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Chlordane (Technical)
CASRN 12789-03-6
02/07/1998
Contents
0142
Chlordane (Technical); CASRN 12789-03-6; 02/07/1998
Health assessment information on a chemical substance is included in IRIS
only after a comprehensive review of chronic toxicity data by U. S. EPA
health scientists from several Program Offices, Regional Offices, and the
Office of Research and Development. The summaries presented in Sections I
and II represent a consensus reached in the review process. Background
information and explanations of the methods used to derive the values given
in IRIS are provided in the Background Documents.
STATUS OF DATA FOR Chlordane
File First On-Line 03/31/1987
Category (section) Status Last Revised
---------------------------------- ----------- -------------
Oral RfD Assessment (I.A.) On-line 02/07/1998
Inhalation RfC Assessment (I.B.) On-line 02/07/1998
Carcinogenicity Assessment (II.) On-line 02/07/1998
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
_I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Chlordane (Technical)
CASRN 12789-03-6
Last Revised 02/07/1998
The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with
uncertainty spanning perhaps an order of magnitude) of a daily exposure to
the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime.
Please refer to the Background Document for an elaboration of these
concepts. RfDs can also abe derived for the noncarcinogenic health effects
of substances that are also carcinogens. Therefore, it is essential to
refer to other sources of information concerning the carcinogenicity of
this substance. If the U. S. EPA has evaluated this substance for
potential human carcinogenicity, a summary of that evaluation will be
contained in Section II of this file.
_I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
0.15 mg/kg-day 300 1 5E-4 mg/kg-day
Hepatic Necrosis NOAEL: 0.15 mg/kg-day
LOAEL: 0.75 mg/kg-day
Study Type Mouse 104-week oral study
Reference Khasawinah and Grutsch, 1989a
*Conversion Factors and Assumptions 1 ppm = 0.15 mg/kg Bw-day (assumed
mouse food consumption).
_I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Khasawinah, A.M. and J.F. Grutsch. 1989a. Chlordane: 24-month
tumorigenicity and chronic toxicity test in mice. Reg. Toxicol. Pharmacol.
10: 244-254.
Velsicol Chemical Corporation. 1983. Twenty-four month chronic
toxicity and tumorigenicity test in mice by chlordane technical.
Unpublished study by Research Institute for Animal Science in Biochemistry
and Toxicology, Japan. MRID No. 00144312, 00132566. Available from U.S.
EPA.
ICR mice (80/sex/group) were fed 0, 1, 5, or 12.5 ppm technical
chlordane in the diet for 104 weeks. The average doses corresponded to 0,
0.15, 0.75, and 1.875 mg/kg-day, respectively. Hematology, biochemistry,
urinalysis, organ weights, and pathology of major tissues and organs were
assessed on all animals that died during the study and on all survivors at
week 104.
Exposure-related effects were restricted to the liver.
Statistically significant increased absolute and relative liver weights
were seen in high-dose males (200 and 203%) and females (144 and 129%)
compared to control values at the end of the study. Absolute but not
relative liver weight also was elevated significantly (p < 0.05) in the
females exposed to 1 (22%) and 5 ppm (14%). Statistically significant
increased incidences over controls were found for hepatocellular swelling
(hypertrophy) in 5- and 12.5-ppm males and females, and hepatic fatty
degeneration was observed in 12.5-ppm males and 5- and 12.5-ppm females.
Hepatic necrosis was noted in males only, including controls (7/80) and the
1-ppm (8/80), 5-ppm (25/80), and 12.5-ppm (27/80) groups. Male mice in
only the 12.5-ppm group showed statistically significant elevated incidence
of hepatocellular adenomas (also called hepatocellular nodules by the study
authors) over controls. Hepatic necrosis is the most adverse lesion of
those occurring at 5 ppm and is judged as the critical effect over both
fatty degeneration and hepatocellular swelling (hypertrophy). Increased
liver cell volume (hypertrophy) is commonly associated with ultrastructural
cellular changes involving increased metabolic capacity resulting from the
presence of the toxicant (Sipes and Gandolfi, 1991) and are considered more
appropriately as nonadverse, adaptive changes. Based on the increased
incidence of hepatic necrosis over controls, 1 ppm chlordane
(0.15 mg/kg-day) was the NOAEL, and 5 ppm chlordane (0.75 mg/kg-day)
was the LOAEL.
_I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 300.
The following uncertainty factors are applied to the NOAEL derived
from the principal study: 10 for consideration of intraspecies variation,
10 for consideration of interspecies extrapolation, and 3 for lack of any
reproductive studies.
MF = 1.
_I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD)
The composition of mixtures called technical chlordane varies, as it
does from mixtures labeled chlordane (CAS No. 57-74-9). The U.S. EPA
(1979) recognizes a mixture composed of 60% octachloro-4,
7-methanotetraydroindane (the "cis" and "trans" isomers) and 40% related
compounds as technical chlordane. Infante et al. (1978) reported on
analysis of technical chlordane having 38-48% cis- and trans-chlordane,
3-7% or 7-13% heptachlor, 5-11% nonachlor, 17-25% other chlordane isomers,
and a small amount of other compounds. Dearth and Hites (1991) identified
147 different compounds in a preparation of technical chlordane that
included cis-chlordane (15%), trans-chlordane (15%), trans-nonachlor (15%),
and heptachlor (3.8%). At least, the principal cis- and trans- isomers of
chlordane and the component heptachlor may be metabolized to epoxides,
oxychlordane and heptachlor epoxide, both of which have been detected in
human tissues (reviewed in Nomeir and Hajjar, 1987). Unless otherwise
indicated, all studies described in this document were carried out with
technical grade chlordane; specific content will be given when available
from the individual study.
Chlordane is extremely lipid soluble, and lipid partitioning of
chlordane and its metabolites have been documented in both in humans and
animals. Concentrations of chlordanes (cis-chlordane, trans-chlordane,
oxychlordane, and trans-nonachlor) detected in human liver samples were
17-fold higher when expressed on a fat rather than a wet-weight basis
(Mussalo-Rauhamaa, 1991). Unpublished work (cited in Adeshina and Todd,
1991) reports the mean fat/blood ratio of oxychlordane to be 290/1 among
workers who had been exposed to technical grade chlordane. This value is
concordant with the results of Khasawinah (1989), who reported this ratio
to be 200-300/1 in rats and monkeys after 90-days of inhalation exposure to
technical chlordane. Taguchi and Yakushiji (1988) measured chlordane
residues (including the epoxide metabolites oxychlordane and hepatchlor
epoxide) in the milk of 15 mothers who had lived in chlordane-treated
residences for an average of 1.8 years, and the investigators evaluated
these measurements with those for the milk of unexposed mothers. In a
subgroup of these women who had been exposed for approximately 2 years in
treated residences, the overall chlordane residues in milk (0.254 mg/kg
milk fat) were similar to those of PCBs (0.389 mg/kg milk fat). Because of
its long retention time in adipose tissue, oxychlordane is believed to be
more toxic than its parent isomers, which are eliminated relatively rapidly
from the body (Satoh and Kikawa, 1992) and, therefore, may be a major
contributor to chlordane toxicity.
Available occupational studies, although limited, give no indication
that the liver is a target organ in humans as a consequence of chronic
exposure to low levels of chlordane. Alvarez and Hyman (1953) found no
hepatic abnormalities after thorough physical examinations and liver
function tests administered to 24 male workers who had worked for 2 months
to 5 years at a chlordane manufacturing plant. Liver function tests were
also normal in 15 workers at a chlordane manufacturing plant, 14 of whom
had been employed 9-16 years (Fishbein et al., 1964). Air exposures of
0.0012-0.0017 mg/cu.m were cited in this report.
Recent epidemiological findings indicate that neurotoxicity may be a
relevant human toxicological endpoint as a consequence of chronic as well
as acute chlordane exposure. Neurotoxicity and possibly hematotoxicity
(Fleming and Timmeny, 1993) are the principal endpoints of acute chlordane
toxicity in both experimentally poisoned animals and accidentally poisoned
humans, with tremors and convulsions being common interspecies symptoms
(Grutsch and Khasawinah, 1991). IRIS chlordane RfC documentation (U.S.
