers, Inter-American Conf. Toxlcol. Occup. Med., 6th,
7th Pesticide Symp., H.B. Delchmann, J.L. Radomskl and R.A. Penalver, Ed.
Halos and Associates, Coral Gables, FL. p. 121-123.
Dldenko, G.G., O.G. Petrovskaya and T.D. Gupalovlch. 1978. Study of possi-
ble blastomogenk properties of polychloroplnene and polychlorocamphene.
Gig. SanH. 7: 110-111.
OlOOh -26- 06/16/87
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DIPasquale, L.C. 1977. Interaction of toxaphene with ascorbic add In the
pregnant guinea pig. Master's Thesis, Wright State Univ., 1976. U.S. EPA
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APPENDIX
Summary Table for Oral Toxldty of Toxaphene Using Male B6C3F1 Mice*
Experimental Exposure/
Dose
Effect
Ql*
(mg/kg/dayr1
0, 7, 20 or 50 ppm
diet for 18 months,
followed by 6 months
observation (0, 0.91,
2.6, 6.5 mg/kg/day)
hepatocellular adenomas
or carcinomas
1.131
*Source: Litton Blonetlcs, Inc., 1978; U.S. EPA, 1980a
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