Health Effects Assessment For Chlordane

EPA-540/1-86-023
Environmental Protection
Agency
.
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EPA/540/1-86-023
September 1984
HEALTH EFFECTS ASSESSMENT
FOR CHLORDANE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER

The Information 1n this report' has been funded wholly or in part by the
United States Environmental Protection Agency under Contract No. 68-03-3112
to Syracuse Research Corporation. It has been subject to the Agency's peer
and administrative review, and it has been approved for publication as an
EPA document. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
ii
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with chlordane.
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 Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n 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. 1980b. Ambient Water Quality Criteria for Chlordane.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-027. NTIS PB81-117384.

U.S. EPA. 1985. Drinking Water Criteria Document on Heptachlor,
Heptachlor Epoxlde and Chlordane. Prepared by the Environmental
Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office
of Drinking Water, Washington, DC. Final draft.

The Intent In these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.

Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 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 Hfespan). 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 Is
assumed. Animal data used for AIS 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.
111
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The AIC, acceptable Intake chronic, 1s similar In concept to the ADI
(acceptable dally Intake). 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 Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route 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 ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983).

For compounds for which there is sufficient evidence of cardnogenlcHy,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context, the
reader Is referred to the preface of this document. The preface outlines
limitations applicable to all documents In this series as well as the appro-
priate Interpretation and use of the quantitative estimates presented.

Data concerning chlordane exposure and cancer 1n human populations are
limited and equivocal. Data concerning cardnogenlclty 1n experimental
animals following Inhalation exposure are lacking.

Two oral cancer bloassays have been conducted (IRDC, 1973; NCI, 1977).
U.S. EPA (1980b) used the IRDC (1973) data as evaluated by Reuber (1978),
which showed an Increased Incidence of hepatocellular carcinoma 1n
chlordane-exposed mice, to estimate cancer risk associated with chlordane
exposure. A human q-j* of 1.6075 (mg/kg/day)'1 was computed. This risk
assessment has been subjected to extensive peer review.
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ACKNOWLEDGEMENTS
TECHNICAL REVIEW

Scientists from the following U.S. EPA offices provided review comments
for this document series:

Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water

EDITORIAL REVIEW

Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH

TECHNICAL SUPPORT SERVICES

Bette Zwayer, Pat Daunt, Karen Mann and Oacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH

The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112.
v1
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TABLE OF CONTENTS

1.
2.

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.

3.3.

3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
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
REGULATORY STANDARDS AND CRITERIA
Page
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TABLE OF CONTENTS (cont.)

Page

6. RISK ASSESSMENT . 16

6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 16
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 16
6.3. CARCINOGENIC POTENCY (q-j*) 16

6.3.1. Oral 16
6.3.2. Inhalation 16

7. REFERENCES 17

APPENDIX A: Cancer Data Sheet for Derivation of q-|* 26

APPENDIX B: Summary Table for Chlordane 27
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LIST OF TABLES
No. Title Page
3-1 Effects of Subchronlc Oral Chlordane Exposure 5
3-2 Effects of Chronic Oral Chlordane Exposure 7
4-1 Cardnogenlclty of Chlordane by Oral Ingestlon 13
1x
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LIST OF ABBREVIATIONS