EPA, 1997) describes the study of Kilburn and Thornton (1995), in which
adults (109 women and 97 men) who had been exposed to uncertain levels of
chlordane via both air and oral routes were examined. Significant (p <
0.05) differences were observed with a battery of neurophysiological and
neuropsychological function tests. Also, profiles of mood states
(including tension, depression, anger, vigor, fatigue, and confusion) all
were affected significantly (p < 0.0005), as compared to a referent
population. These results indicate that neurological effects are a
relevant endpoint in humans exposed to chlordane.
Other oral studies confirm the liver as the target organ of chlordane
in rodents.
In a 30-month oral study (Khasawinah and Grutsch, 1989b), Fischer 344
rats (80/sex/group) were exposed to 0, 1, 5, or 25 ppm technical chlordane
in the diet (0, 0.055, 0.273, or 1.409 mg/kg-day for females). Because
symptoms of age-related leukemia (necrosis, swelling, hypertrophy, and
fatty degeneration; Solleveld et al., 1984; Stromberg and Vogtsberger,
1983) confounded exposure-related liver lesions, incidence of nonneoplastic
liver lesions only in nonleukemic rats were evaluated. A review of these
data (ICF-Clement, 1987) indicated that exposure-related lesions were found
only in the liver. Absolute liver weight was increased significantly (p <
0.05) in 5- and 25-ppm males at 130 weeks and in 25-ppm females at 26 and
52 weeks. The livers of nonleukemic female rats in the 25-ppm (15/44) and
5-ppm (9/40) groups [but not the livers of animals exposed to 1 ppm (4/43)]
had statistically significant increases in regional hepatocellular
hypertrophy relative to controls (2/37). No such effects were noted in the
nonleukemic males, although group sizes were smaller (n = 16-23). Because
of the confounding of leukemia and the nonadverse nature of hepatocellular
hypertrophy, no effect levels were assigned to this study. The study
indicates that rats may be more insensitive to the hepatotoxic effects of
chlordane than are mice, which manifested adverse hepatic effects (necrosis
and fatty degeneration) at comparable exposure levels.
Groups of 100 male and 100 female CD-1 mice were fed diets containing
analytical grade chlordane at concentrations of 0, 5, 25, or 50 ppm
(approximately 0, 0.71, 3.57, or 7.14 mg/kg-day, respectively) for 18
months (IRDC, 1973). Mice were 6 weeks of age when exposure began, and the
terminal sacrifice was at 19.5 months. Survival in the 50-ppm group was
reduced greatly compared to controls. At the 5-ppm exposure level, which
did not produce a carcinogenic response, hepatocyte hyperplasia was found,
but not at an incidence that was significantly different from controls.
Groups of 50 male and 50 female Osborne-Mendel rats were fed low- or
high-dose diets for 80 weeks and then observed for 29 weeks (NCI, 1977).
Average doses were 10.2 and 20.4 mg/kg-day for male rats and 6.0 and 12.1
mg/kg-day for female rats. Surviving rats were sacrificed at 109 weeks.
Statistically significant differences between exposed groups and control
groups were restricted to observations that average body weight of high-dose
male and female rats were consistently lower (by about 10%) than that
of control rats throughout the study, and that obvious signs of toxicity
(rough and discolored hair coats, palpable masses) occurred "frequently" in
treated rats during the first year and increased in frequency during the
second year. The lower dose (6-10.2 mg/kg-day) is a LOAEL for both sexes.
This same study also reported cancer but no noncancer effects in the livers
of B6C3F1 mice (50/sex/group) that were fed diets with analytical chlordane
for 80 weeks and then observed for 10 weeks. Average doses were 4.3 and
8.0 mg/kg-day for male mice and 4.3 and 9.1 mg/kg-day for female mice.
Surviving mice were sacrificed at 90-91 weeks. Survival of male mice in
both exposed groups was decreased significantly relative to control males.
Neurotoxicity (tremors) was observed in high-dose males and females after
20 weeks (no further specifics given).
No multi-generational reproductive studies, by any route, exist for
technical chlordane. Several items within the current chlordane database
suggest that reproductive effects could be a relevant endpoint for
chlordane. The study of Cassidy et al. (1994) indicates alterations in
reproductive- related behavior in male rats as a consequence of chlordane
exposure. Data on tissue distribution of chlordane or its metabolites also
indicate the potential for reproductive consequences. Rani et al. (1992)
reported accumulation of a major component of technical chlordane
(heptachlor) in ovary, uterus, and adrenals in nonpregnant rats within 30
minutes after an oral dose of 120 mg/kg heptachlor. In pregnant rats,
levels were markedly elevated in the uterus compared to nonpregnant rats;
the higher accumulation is believed to be a result of a slower metabolic
turnover of heptachlor. These results indicate that chlordane or some of
its components/metabolites have an increased affinity towards reproductive
organs during pregnancy and may have potential to adversely affect
reproductive processes.
In contrast to the situation for reproductive effects, a number of
studies have examined the potential of chlordane or its metabolites to
affect developmental processes through investigations of a variety of
endpoints.
Pregnant albino mice (6/group) were exposed orally by gavage to 0, 1,
or 2.5 mg/kg-day technical grade chlordane dissolved in olive oil for
7 consecutive days during late gestation (i.e., gestational days 12 19)
(Al-Hachim and Al-Baker, 1973). Each mouse received a total of 5 7 doses.
It was not indicated whether animals were nursed or foster reared, and,
thus, whether exposure also occurred through the milk. Groups of 10
randomly selected offspring were tested for conditioned avoidance response
( < 37 days of age), electroshock threshold (38 days of age), and response in
open-field tests (6 weeks of age). Exposed animals exhibited depressed
acquisition of avoidance response (mean responses 13.1, 9.7, and 9.7 in
controls and low- and high-dose groups, respectively), increased seizure
threshold (mean responses 90.1, 108.6 and 134.9 in controls and low- and
high-dose groups, respectively), and increased exploratory activity (mean
responses 93.9 and 88.4, and 137.7 in controls and low- and high-dose
groups, respectively). Three-way ANOVA was performed and indicated
significant differences between treatment groups (p < 0.001) that were
dose-related. The lowest dose, 1 mg/kg-day, is a LOAEL.
Several investigations have assessed the effects of chlordane on the
immunological system of offspring exposed during gestation and found that
chlordane may affect cell-mediated immunity. Pregnant BALB/c mice
(6/group) were fed 0, 0.16, or 8 mg/kg-day chlordane during the 19-day
gestation period (Spyker-Cranmer et al., 1982). At birth, pups were
randomized within treatment groups (45 pups/group), weaned at 28 days, and
fed normal diets. Immunological tests performed at 101 days of age showed
a marked decrease (p < 0.01) in cell-mediated immune response (contact
hypersensitivity assay) in the 8-mg/kg-day group. The lower dose of 0.16
mg/kg-day is a NOAEL for this endpoint. Barnett et al. (1985a) found that
in utero exposure to either 8 or 16 mg/kg-day chlordane (in peanut butter)
in pregnant BALB/c mice during gestational days 1-18 resulted in a
significant decrease (p < 0.05) in virus-specific delayed-type
hypersensitivity response in the offspring (degree of footpad swelling),
but only at 48 hours post injection of an influenza type A virus. No
differences were apparent at 72 hours postinjection. The LOAEL is
8 mg/kg-day. In another mice study by Barnett et al. (1985b), delayed
hypersensitivity response in offspring, as well as depressed mixed
lymphocyte reactivity of spleen cells in male offspring, occurred after in
utero exposure to 4 or 16 mg/kg-day during gestational days 1-19. The
LOAEL is 4 mg/kg-day. For both of these studies, offspring also were
exposed to chlordane via milk.
Fleming and Timmeny (1993) reviewed case studies of aplastic anemia
associated with acute exposure to chlordane and other chlorinated
pesticides, implicating these pesticides in bone marrow toxicity. In an
effort to understand the effects of prenatal chlordane exposure on adult
bone marrow expansion potential, Barnett et al. (1990a) exposed female mice
orally to chlordane at 0, 4, or 8 mg/kg-day for 18 days during pregnancy.
Offspring were nursed, which would provide some postnatal chlordane
exposure. Bone marrow hematopoietic activity, as measured by the ability
of bone marrow cells to undergo clonal expansion in response to stimulating
factors, and spleen colony forming units (after irradiation) both were
evaluated in offspring of these mice at 100 and 200 days of age. Results
showed a significant dose-related depression (p < /= 0.05) of both measures
at both 100 and 200 days postexposure. In a subsequent study in which
these same measures were evaluated at 18 days gestational age (and without
chlordane exposure via milk), these results were confirmed, indicating that
damage to stem cells occurred during the fetal period (Barnett et al.,
1990b). A LOAEL of 4 mg/kg-day is indicated by these results.
Cassidy et al. (1994) tested the hypothesis that chlordane or its
isomers/metabolities act to mimic sex steroids or change their
concentrations to alter (in this case to masculinize) functions and
behaviors. Pregnant Sprague-Dawley rats were dosed orally with 0, 0.1,
0.5, or 5 mg/kg-day technical grade chlordane from day 4 of gestation to
day 21 of lactation, and offspring were dosed from postnatal day 22 to 80.
A number of gender-related behavior patterns and effects were examined
postnatally, including some aspects of male mating behavior. The authors
claim the results from these tests demonstrate a consistent pattern of
masculinization of male and female offspring. The lack of consistent dose-response
relationships among the effects noted in this study, as well the
uncertainty of their toxicological significance, preclude a clear
interpretation of this study and assignment of any adverse effect levels.
These observations show that, if testosterone or its receptors are somehow
involved in the effects of chlordane, the dose-response model (or
mechanism) for the effects must be extremely complex and is in need of
further clarification.
_I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
The overall confidence for this RfD assessment is medium. The
principal study, assigned a confidence of medium, is a rat chronic oral
study performed with relatively large groups sizes, in which
histopathological analyses on the known animal target tissue, the liver,
were thoroughly performed. The confidence in the database for chlordane is
rated medium. The critical effect of hepatic toxicity was consistent
across routes of exposure (the inhalation RfC is also based on hepatic
toxicity). Recent evidence, however, indicates that neurotoxicity, a known
human endpoint in acute exposures, may be a relevant endpoint in chronic
human exposures, and no chronic animals studies have examined
neurotoxicity. Studies on pre-and postnatal animals indicating chlordane
mimicry of sex-steroids raise reproductive concerns and no
multigenerational reproductive studies, by any route, exist. Thus, there
is some concern that the appropriate endpoints have not been examined
adequately in the existing database. Despite this concern, the wide array
of special studies (which may raise similar controversy for other chemicals
having less data than does chlordane) and numerous chronic studies with
consistent results are judged adequate information to rate the overall
confidence in the database as medium.
An area of scientific uncertainty in this assessment concerns the role
of neurotoxicity, and possibly hematotoxicity, in chronic chlordane
toxicity in humans. In acute chlordane exposures, neurotoxicity has been
established as a common endpoint, with similar symptomatologies in both
humans and animals (Grutsch and Khasawinah, 1991). Chronic studies with
chlordane in animals have considered and found the liver to be the primary
target organ, whereas occupational studies of workers with chronic
chlordane exposure have not established any effect (neurological, hepatic,
or hematotoxic). Recent epidemiology results from a nonoccupationally
exposed cohort, however, do show strong evidence of neurotoxicity (Kilburn
and Thornton, 1995). These findings could mean that, in rats, the liver is
more sensitive to chlordane effects than is the nervous system. Some data
do exist in rats (transient tremors in mice observed in NCI, 1977)
indicating neurotoxicity to occur in chronic studies at levels higher than
those eliciting liver effects. This possibility cannot be confirmed,
however, because no long-term, repeated-dose animal study has been
conducted in which neurotoxicity has been evaluated specifically. These
findings also could be a result of study design because the occupational
studies were designed to elucidate hepatic effects; both Alvarez and Hyman
(1953) and Fishbein et al. (1964) employed a number of liver function tests
and addressed only neurological symptoms through a general physical exam
and immunological effects not at all, although these protocols would
probably have elucidated any hematotoxicity. The possibility exists that
this assessment is based on studies that have not focused on the
appropriate endpoints. Because of this circumstance, any future alteration
of the RfC based on an improved database (such as the inclusion of chronic
study) would have to be considered in light of what is made known about the
neurotoxic potential of chlordane in both animals and humans.
Another area of scientific uncertainty in this assessment concerns the
toxicological significance of endocrine mimicry effects of chlordane.
Toxicity data for this chemical include a study demonstrating biochemical
and behavioral alterations consistent with technical chlordane (or its
metabolites) mimicking male sex-steroids (Cassidy et al., 1994). That
these effects could include reproductive behaviors is suggested in this
study. Tissue distribution data also offer evidence that
developmental/reproductive toxicity could be a potential endpoint because
technical chlordane (or its metabolites) appears to have an increased
affinity toward reproductive organs during pregnancy. Evidence that these
altered behaviors and circumstances would have functional consequences that
could alter reproduction is, however, lacking because no multigenerational
reproductive studies exist.
_I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- Toxicological Review of Chlordane, U.S. EPA, 1997.
This assessment was peer reviewed by external scientists. Their
comments have been evaluated and incorporated in finalization of this IRIS
summary. A record of these comments is included as an appendix to U.S.
EPA, 1997.
Other EPA Documentation -- U.S. EPA, 1986.
Agency Consensus Date -- 11/03/1997
_I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions
concerning this assessment or IRIS, in general, at (513)569-7254 (phone),
(513)569-7159 (FAX), or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Chlordane (technical)
CASRN -- 12789-03-6
Last Revised 02/07/1998
_I.B.1. INHALATION RfC SUMMARY
Critical Effect Experimental Doses* UF MF RfC
Hepatic effects 1.0 mg/cu.m 1000 1 7E-4 mg/cu m
NOAEL 1.0 mg/cu m
NOAEL (ADJ) 0.24 mg./cu m
NOAEL (HEC) 0.65 mg/cu m
Study Type -- Rat subchronic inhalation study
Reference -- Khasawinah et al., 1989a
Conversion Factors and Assumptions -- MW (general) = 409. NOAEL(ADJ) = 10
mg/cu.m x (8 hours/24 hours) x (5 days/7 days) = 0.24 mg/cu.m.
Scenario -- The NOAEL(HEC) is calculated for a particle: extra-respiratory
effect (liver). The estimated RDDR(ER) is 2.7 for an MMAD of 1.8 um and
sigma g of 3.1, based on dosimetric modeling (U.S. EPA, 1994). NOAEL(HEC)
= NOAEL(ADJ) x RDDR(ER) = 0.24 mg/cu.m x 2.7 = 0.65 mg/cu.m.
_I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Khasawinah, A., C. Hardy, and G. Clark. 1989a. Comparative
inhalation toxicity of technical chlordane in rats and monkeys. J.
Toxicol. Environ. Health 28(3): 327-347. (The 90-day rat study.)
Wistar rats (35 47/sex/group) were exposed to 0, 0.1, 1.0, or 10
mg/cu.m technical chlordane, 8 hours/day, 5 days/week, for 13 weeks,
followed by a 13-week recovery period. The NOAEL(HEC) is calculated for a
particle:extrarespiratory effect (liver). The estimated RDDR(ER) is 2.7,
based on available information (MMAD of 1.8 um and sigma g of 3.1) and on
dosimetric modeling (U.S. EPA, 1994). NOAEL(HEC) = NOAEL(ADJ) x RDDR(ER) =
0.24 mg/cu.m x 2.7 = 0.65 mg/cu.m. Blood chemistry and urinalysis were
performed before and at 5 and 13 weeks of exposure. Histopathology was
performed on all major tissues, including nasal passages. At the end of
the exposure period, increased liver weights (p < 0.01) were observed for
male and female rats exposed to 10 mg/cu.m at weeks 9 and 14. Analysis of
blood chemistry results gave indications of hepatic functional alteration,
but only among rats exposed to the highest concentration. Alterations
included a significant decrease in glucose (83% of control for females),
increased globulins (114% of control for males), increased total protein
(104% of control for males), decreased albumin (95% of control for males),
an increase in cholesterol (158% of control for females), and an altered
albumin/globulin (A/G) ratio in males. This pattern of alterations in
blood chemistry is indicative of changes in the functioning of the liver,
the major site of synthesis of plasma proteins (Kaneko, 1989). In view of
what is known about the progression of liver effects with increasing
concentrations of chlordane (see discussion of 28-day inhalation study
below), this pattern of changes is considered an adverse effect, with a
LOAEL of 10 mg/cu.m and a NOAEL of 1 mg/cu.m.