ADI Acceptable dally Intake

AIC Acceptable Intake chronic

AIS Acceptable Intake subchronlc

BCF Bloconcentration factor

bw Body weight

CNS Central nervous system

CS Composite score

DNA Deoxyr1bonucle1c add

LDso Median lethal dose

MED Minimum effective dose

NOEL No-observed-effect level

ppm Parts per million

RNA Rlbonuclelc add

TLV Threshold limit value

TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE

The relevant physical and chemical properties and environmental fate of
chlordane (CAS No. 57-74-98 for mixture; 5103-74-2 for els Isomer; 5103-71-9
for trans Isomer) are as follows:
Chemical class:
Moleculer weight:
Vapor pressure:
Water solubility:
Log octanol/water partition
coefficient:
BCF:
Half-lives 1n
Water:
Soil:
pesticide
406 (Callahan et al., 1979)
lxlO~s mm Hg at 25°C (I-ARC, 1979)
9 yg/J. at 25°C for technical
grade and 56 yg/l for ds:trans
(75:25) chlordane (Verschueren,
1983; Delchmann, 1981)
3.32 (Rao and Davidson, 1982)
4700 for aquatic organisms with 1%
I1p1d content (U.S. EPA, 1980b)
28-33 hours (Atlas et al., 1982)
several years (Sanborn et al., 1977)
Information 1n the available literature 1s Insufficient to estimate the
half-life of chlordane 1n the atmosphere. Based on Us reactivity In
aquatic media (Callahan et al., 1979) and the reported presence of this
compound 1n rainwater (Sanborn et al., 1977), however, both photolysis and
physical removal mechanisms (wet and dry deposition) probably control the
fate of atmospheric chlordane.
No pertinent information pertaining to the Teachability of chlordane
from soil to groundwater could be located in the available literature. The
aqueous solubility and the octanol/water partition coefficient of this com-
pound are such that significant leaching from soil is not expected to occur.
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The long persistence time of this compound 1n soil may permit some leaching
from soils, however, especially from soils with low adsorption for this
compound.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Although quantitative data regarding the absorption of chlordane from
the gastrointestinal tract of animals and humans are not available, the
toxic effects observed after chlordane 1ngest1on Indicate that at least some
absorption occurs. One male and one female Sprague-Dawley rat were given a
single dose (0.05, 0.2 or 1.0 mg/kg) of [14C]-HCS-3260, which 1s a highly
purified chlordane preparation containing the ds- and trans-chlordane
Isomer 1n a 3:1 ratio (Barnett and Oorough, 1974). Within 7 days after
treatment, 6% of the administered radioactive label was found 1n the urine
of the female and 2% 1n the urine of the male. When ds- and trans-chlor-
dane were given separately to female rats, 8.5 and 5%, respectively, of the
administered radioactive label was eliminated 1n the urine. However, 33% of
the administered radioactive label was excreted 1n the urine and 21% 1n the
feces of a male rabbit within 2 days of receiving 25 ppm [14C]-HCS-3260 1n
the diet. In cases where children (Curley and Garrettson, 1969; Aldrich and
Holmes, 1969) have Ingested chlordane, measurable quantities of chlordane
have appeared 1n serum and fat several hours after the poisonings.
2.2. INHALATION
A peak concentration of radioactivity (-4% of the administered dose)
appeared in the blood of Sprague-Oawley rats within 5 minutes of 1ntra-
tracheal administration of an unspecified amount of 14C-chlordane (11,500
dpm/yg) in 20 yl ethanol as an aerosol spray (Nye and Dorough, 1976).
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Ambrose et al. (1953a,b) exposed groups of three to five
rats to food containing chlordane at levels from 10-1280 ppm for 400 days
(Table 3-1). In males, Increased liver weights were recorded at an exposure
of 160 mg chlordane/kg diet. In females, Increased liver weights were first
observed In the group exposed to 10 mg chlordane/kg diet. Decreased body
weight gain and Increased severity of hepatic hlstopathologlcal lesions were
dose-related beginning at 160 mg/kg. Intracytoplasmlc bodies were seen In
livers at a dose level of 160 mg chlordane/kg diet. At higher dose levels,
vacuollzatlon and enlarged nuclei were seen 1n the liver.
DeLong and Ludwlg (1954) treated an unspecified number of male and
female rats with chlordane-contamlnated dog pellets. The dose level of
chlordane, calculated from amount of food consumption, was 1.2 mg/kg/day.
After 5 months no hlstopathologlc damage to lungs, heart, stomach, liver,
kidneys, spleen or testes was reported. One treated rat had a kidney adeno-
cardnoma believed to be unrelated to chlordane exposure.
Shaln et al. (1977) fed 19.5 mg/kg/day of chlordane to male Sprague-
Dawley rats for 90 days. A randomly selected subgroup of 12 rats had
significantly depressed body weight gain; another subgroup of 24 rats did
not have depressed body weight gain. The purpose of this study was to
Investigate the effects of chlordane on the prostate gland. Nuclear, but
not cytoplasmlc, androgen binding sites were significantly Increased, and
RNA and DNA content and ventral prostate protein content were significantly
decreased In the chlordane-treated rats.
Benign prollferatlve lesions In the liver were reported 1n 2% of the low
dose (25 ppm) and 7% of the higher dose (50 ppm) groups of mice fed dietary
chlordane for at least 36 weeks (Becker and Sell, 1979).