Khasawinah, A., C. Hardy, and G. Clark. 1989b. Comparative
inhalation toxicity of technical chlordane in rats and monkeys. J.
Toxicol. Environ. Health 28(3): 327-347. (The 28-day rat study.)
In a 28-day range-finding study, Wistar (Crl:Cobs WI Br strain) rats
(10/sex/group) inhaled 0, 5.8, 28.2, 154, or 413 mg/cu.m technical
chlordane, 8 hours/day, 5 days/week. Body and organ weights and food and
water consumption were measured, and hematology, urinalysis, and
microscopic examination were performed. Deaths occurred in the 413- and
154-mg/cu.m groups. Livers were enlarged in the 154-mg/cu.m males and were
discolored in the 413- and 154-mg/cu.m males. Hepatic necrosis,
vacuolation, and hepatocellular hypertrophy were noted among rats exposed
to 413 mg/cu.m. Hepatocellular hypertrophy, with or without vacuolation,
was observed among rats exposed to 154 mg/cu.m. Among rats exposed to 28.2
mg/cu.m, hepatocellular hypertrophy, increased kidney and thyroid weight,
and decreased thymus weights were observed. At this concentration, there
also were indications of hepatic function alteration from blood chemistry
results, including a significant decrease in glucose (73% of control for
males and 78% of control for females), increased globulins (116% of control
for males and 119% of control for females), increased total protein (116%
of control for females), increased albumin (117% of control for females),
an increase in cholesterol (133% of control for females), and an altered
albumin/globulin (A/G) ratio. The LOAEL was 28.2 mg/cu.m, based on the
wide range of biochemical indicators demonstrating alteration of hepatic
function at this concentration. The NOAEL was 5.8 mg/cu.m. The occurrence
of these alterations in blood chemistry, as part of a toxicological
progression of lesions, in this short-term study provides justification for
the designation of these effects as a LOAEL in the subchronic study
(Khasawinah et al., 1989a).
_I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- 1000.
The following uncertainty factors are applied to the NOAEL(ADJ): 10
for subchronic to chronic extrapolation; 10 for consideration of
intraspecies variation. Partial uncertainty factors are used for
interspecies extrapolation (which already has been addressed partially by
calculation of an HEC) and for database deficiencies (lack of any
reproductive studies).
MF -- 1.
_I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC)
The composition of mixtures called technical chlordane varies, as does
mixtures labeled chlordane (CAS No. 57-74-9). The U.S. EPA (1979)
recognizes a mixture composed of 60% octachloro-4,7-methanotetraydroindane
(the "cis" and "trans" isomers) and 40% related compounds as technical
chlordane. Infante et al. (1978) reported on analysis of technical
chlordane having 38-48% cis- and trans-chlordane, 3-7% or 7-13% heptachlor,
5-11% nonachlor, and 17-25% other chlordane isomers, and a small amount of
other compounds. Dearth and Hites (1991) identified 147 different
compounds in a preparation of technical chlordane that included cis-chlordane
(15%), trans-chlordane (15%), trans-nonachlor (15%), and
heptachlor (3.8%). At least the principal cis- and trans-isomers of
chlordane and the component heptachlor may be metabolized to epoxides,
oxychlordane and heptachlor epoxide, both of which have been detected in
human tissues (reviewed in Nomeir and Hajjar, 1987). Unless otherwise
indicated, all studies described in this document were carried out with
technical grade chlordane; specific content will be given when available
from the individual study.
Chlordane is extremely lipid soluble, and lipid partitioning of
chlordane and its metabolites have been documented in both in humans and
animals. Concentrations of chlordanes (cis-chlordane, trans-chlordane,
oxychlordane, and trans-nonachlor) detected in human liver samples were
17-fold higher when expressed on a fat rather than a wet weight basis
(Mussalo-Rauhamaa, 1991). Unpublished work (cited in Adeshina and Todd,
1991) reports the mean fat/blood ratio of oxychlordane to be 290/1 among
workers that had been exposed to technical grade chlordane. This value is
concordant with the results of Khasawinah (1989), who reported this ratio
to be 200-300/1 in rats and monkeys after 90-days of inhalation exposure to
technical chlordane. Taguchi and Yakushiji (1988) measured chlordane
residues (including the epoxide metabolites oxychlordane and heptachlor
epoxide) in the milk of 15 mothers who had lived in chlordane treated
residences for an average of 1.8 years, and the investigators evaluated
these measurements with those for the milk of unexposed mothers. In a
subgroup of these women who had been exposed for approximately 2 years in
treated residences, the overall chlordane residues in milk (0.254 mg/kg
milk fat) were similar to those of PCBs (0.389 mg/kg milk fat). Because of
long retention time in adipose tissue, oxychlordane is believed to be more
toxic than its parent isomers, which are eliminated relatively rapidly from
the body (Satoh and Kikawa, 1992) and, therefore, may be a major
contributor to chlordane toxicity.
The relative contributions of particulate and vapor states of
chlordane in inhalation experiments are unclear. The vapor pressure for
pure chlordane has been reported as 1E-5 and, for technical grade
chlordane, reported as 4.6E-4 mmHg at 25 degrees C (IARC, 1991). Based on
these values (and a molecular weight of 409), a saturated vapor
concentration for pure chlordane would be about 0.2 mg/cu.m; for technical
chlordane, it would be approximately 10 mg/cu.m. Particle sizing measures
performed in the Khasawinah et al., (1989a) study indicate that particulate
chlordane was collected at the reported exposure levels of 1 and 10
mg/cu.m.
Other studies in rodents confirm the liver as the target organ for
chlordane. The oral reference dose (RfD) currently on IRIS is based on
hepatic necrosis observed in mice exposed orally to chlordane (Khasawinah
and Grutsch, 1989; U.S. EPA, 1997).
Currently available occupational studies, although limited, give no
indication that the liver is a target organ in humans as a consequence of
chronic exposure to low levels of chlordane. Alvarez and Hyman (1953)
found no hepatic abnormalities after thorough physical examinations and
liver function tests administered to 24 male workers who had worked from 2
months to 5 years at a chlordane manufacturing plant. Liver function tests
were also normal for 15 workers at a chlordane manufacturing plant, 14 of
whom had been employed 9-16 years (Fishbein et al., 1964). Air exposures
of 0.0012-0.0017 mg/cu.m were cited in this report.
Neurotoxicity [and possibly hematotoxicity (Fleming and Timmeny,
1993)] are the principal endpoints of acute chlordane toxicity in both
experimentally poisoned animals and accidentally poisoned humans, with
tremors and convulsions being common interspecies symptoms (Grutsch and
Khasawinah, 1991). Recent epidemiological findings indicate that
neurotoxicity may be a more relevant human toxicological endpoint as a
consequence to chronic chlordane exposure. Kilburn and Thornton (1995)
administered batteries of neurophysiological and neuropsychological tests
to 216 adult occupants (109 women and 97 men) of an apartment complex, the
exterior of which had been sprayed with an unknown concentration of
chlordane 7 years prior to the administration of the tests. Chlordane
levels were assayed for 3-4 years after the initial spraying and showed
indoor concentrations of chlordane as high as 0.0136 mg/929 sq.cm (wipe
samples) and indoor air levels reported as above 0.0005 mg/cu.m for 8-hour
samples. The duration of the individuals residence at the complex was not
reported. Blood and fat samples from eight of these residents (number
actually tested not given) showed measurable and elevated levels of
heptachlor, oxychlordane, and trans-nonachlor. The exposed group was
compared with 174 unexposed referents matched on age and educational level.