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TABLE 3-1

Effects of Subchronlc Oral Chlordane Exposure
i
en
i
Dose or Duration Duration
Exposure of of
(rog/kg diet) Treatment Experiment
0 400 days 400 days
10
20
40
80
160
320
640
1280
0 5 months 5 months
1.2 mg/kg bw
0 90 days 90 days
19.5 mg/kg bw

0 >36 weeks >36 weeks
25
50

Species/ Sex
Strain
rat/NR H/F
H/F
M/F
H/F
H/F
H/F
H/F
H/F
H/F
rat/NR H/F
H/F
rat/ H
Sprague-
Dawley

mouse/ H
C57BC 6N

Number Effects Reference
Treated
3-5 Increased liver weights, without Ambrose et al.. 1953a.b
additional symptoms, first
occurred In females at a dose of
10 mg/kg diet. Increased liver
weights accompanied by dose- '
related liver hlstopathology
occurred In males at 160 mg/kg
diet.

NR No effects were reported. DeLong and Ludwlg, 1954

42 Decreased body weight gain. Shaln et al., 1977
42 No significant weight changes
In testes or ventral prostate.
See text for additional
Information.
200 Benign prollferatlve lesions were Becker and Sell. 1979
NR reported to occur In the liver In
NR the low-dose (2X) and high-dose
(75C) groups.
NR = Not reported
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3.1.2. Inhalation. Pertinent data regarding the subchronlc toxldty of
Inhaled chlordane could not be located 1n the available literature.
3.2. CHRONIC
3.2.1. Oral. Ingle (1952) treated groups of 20 rats/sex with chlordane
1n their food at a dose range of 5-300 mg/kg diet for 2 years (Table 3-2).
Extensive hlstologlcal data were reported, but organ and body weight data
were not Included. After 80 weeks of exposure at a dose level of 30 mg/kg
diet, the animals developed tremors. At dose levels of >150 mg/kg diet,
liver and kidney hypertrophy were detected, and hlstopathology was reported
In the liver, kidney, lung, myocardium, adrenal gland and spleen.
In the IRDC (1973) study reviewed by Epstein (1976), groups of 100 mice/
sex were exposed to 5, 25 and 50 mg of chlordane/kg diet for 18 months. The
female mice appeared to be more sensitive than the male mice 1n this study,
as Indicated by the Increased liver weights accompanied by hepatocytomegaly
at a dose level of 5 mg/kg chlordane 1n the diet. Although hepatocytomegaly
was present 1n male mice at this dose level, Increased liver weight was not
observed 1n males until they were exposed to the 25 mg/kg dose level. The
highest dose level 1n this study (50 mg/kg diet) produced Increased mortal-
ity 1n both sexes.
In the NCI (1977) study, both rats (50/sex/group) and mice (50/sex/
group) were maintained on diets containing analytical grade chlordane for 80
weeks, followed by an observation period. Because the dose levels were
changed during the experiment, the dosage listed 1n Table 3-2 Is a TWA as
calculated by the NCI (1977). Rats received higher dose levels 1n mg/kg bw
than mice 1n this study. Female rats appeared to be more sensitive than
male rats, as evidenced by Increased mortality 1n females. High dose
females, but not males, had tremors after 44 weeks of treatment.
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TABLE 3-2

Effects of Chronic Oral Chlordane Exposure
Dose or Duration Length Species/
Exposure of of Strain
(ppm) Treatment Experiment
5 up to 2 years 2 years rat/
10 Osborne-
30 Mendel
150
300

Sex
M/F
M/F
N/F
M/F
M/F

Number
Treated
20/20
20/20
20/20
20/20
20/20

Effects
Occasional hypertrophy of hepato-
cytes occurred at 5 mg/kg diet.
but no other effects were observed.
Slight tremors were present after 80
weeks at 30 mg/kg diet. Decreased
growth rate, anorexia and tremors
were seen In animals treated with
150 mg/kg diet; liver and kidney
hypertrophy was present, as well
as moderate to marked kidney, lung.
myocardlal, adrenal and spleen
damage. At 300 mg/kg diet the
animals died earlier and had
severe liver, kidney, heart.
adrenal, lung, myocardlal and
spleen damage.
Reference
Ingle, 1952

0
5
25
50
29.
56.
0
30.1
63.8
18 months
18 months
mouse/
CD-I
M/F
M/F
N/F
M/F
33/45
55/61
52/50
39/37
80 weeks
80 weeks
91 weeks
91 weeks
mouse/
B6C3F1
mouse/
B6C3F1
M
M
M

F
F
F
18
48
49

19
47
49
Increased liver weight was Epstein, 1976
significant at all dose levels
for females and at 25 and 50
mg/kg diet for the males after
18 months of exposure. Survival
was decreased for both males and
females at 50 mg/kg diet.
Hepatocytomegaly was observed In
all treatment groups In both sexes.