Significant (p < 0.05) differences found between the exposed and referent
population included slowing of reaction times, balance dysfunction, and
reductions in cognitive function and immediate and delayed recall.
Profiles of mood states, including tension, depression, anger, vigor,
fatigue, and confusion, were affected significantly (p < 0.0005), as
compared to the referent population. Confounding factors that could affect
the results, such as alcohol consumption, illicit drug use, neurological or
psychiatric diseases, were addressed and dismissed as not having any
influence on the results. These results show significant impairment of
both neurophysiological and psychological functions in a nonoccupational
population exposed to uncertain levels of chlordane, predominately through
the inhalation route via indoor air. These results indicate that
neurological effects are a relevant endpoint in humans exposed to airborne
chlordane at air levels in the range of 0.0005 mg/cu.m. However, no
dose-response information and no reliable exposure information, either
levels or duration of exposure or information about co-exposure to other
neurotoxicants such as lead, could be gleaned from this report, and no
effect levels can be assigned to this study.
No multi-generational reproductive studies, by any route, exist for
technical chlordane. Several items within the current chlordane database
suggest that reproductive effects could be a relevant endpoint for
chlordane. The study of Cassidy et al. (1994) indicates alterations in
reproductive-related behavior in male rats as a consequence of chlordane
exposure. Data on tissue distribution indicate the potential for
reproductive consequences from exposure to chlordane or its metabolites.
Rani et al. (1992) reported accumulation of a major component of technical
chlordane (heptachlor) in ovary, uterus, and adrenals in nonpregnant rats
within 30 minutes after an oral dose of 120 mg/kg heptachlor. In pregnant
rats, levels were markedly elevated in the uterus compared to nonpregnant
rats; the higher accumulation is believed to be a result of a slower
metabolic turnover of heptachlor. These results indicate that chlordane or
some of its components/metabolites have an increased affinity toward
reproductive organs during pregnancy and may have potential to adversely
affect reproductive processes.
In contrast to the situation for reproductive effects, a number of
studies have examined the potential of chlordane or its metabolites to
affect developmental processes through investigations of a variety of
endpoints. Prenatally treated mice exhibited altered behavioral responses
at the lowest dose tested, 1 mg/kg-day (Al-Hachim and Al-Baker, 1973).
Spyker-Cranmer et al. (1982) noted a marked decrease in cell-mediated
immune responses among offspring exposed to chlordane during gestation at 8
mg/kg-day, but not at 0.16 mg/kg-day. Barnett et al. (1985) found a
significant decrease in hypersensitivity response among offspring exposed
in utero to chlordane at both levels tested, 8 or 16 mg/kg-day. Barnett et
al. (1990a) noted a dose-related depression in bone marrow hematopoietic
activity among offspring exposed in utero to chlordane at 4 or 8 mg/kg-day
that apparently resulted from stem cell damage (Barnett et al., 1990b).
Cassidy et al. (1994) tested the hypothesis that chlordane acted to mimic
sex steroids among offspring exposed in utero to levels as low as 0.1
mg/kg-day with equivocal results. These studies are described more
extensively in the IRIS RfD and U.S. EPA (1997).
_I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Medium
Data Base -- Low
RfC -- Low
The overall confidence in this RfC assessment is low. The principal
study, rated as medium, is a rat subchronic inhalation study performed with
relatively large group sizes in which histopathological analyses on the
known animal target tissue, the liver, was thoroughly performed. There is
a degree of technical uncertainty in the study about the particle
distribution characteristics that were estimated from the available data.
The confidence in the database for technical chlordane is rated low. In
animal studies, the critical effect of hepatic toxicity was consistent
across routes of exposure because oral studies also indicate hepatotoxicity
as the critical endpoint of toxicity (Khasawinah and Grutsch, 1989).
However, recent evidence indicates that neurotoxicity, a known human
endpoint in acute exposures, may be a relevant endpoint in chronic human
exposures, and no chronic animal studies have examined neurotoxicity.
Studies on pre- and postnatal animals that indicate chlordane mimicry of
sex steroids raise reproductive concerns, and no multigenerational
reproductive studies, by any route, exist.
An area of scientific uncertainty in this assessment concerns the role
of neurotoxicity in chronic chlordane toxicity in humans. In acute
chlordane exposures, neurotoxicity has been established as a common
endpoint with similar symptomatologies in both humans and animals (Grutsch
and Khasawinah, 1991). Chronic studies with chlordane in animals have
considered and found the liver to be the primary target organ, whereas
occupational studies of workers with chronic chlordane exposure have not
established any effect, either neurological or hepatic, although protocols
in these studies should have elucidated any hematoxicity. Recent
epidemiology results from a nonoccupationally exposed cohort, however, do
show strong evidence of neurotoxicity (Kilburn and Thornton, 1995). These
findings could mean that, in rats, the liver is more sensitive to chlordane
effects than is the nervous system. Some data do exist in rats [transient
tremors in rats observed in NCI (1977)] that indicate neurotoxicity to
occur in chronic studies at levels higher than those eliciting liver
effects. This possibility cannot be confirmed, however, as no long-term,
repeated-dose animal study has been conducted in which neurotoxicity has
been specifically evaluated. These findings could also be a result of
study design, because the occupational studies available were designed to
elucidate hepatic effects; both Alvarez and Hyman (1953) and Fishbein et
al. (1964) employed a number of liver function tests and only addressed
neurological symptoms through a general physical exam. The possibility
exists that this assessment is based on studies flawed in design and
endpoint assessment. Because of this circumstance, any future alteration
of the RfC based on an improved database (such as a chronic study) would
have to be considered in light of what is discovered about the neurotoxic
potential of chlordane in both animals and humans.
Another area of scientific uncertainty in this assessment concerns the
toxicological significance of endocrine mimicry effects of chlordane.
Toxicity data for this chemical include a study demonstrating biochemical
and behavioral alterations consistent with technical chlordane (or its
metabolites) mimicking male sex steroids (Cassidy et al., 1994). That
these alterations could include effects on reproductive behavior is
suggested in this study. Tissue distribution data also offer evidence that
developmental/reproductive toxicity could be a potential endpoint because
technical chlordane (or its metabolites) appears to have an increased
affinity toward reproductive organs during pregnancy. Evidence that these
altered behaviors and circumstances would have functional consequences that
could alter reproduction is, however, lacking because no multi-generational
reproductive studies exist.
_I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- Toxicological Review of Chlordane, U.S. EPA, 1997.
This assessment was peer reviewed by external scientists. Their
comments have been evaluated and incorporated in finalization of this IRIS
summary. A record of these comments is included as an appendix to U.S.
EPA, 1997.
Other EPA Documentation -- U.S. EPA, 1986. Carcinogenicity Assessment
of Chlordane and Heptachlor/Heptachlor Epoxide. Washington, DC: Office
of Health and Environmental Assessment. NTIS PB87-208757.
Agency Consensus Date -- 11/03/1997
_I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions
concerning this assessment or IRIS, in general, at (513)569-7254 (phone),
(513)569-7159 (FAX), or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Chlordane (technical)
CASRN -- 12789-03-6
Last Revised 02/07/1998
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment
of the likelihood that the substance is a human carcinogen, and
quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways.
The slope factor is the result of application of a low-dose extrapolation
procedure and is presented as the risk per (mg/kg)/day. The unit risk is
the quantitative estimate in terms of either risk per ug/L drinking water
or risk per ug/cu.m air breathed. The third form in which risk is
presented in a concentration of the chemical in drinking water or air
providing cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 100,000,000.
The rationale and methods used to develop the carcinogenicity information
in IRIS are described in The Risk Assessment Guidelines of 1986
EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred
to Section 1 of this IRIS file for information on long-term toxic effects
other than carcinogenicity.
_II.A. EVIDENCE FOR HUMAN CARCINOGENICITY
_II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION
Chlordane is classified as B2; probable human carcinogen, using the
1986 Guidelines for Carcinogen Risk Assessment. Under the 1996 Proposed
Guidelines, it would be characterized as a likely carcinogen by all routes
of exposure. These characterizations are based on the following summaries
of the evidence available: (1) human epidemiology studies showing non-Hodgkin's
lymphoma in farmers exposed to chlordane and case reports of
aplastic anemia, chlordane associated with home use are inadequate to
demonstrate carcinogenicity; (2) animal studies in which benign and
malignant liver tumors were induced in both sexes of four strains of mice
and occurred with an elevated, but not statistically significant, incidence
in a fifth strain, as well as liver toxicity but no tumors in rats of two
strains; and (3) structural similarity to other rodent liver carcinogens.
_II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate evidence. Three types of studies have been reported: (1)
Case- control studies of non-Hodgkin's lymphoma among farmers, (2)
occupational cohort studies in a chlordane manufacturing plant and of
professional pesticide applicators, and (3) individual case reports of
disease in people exposed to chlordane in home situations.
Case-Control Studies
Cantor et al. (1992) compared 622 white men newly diagnosed with
non-Hodgkin's lymphoma in Iowa and Minnesota with 1245 population-based
controls, matched with respect to age, vital status at the time of
interview, and state of residence. Detailed interviews elicited
information about their pesticide handling practices on farms. Chlordane
was one of 12 chemicals evaluated as animal (livestock) insecticides and
one of 15 chemicals evaluated as crop insecticides. The investigators
found that the odds of chlordane use as an animal insecticide were
significantly greater among cases than among controls (OR = 1.7, 95% CI =
1.0-2.9). The odds of chlordane use as both an animal and a crop
insecticide were also significant (OR = 1.8, 95% CI = 1.1-3.1). The
pattern of odds ratios for other chemicals studied was similar, in that
livestock use had greater odds ratios than crop use; this consistency
indicated to the authors that the increased odds ratios resulted from
greater exposure with livestock than crops, rather than some random error.
In discussing the limitations of their study, the authors point out the
difficulty of attributing the results to individual pesticides when the
exposures were multiple, and they also point out the possibility that
important associations may have been missed because of non-differential
exposure mis-classification resulting from the difficulties in accurate
recall of past pesticide exposures. They concluded that chlordane (as well
as some other specifically mentioned pesticides) has an important role in
the etiology of non-Hodgkin's lymphoma among farmers.
In a study of similar design to that of Cantor et al. (1992), Brown et
al. (1990) conducted a population-based case-control study of leukemia
among 578 white men with leukemia and 1245 controls living in Iowa and
Minnesota. No significantly elevated odds ratios for leukemia were
associated with chlordane exposures. Chlordane was one of 17 crop
insecticide exposures and one of 16 animal insecticide exposures evaluated.
Woods et al. (1987) published a population-based case-control study of
128 soft-tissue sarcomas and 576 non-Hodgkin's lymphomas among men in
western Washington state, where phenoxy herbicides and chlorinated phenols
are used widely in the agricultural, forestry, and wood products
industries. They investigated other chemical handling practices, including
the use of chlordane, that potentially could modify or independently affect
the risk of these diseases. Although their main interests were herbicides
and phenols, one of their findings was an elevated, but not statistically
significant, odds ratio of non-Hodgkin's lymphoma among farmers who worked
with chlordane (OR = 1.46, CI = 0.8-2.8). This study is mentioned here in
connection with chlordane use by farmers, not because it is strong evidence
of chlordane risk, but because it supports the findings of Cantor et al.
(1992) that are discussed above.
Brown et al. (1993) published a population-based case-control study of
multiple myeloma among 173 white men in Iowa, compared with 650 controls to
evaluate possible contribution of agricultural risk factors and exposure to
individual pesticides. They found no statistically significant odds ratios
associated with the handling of pesticide classes or individual compounds.
Chlordane was one of seven animal insecticides evaluated.
Pesatori et al. (1994) updated an earlier study of licensed structural
pest control workers in Florida (Blair et al., 1983). The original cohort
of 3827 men was begun in 1965 and followed until 1977, and the 1994 study
updated the follow-up period to 1982. In view of the elevated lung cancer
mortality found in the original study, the investigators conducted a nested
case-control study of 65 lung cancer cases. Two hundred and ninety-four
controls were interviewed; these interviews gathered information on tobacco
use, occupation, work practices, and dietary habits. The authors found, in
the case-control study, that tobacco use, diet, and other occupations had
little effect on the excess lung cancer associated with occupational
pesticide exposure. This excess was larger among those licensed before the
age of 40 and those licensed for more than 20 years. Because of the small
sample size, the use of individual pesticides could not be evaluated, but
carbamates and phenoxyacetic acids were elevated significantly and use of
inorganics, organobromides, organochlorines, and organophosphates were
elevated non-significantly in these lung cancer cases. Use of chlordane
specifically was not associated with lung cancer.
Occupational Cohort Studies
Wang and MacMahon (1979) studied the mortality patterns of male workers
in two plants, one in Illinois that manufactured chlordane, and the other
in Tennessee, which manufactured heptachlor and endrin. The authors did
not have a measure of exposure to chlordane. The employees working from
the start-up of the plants (1946 for the chlordane plant and 1952 for the
other plant) until 1976 were eligible for the study. In the 113 deaths at
the two plants, including 13 deaths in the chlordane plant, there was no
statistically significant excess of deaths from cancer, even in those
followed for more than 20 years after the beginning of employment. The
study is too small to conclude that there is negligible risk.
Brown (1992) reported follow-up data through 1987 of a cohort mortality
study of white male workers employed at four organochlorine pesticide
manufacturing plants, two of which were the same plants studied by Wang and
MacMahon (1979). The original study, Ditraglia et al. (1981), included all
employees who worked at least 6 months prior to 1964, and vital statistics
were followed until 1976. There was no excess cancer mortality in either
the original study or in Brown's follow-up study. The small number of
deaths in the chlordane plant workers (159) available for analysis
precludes the ability to arrive at definitive conclusions about the effects
of chlordane exposure.
Shindell and Ulrich (1986) published a retrospective mortality study of
workers in the same plant. Their population was employees who worked for
more than 3 months from 1946 through June 1985. No excess cancer rates
were found in this study (based on 37 cancer deaths analyzed), but the
authors presented no information about expected rates. In a letter, the
editors, Infante and Freeman (1987), challenged these results by
calculating expected rates based on other studies of this cohort and
asserted that there was an increasing trend of the SMR with increasing
duration of employment. Shindell responded in the same 1987 publication
with a table showing the expected rates and stated that there was no trend
in mortality rates with respect to length of employment.
Wang and MacMahon (1979) studied the prospective mortality of male
pesticide applicators employed by three nationwide companies between 1967
and 1976. In the 16,126 men in the study, there were 311 deaths with no
statistically significant excess cancer mortality. A follow-up of this
cohort to 1984 was published by MacMahon et al. (1988); it showed no
statistically significant excess mortality for any cancer except for lung,
and that was for employment for less than 5 years. Attributing that
finding to chlordane exposure is unlikely, because there was no increase in
lung cancer among termite control operators, the group most likely to be
exposed. A maximum latent time of 17 years may not have been long enough
to observe cases that could have been induced by chlordane exposure.
Case Reports
Epstein and Ozonoff (1987) presented 25 new cases (cases not previously
reported to EPA) of blood dyscrasias (thrombocytopenic purpura, aplastic
anemia, and leukemia) following exposure to chlordane and heptachlor; four
of these were leukemia cases. In 16 of the 25 cases, no exposure other
than to chlordane or heptachlor was reported, and over 75% of these cases
involved homeowners following termite treatment or garden and lawn
applications.
Infante et al. (1978) presented 11 clinical cases of blood dyscrasias
associated with chlordane exposure. There were five cases of neuroblastoma
in children exposed to chlordane, three of which were prenatal exposures to
the mother during pregnancy. They also discussed three cases of aplastic
anemia, two of which reported chlordane-only exposure, and three cases of
leukemia, two of which also reported chlordane-only exposure. They also
reviewed 25 cases of blood dyscrasias previously reported to be associated
with chlordane and heptachlor exposure.