High-dose males and females had NCI, 1977
tremors at 20 weeks. Male
mortality rate was significantly
Increased compared with controls
In both the high- and low-dose
treatment groups. No effect on
mortality was seen In the females.
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TABLE 3-2 (cont.)
Dose or
Exposure
(ppm)
0
203.5
407.0

0
120.8
241.5
0.3
3.0
15.0
30.5
Duration
of
Treatment
80 weeks

80 weeks

2 years

Length
of
Experiment
109 weeks

109 weeks

Species/
Strain

rat/
Osborne-
Hendel

rat/
Osborne-
Hendel
dog

Sex

N
M
N

F
F
F
NR

Number
Treated

6
34
31

10
43
32
NR

Effects Reference

Decreased body weights were seen NCI. 1977
In high-dose males and both dose
levels of females. Tremors
occurred In the high-dose females
at 44 weeks. Dose-related Increased
mortality occurred In the females
but not males.
A review panel for WHO/FAO Mazeter, 1968
Indicated that 3 mg/kg diet was
a NOEL.

NR = Not reported
CO
i
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In a study by Wazeter (1968), dogs exposed orally to chlordane developed
enlarged livers with hlstopathologlcal changes. A scientific review panel
of WHO/FAO examined this study and concluded that a dose of 3 mg/kg diet was
a NOEL (Vettorazzl, 1975). No further Information was available.
3.2.2. Inhalation. Pertinent data regarding the chronic toxldty of
Inhaled chlordane could not be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Ingle (1952) Investigated the effect of chlordane-contami-
nated diets at dose levels of 5, 10, 30, 150 and 300 ppm on the fetus in
utero and the newborn while nursing. Two female Osborne-Mendel rats from
each dose level were mated after 24 and 48 weeks of chlordane exposure. No
effect on fetal mortality and health or on litter size was reported. After
birth, three pups remained with their chlordane-treated mothers, while three
others were placed with foster mothers that had not been exposed to
chlordane. Pups nursed by mothers exposed to chlordane levels of 150 and
300 mg/kg diet developed symptoms of toxldty, such as hyperexcitabillty,
tremors, decreased body weight and death. Toxic symptoms developed 1n the
pups that were nursed by mothers treated with chlordane-contaminated (>150
ppm) diets, whether or not they had been exposed 1_n utero. However, the
pups whose mothers were exposed to high levels of chlordane (>150 ppm)
during pregnancy did not develop toxic symptoms when they were nursed by
foster mothers exposed to low levels (5, 10 and 30 ppm) of chlordane.
3.3.2. Inhalation. Pertinent data regarding the teratogenicity or
fetotoxldty of chlordane inhalation could not be located in the available
literature.
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3.4. TOXICANT INTERACTIONS
IntraperHoneal injection of phenobarbHal 1n neonatal Sprague-Dawley
rats reduced the ID™ of chlordane Injected intraperltoneally (Harbison,
1975). Pretreatment of rats with chlordane potentiated the hepatocellular
necrosis produced by carbon tetrachlorlde (Stenger et al., 1975). Male
weanling Wlstar rats (Boyd and Taylor, 1969) on a low-protein diet (3.5%)
for 28 days had a much lower ID™ (137^30 mg/kg bw) than a group of wean-
ling rats that ate commercial rodent chow (LD5Q=311 mg/kg bw).
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Acute oral exposure to chlordane 1n humans (Curley and
Garretson, 1969; Lensky and Evans, 1952; Aldrich and Holmes, 1969; Derbes et
a!., 1955; Oadey and Kammer, 1953) as a result of Intentional or accidental
poisoning causes CNS toxldty Including, but not limited to, Irritability,
salivation, labored respiration, muscle tremors, convulsions and death.
Pertinent data regarding the effects of chronic and subchronlc human oral
exposure to chlordane could not be located In the available literature;
however, chlordane can cross the placenta (Curley et al., 1969; Wassermann
et al., 1972; Zavon et al., 1969), and chlordane metabolites are found 1n
milk (Savage et al., 1973; Strassman and Kutz, 1977). Neuroblastoma has
been associated with perinatal exposure to chlordane (Infante et al., 1978).
4.1.2. Inhalation. Most Inhalation exposure to chlordane occurs as work-
related exposure either 1n the manufacturing or application of chlordane.
Exposure to several chemicals 1n addition to chlordane often confounds
evaluation of the human data. Aplastlc and refractory megoblastlc anemia,
as well as acute stem cell, acute lymphoblastlc and acute myelomonocytlc
leukemia, have been reported to result from chlordane exposure, primarily
through Inhalation (Infante et al., 1978; Klemmer et al., 1977; Furle and
Trubowltz, 1976). A retrospective mortality study of 1403 white male
workers employed for >3 months In the manufacture of chlordane and hepta-
chlor Indicated that the observed Incidences of all types of cancer except
lung cancer were less than expected (Wang and MacMahon, 1979). The
Increased Incidence of lung cancer was not statistically significant.
Insufficient population size, exposure duration and follow-up periods 1n
this and other studies (Alvarez and Hyman, 1953; DHraglla et al., 1981;
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Flshbein et a!., 1964; Prlnd and Spurbeck, 1951; Klemmer et al., 1977)
preclude definitive conclusions regarding the effects of human occupational
exposure.
4.2. BIOASSAYS
4.2.1. Oral. In the unpublished report by the IRDC (1973) reviewed by
Epstein (1976), the liver lesions produced during chlordane treatment were
originally diagnosed as preneoplastlc lesions. A subsequent re-diagnosis of
hepatocellular carcinoma was made by Reuber (1978) and other pathologlsts
(Epstein, 1976). The results of this reevaluatlon are presented In
Table 4-1.
In the NCI (1977) study, the dose levels were changed during the experi-
ment for both mice and rats. The TWA dose levels calculated by the NCI
(1977) are given 1n Table 4-1. Mice 1n the NCI (1977) study developed a
dose-related Increase 1n the Incidence of hepatocellular carcinoma. As 1n
the IRDC study (Epstein, 1976), the male mice appeared more sensitive. Rats
1n the NCI (1977) study developed miscellaneous neoplasms; these occurred
spontaneously 1n the control groups as well as In the treated animals. The
only significant dose-related Increase 1n tumors was In fibrous hlstlo-
cytomas 1n male rats. These tumors were discounted as biologically signifi-
cant since the Incidence 1s known to vary greatly. The Incidence of thyroid
tumors was not consistently significant or dose-related. One of the two
hepatocellular carcinomas occurred in a low dose male; the other occurred 1n
one of the pooled control animals.
Becker and Sell (1979) correlated elevated levels of alpha-fetoproteln
with primary hepatocellular carcinoma In mice exposed for 36 weeks to diets
containing 25 or 50 ppm of chlordane.
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TABLE 4-1

Carclnogenlclty of Chlordane by Oral Ingestlon
CO
i
Dose or
Exposure
(ppm)
0
5
25
SO

0
5
25
50
0
29.9
56.2

0
30.1
63.8
0
203.5
407.0

0
120.8
241.5
Duration
of
Treatment
550 days

550 days

80 weeks

Length
of
Experiment
550 days

550 days

91 weeks

109 weeks

Species/
Strain
mouse/
CD-I

mouse/
CD-I

mouse/
B6C3F1

rat/
Osborne-
Hendel

rat/
Osborne-
Hendel
Sex
N
H
N
N

F
F
F
F
N
N
N

F
F
F
N
H
N

F
F
F
Number
Treated
33
55
52
39

45
61
50
37
18
48
49

19
47
49
6
34
31

10
43
32
Target
Organ
liver

liver

thyroid

Tumor
Incidence
3/33
5/55
41/52
32/39

0/45
0/61
32/50
26/37
2/18
16/48
43/49

0/19
3/47
34/49
0/6
6/34
11/31

3/10
7/43
16/32
Comments Reference
Male mice appeared more Epstein, 1976
sensitive to the
carcinogenic effects
of chlordane In the
liver.

Dose-related Increase NCI. 1977
In the Incidence of
hepatocellular carcinoma
was highly significant
(p<0.0001) for both
males and females.