Three studies of cancer patients [Caldwell et al., 1981; (colon cancer
in adolescents living on farms where pesticides were used); Teufel et al.,
1990 (eight different childhood cancers); and Falck et al., 1992 (breast
cancer)] reported no differences in tissue levels of chlordane between
controls and cancer patients. These studies were done to test the
hypothesis that chlordane is a risk factor for these populations.
_II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Chlordane treatment has induced benign or malignant liver
tumors in each of the five strains of mice in which bioassays have been
reported [CD-1 (IRDC, 1973), B6C3F1 (NCI, 1977), ICR (Khasawinah and
Grutsch, 1989a), C57Bl/10J (Barrass et al., 1993), and B6D2F1 (Malarkey et
al., 1995)]. In rats, no tumors were induced in two strains [Osborne-Mendel
(NCI, 1977), and Fischer 344 (Khasawinah and Grutsch 1989b)].
Mouse Studies
Groups of 100 male and 100 female CD-1 mice were fed diets containing
analytical grade chlordane at concentrations of 0, 5, 25, or 50 ppm
(approximately 0, 0.71, 3.57, or 7.14 mg/kg-day, respectively) for 18
months (IRDC, 1973; U.S. EPA, 1986). At the 19.5-month terminal sacrifice,
no exposure-related changes in body weight gain or food consumption were
observed, but survival in the 50-ppm group was greatly reduced compared to
controls (only 39 males and 37 females were examined histologically). Many
mice were lost because of autolysis, so that only about half of the mice
were examined histologically. EPA-sponsored examination of the liver
histological slides found statistically significant increased incidence of
hepatic carcinomas in males and females in the 25- and 50-ppm groups.
Groups of 50 male and 50 female B6C3F1 mice were fed diets with low and
high concentrations of analytical chlordane for 80 weeks and then were
observed for 10 weeks (NCI, 1977). Time-weighted average concentrations
were 29.9 and 56.2 ppm for male mice and 30.1 and 63.8 ppm for female mice
and correspond to approximate average doses of 4.3 and 8.0 mg/kg-day for
male and 4.3 and 9.1 mg/kg-day for female mice for low and high doses,
respectively. Matched controls consisted of 10 male and 10 female
untreated mice. A pooled control group consisted of the matched control
mice and 70 male and 80 female untreated mice from similar bioassays
conducted during periods that overlapped with the chlordane bioassay by at
least a year. Surviving mice were sacrificed at 90-91 weeks. Major organs
and tissues from sacrificed mice and from mice found dead were examined
grossly and microscopically.
No significant exposure-related changes in average body weight were
found in male or female mice (NCI, 1977). Survival of exposed female mice
was essentially the same as control female mice, but survival of male mice
in both exposed groups (60%) was significantly decreased relative to
control males (100%).
Exposure-related neoplastic or nonneoplastic lesions in mice were
restricted to the liver (NCI, 1977). Hepatocytomegaly, nodular
hyperplasia, and diffuse hyperplasia were found in exposed male and female
mice, but not at incidences that were statistically significantly different
from controls. Statistically significant elevated incidences for
hepatocellular carcinomas, relative to controls, were found in low- and
high-dose male mice and in high-dose female mice. Tumor incidence data are
presented in Section II.B.2.
ICR mice (80/sex/group) were fed 0, 1, 5, or 12.5 ppm technical
chlordane in the diet for 104 weeks (Khasawinah and Grutsch, 1989a;
Velsicol Chemical Corporation, 1983). The study authors reported that
average doses corresponded to 0, 0.15, 0.75, or 1.875 mg/kg-day,
respectively, based on food consumption and body weight data. Hematology,
biochemistry, urinalysis, organ weights, and pathology (of major tissues
and organs) were assessed at week 52 (8 males and 8 females/group), on all
animals that died during the study, and on all survivors at week 104.
When male mice were analyzed without regard to the presence or absence
of tumors, no consistent, exposure-related changes were found, except that
12.5-ppm male mice showed a statistically significant elevation in serum
alanine transferase activity (SGPT or ALT) at week 104. However, when
animals with adenocarcinomas were compared with those without adenomas or
adenocarcinomas, the animals with malignant tumors had statistically
significant elevations of all blood biochemistry measurements made (SGOT,
SGPT, glucose, urea nitrogen, cholesterol, and protein). The authors
concluded that the presence of the malignant tumors, and not the exposure
to chlordane, altered the blood biochemistry parameters. Statistically
significant increased relative and absolute liver weights were seen in
high-dose males (p < 0.0001) and females (p < 0.01), compared to control
values at the end of the study. No consistent changes in other organ
weights were found (Khasawinah and Grutsch, 1989a; Velsicol Chemical
Corporation, 1983).
Exposure-related neoplastic and nonneoplastic lesions were restricted
to the liver. Statistically significant increased incidences, relative to
controls, were found for the following nonneoplastic lesions:
hepatocellular swelling in male and female mice in the 5- and 12.5-ppm
groups, hepatic fatty degeneration in 12.5-ppm males, and hepatic necrosis
in 5- and 12.5-ppm male mice. Male mice in the 12.5-ppm group showed
statistically significant elevated incidence of hepatocellular adenomas
(also called hepatocellular nodules by the study authors) and hepatic
hemangiomas compared with controls. The hepatic hemangiomas were described
as benign tumors of capillary cells associated with the hepatocellular
adenomas. The 1989 report mentions the occurrence of liver adenocarcinomas
but does not present incidence data. However, the earlier report of this
assay (Velsicol Chemical Corporation, 1983, cited by U.S. EPA, 1986) shows
that the hepatocellular carcinoma incidence in males in the 0-, 1-, 5-, and
12.5-ppm groups is 3/71, 3/71, 7/72, and 8/72, respectively. These data
are used for the quantitative cancer risk estimates in Section II.B.2. No
other statistically significant differences between control and exposed
groups of mice were found for incidences of nonneoplastic or neoplastic
lesions (Khasawinah and Grutsch, 1989a).
Barrass et al. (1993) carried out two assays in which chlordane with a
concentration of 50 ppm was fed to C57Bl/10J mice. The first was a
24-month bioassay of chlordane in a group of 100 male mice, with
histopathological analysis of liver sections. The authors found that, in
the animals surviving after 2 years of treatment, the incidences of
hepatocellular adenomas and carcinomas were 15/39 and 5/39, respectively.
In the animals with unscheduled deaths during the assay, the incidences of
adenomas and carcinomas were 1/40 and 2/40, respectively. The incidence of
total liver tumors in a concurrent colony control group was 8/400.
Therefore, the incidence of adenomas and carcinomas combined was 23/79,
which is statistically significant relative to controls. However, because
the incidence of carcinomas alone in the control group was not given, the
statistical significance of the carcinomas alone can not be calculated, nor
can the risk of carcinoma alone be determined.
The second assay was a 6-month cell proliferation study with nine
serial sacrifices, in which replicating cells were labeled by infusing BrdU
via subcutaneous mini-osmotic pumps 3 days before sacrifice. Thyroid and
liver cell replication and histopathology were measured. In this assay,
there were no morphological thyroid abnormalities; the thyroid labeling
index reached a peak after 5 days and reached control levels after 99 days.
Centrilobular hepatocellular hypertrophy was seen early and became more
severe throughout the experiment. The liver-labeling index showed an
initial peak phase lasting 4 weeks and a sustained elevated phase lasting
for the entire 200-day period, but gradually declining by day 200.