Thyroid tumors Included NCI, 1977
folUcular cell adenoma
and carcinoma as well as
C-cell adenoma and
carcinoma. Only two
hepatocellular carcinomas
were observed.
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4.2.2. Inhalation. Pertinent data regarding the Inhalation cardnogen-
1c1ty of chlordane could not be located 1n the available literature.
4.3. OTHER RELEVANT DATA
Chlordane did not cause reverse mutations 1n nine strains of Salmonella
typhimurium or In two strains of Escher1ch1a coll with or without metabolic
activation (Probst et a!., 1981; Gentile et al., 1982); unscheduled ONA
synthesis 1n rat, mouse or hamster primary hepatocyte cultures (Probst et
al., 1981; Maslansky and Williams, 1981); or dominant lethal mutations In
CD-I mice following 1ntragastr1c or 1ntraper1toneal administration (Arnold
et al., 1977). Positive results were obtained for mltotlc gene conversion
assays In Saccharomyces cerevlslae only after metabolic activation (Gentile
et al., 1982), and for unscheduled DNA synthesis in SV-40 transformed human
flbroblasts only In the absence of metabolic activation (Ahmed et al., 1977).
4.4. WEIGHT OF EVIDENCE
Oral exposure to chlordane was associated with hepatocellular carcinoma
in male and female CD-I and B6C3F1 mice (Epstein, 1976; NCI, 1977), but
Hver tumors In mice may occur spontaneously at a high rate and their valid-
ity as an indicator of potential human cardnogenlclty has not been estab-
lished. IARC (1982) concluded that the evidence for the cardnogenlcity of
chlordane in humans and for the mutagenlcity of chlordane 1n short-term
tests was inadequate; the evidence for the cardnogenlcity of chlordane In
animals was considered limited. Applying the criteria proposed by the
Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984),
chlordane 1s most appropriately classified as a Group C chemical.
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5. REGULATORY STANDARDS AND CRITERIA

A tolerance of 0.3 mg/kg has been established by the U.S. EPA (Federal

crops (Code of Federal Regulations, 1976). The ACGIH (1983) has adopted TLV

values only for percutaneous chlordane exposure.
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Chlordane 1s a chemical for which a carcinogenic potency has been
computed and that may be carcinogenic 1n humans. It 1s, therefore, Inappro-
priate to calculate an oral or Inhalation AIS for chlordane.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Chlordane 1s a chemical for which a carcinogenic potency has been
computed and that may be carcinogenic 1n humans. It 1s, therefore, Inappro-
priate to calculate an oral or Inhalation AIC for chlordane.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The data from the IRDC (1973) study, reported by Epstein
(1976) and diagnosed by Reuber (1978), on the development of hepatocellular
carcinoma 1n male B6C3F1 mice exposed orally to chlordane was used by the
U.S. EPA (1980b) to derive a q^ for humans of 1.6075 (mg/kg/day T1.
This study resulted 1n greater Incidences at lower doses than did the NCI
(1977) bloassay 1n mice and, therefore, would result 1n a more conservative
q,*, 1.607 (mg/kg/day)"1. The data upon which this determination 1s
based are presented 1n Appendix A.
6.3.2. Inhalation. Data were not available for estimation of carcino-
genic potency following Inhalation exposure.
-16-
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7. REFERENCES .

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Arnold, D.W., G.L. Kennedy, Jr., M.L. Keplinger, J.C. Calandra and C.J.
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APPENDIX A

Cancer Data Sheet for Derivation of q-j*
Compound: Chlordane

Reference: Epstein, 1976

Species, Strain, Sex: Mice, CD-I, male

Body weight: 0.041 kg (measured)

Length of exposure (le) = 546 days

Length of experiment (Le) = 546 days

Llfespan of animal (L) = 546 days

Tumor site and type: liver, carcinoma

Route, vehicle: oral, diet
Experimental Doses
or Exposures
(ppm)
0
5
25
50*

Transformed Dose
(mg/kg/day)
0
0.65
3.25
6.5*
Incidence
No. Responding/No. Tested
or Examined
3/33
5/55
41/52
32/39*
*H1gh-dose data are dropped to comply with goodness of fit.

Unadjusted q-)* from study = K3448X10"1 (mg/kg/day)"1
Human q-j* = 1.607 (mg/kg/day)"1
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APPENDIX B

Summary Table for Chlordane
ro
-j
Species Experimental
Dose/Exposure
Inhalation
AIS
AIC
Carcinogenic
potency
Oral
AIS
AIC
Carcinogenic mice 5, 25 and
potency 50 ppm
Effect QT*

NO
ND
ND

ND
ND
hepatocellular 1.6075
carcinoma [mg/kg/day]'1
Reference

Epstein, 1976;
U.S. EPA, 1980b
ND~= Not derived
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