Malarkey et al. (1995) reported on the age-specific prevalence of
malignant and benign tumors in male mice of two strains [B6C3F1 (210
treated animals) and B6D2F1 (160 treated animals)] fed 55 ppm of chlordane
continuously for 18 and 22 months, respectively. Groups of 100 B6C3F1 mice
and 50 B6D2F1 mice served as controls. The investigators also measured the
time course of two measures of liver toxicity (centrilobular hypertrophy
and "toxic change", defined as cellular necrosis and vacuolization and
tissue inflammation). They found that all the mice of both strains
eventually had tumors, and that the onset was more rapid in B6C3F1 mice by
about 100 days. After 72 weeks of treatment (568 days of age), which was
about 8 weeks less than the duration of the NCI (1977) test, the prevalence
of carcinomas in B6C3F1 mice was about 88%, as determined from the
prevalence vs. time graphs in the Malarkey et al. paper. This is the same
as the incidence of tumors in the NCI bioassay, which was 43/49 = 88% after
80 weeks of treatment. Therefore, the incidence of carcinomas in the
current study closely matches the experiment done under similar conditions
18 years earlier in mice of a different strain. The multiplicity of
adenomas (tumors per tumor-bearing animal) increased over time, whereas
that of carcinomas was constant. Centrilobular hypertrophy preceded the
development of tumors by over 100 days, whereas the toxic change occurred
at about the same time as the development of tumors. In one group of
B1C3F1 mice in which the chlordane was withdrawn from the diet after 14
months, there was a partial regression (reduction in prevalence) of both
adenomas and carcinomas, as well as a reduction of adenoma multiplicity.
There were no mutations of H-ras or K-ras oncogenes in tumors of treated
animals of either strain, whereas H-ras mutations occurred in 4 of 10
spontaneous tumors in control animals. The authors also observed that the
proliferative lesions preceding tumor formation in treated animals
consisted of large hepatocytes with acidophilic cytoplasm, whereas, in
control animals, they were of normal size, with basophilic staining. The
authors postulate a progression of tumors from a dependent stage, where
growth is dependent on the presence of chlordane, to an autonomous stage
that does not regress after its withdrawal.
Rat Studies
Groups of 50 male and 50 female Osborne-Mendel rats were fed low- or
high-dose diets containing analytical grade chlordane for 80 weeks and then
observed for 29 weeks (NCI, 1977). The test material contained 71.7%
cis-chlordane, 23.1% trans-chlordane, 0.3% heptachlor, 0.6% nonachlor,
1.1% hexachlorocyclopentadiene, and 0.25% chlordane isomers. Time-weighted
average concentrations were 203.5 and 407 ppm for males and 120.8 and 241.5
ppm for females, respectively. These concentrations correspond to
approximate average doses of 10.2 and 20.4 mg/kg-day for male and 6.0 and
12.1 mg/kg-day for female rats, respectively. Matched controls consisted
of 10 male and 10 female rats. A pooled control group consisted of the
matched-control rats and 50 male and 50 female untreated rats from similar
bioassays conducted during periods that overlapped the chlordane bioassay
by at least a year. Surviving rats were sacrificed at 109 weeks. Major
organs and tissues from sacrificed rats and from rats found dead, were
examined grossly and microscopically.
Obvious clinical signs of toxicity (rough and discolored hair coats and
palpable masses) occurred "frequently" in treated rats during the first
year and increased in frequency during the second year. No statistically
significant differences in survival were found for exposed male rats
compared with control rats, but there was a significant dose-related trend
for decreased survival in exposed female rats. No statistically
significant increased incidence of liver tumors or liver nonneoplastic
lesions was found in exposed rats compared with control rats.
Statistically significant increased incidences of proliferative lesions of
follicular cells of the thyroid and of malignant fibrous histiocytoma were
found in exposed male rats compared with controls. The study authors
concluded, however, that these differences were not biologically
significant, because the incidences were within the range of incidence for
control rat populations. No other exposure-related neoplastic or
nonneoplastic lesions were found in rats in this study.
In a 30-month oral study, Fischer 344 rats (80/sex/group) were exposed
to 0, 1, 5, or 25 ppm technical chlordane in the diet (Khasawinah and
Grutsch, 1989b; Velsicol Chemical Corporation, 1983; ICF-Clement, 1987;
U.S. EPA, 1988). Based on food consumption and body weight data, the study
authors calculated the doses to be 0, 0.045, 0.229, or 1.175 mg/kg-day for
males and 0.055, 0.273, and 1.409 mg/kg-day for females, respectively.
Because the original 1983 pathology report was completed before the
publication of NTP's diagnostic criteria for proliferative liver lesions,
and diagnostic discrepancies were found in the original pathology report,
the sponsor of the study (Velsicol Chemical Corporation) convened a
pathology working group (PWG) of six U.S. pathologists to review the liver
histopathological slides. The PWG's liver pathology findings are reported
herein.
No treatment-related clinical signs, deaths, or biochemical and
hematological parameters were observed (Khasawinah and Grutsch, 1989b).
The original pathologist noted that exposure-related lesions were found
only in the liver. Absolute liver weight was increased significantly (p <
0.05) in 5- and 25-ppm male rats at 130 weeks and in 25-ppm female rats at
26 and 52 weeks. Large granular lymphocyte leukemia was found at a high
incidence in all groups of female and male rats, including controls.
Elevated incidence of leukemia in control F344 rats living beyond 104
weeks, relative to rats sacrificed at 104 weeks, was reported as a common,
age-related occurrence that is accompanied by nonneoplastic liver lesions,
including necrosis, cytomegaly (i.e., swelling or hypertrophy), and fatty
degeneration (Solleveld et al., 1984; Stromberg and Vogtsberger, 1983).
Because age-related leukemia confounded exposure-related liver lesions, the
PWG examined incidence of nonneoplastic liver lesions in rats without
leukemia. Nonleukemic female rats in the 5- and 25-ppm groups had
statistically significant increases in hepatocellular hypertrophy relative
to controls, whereas nonleukemic females in the 1-ppm group and nonleukemic
males in the 1-, 5- and 25-ppm groups had no significant increases.
Overall incidence for hepatocellular adenomas in 25-ppm male rats (not
including interim-kill rats) was increased by a marginally statistical
significance relative to controls (7/64 vs. 2/64). Incidences for hepatic
neoplasms in other exposed groups were not increased. According to the
authors, no increased incidence of foci of cellular alteration in
nonleukemic livers (the first stage of rat liver carcinogenesis) was found
in exposed groups relative to controls.
Incidences for hepatocellular adenomas in the concurrent F344 rat
controls (3.1% in males and 0% in females) were below historical values for
control F344 rats in U.S. (range 0-17%) and Japanese laboratories (2.5% for
males dying before 104 weeks and 9.6% for males in studies of longer
duration). In consideration of this and the marginal significance of the
observed increased incidence of hepatocellular adenomas in 25-ppm males
compared with controls (p = 0.08), the PWG concluded that chlordane
treatment in this study did not produce a tumorigenic response in male or
female F344 rats. The Toxicology Branch of EPA's Office of Pesticides and
Toxic Substances concurred with this conclusion (U.S. EPA. 1988).
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
U.S. EPA (1986) evaluated genotoxicity studies on chlordane and
concluded that the available genotoxicity data did not provide a fully
comprehensive data set on which to definitively assess the mutagenic
potential of chlordane.
In a more recent review of chlordane genotoxicity studies, Jackson et
al. (1993) concluded that three studies provided sufficient evidence to
classify chlordane as having "limited evidence of mutagenicity". These
studies found weakly positive results for gene mutation in V-79 cells
(Ahmed et al., 1977), positive results in the mouse lymphoma assay
(McGregor et al., 1988), and positive results for the induction of sister
chromatid exchanges in cultured human lymphocytes (Sobti et al., 1983).
In general, chlordane has been classified as a "non-genotoxic murine
hepatocarcinogen", but the mechanisms whereby it produces cancer in rodents
are uncertain (see, for example, Malarkey et al., 1995). Whereas the
evidence of mutagenicity for chlordane is limited, several toxicological
properties have been described that may play roles in the expression of
chlordane carcinogenicity in rodents, including chlordane induction of hair
follicle nuclear aberrations in CD-1 mice (Schop et al., 1990);
irreversible binding of chlordane metabolites to intracellular
macromolecules, including DNA and RNA (Brimfield and Street, 1981);
chlordane inhibition of intercellular communication (Telang et al., 1982;
Ruch et al., 1990; Bessi et al., 1995); chlordane stimulation of protein
kinase C activity (Moser and Smart, 1989); chlordane induction of in vitro
hepatic lipid peroxidation and DNA single-strand breaks (Hassoun et al.,
1993); and chlordane suppression of in vitro immune responses (Johnson et
al., 1987; Chuang et al., 1992).
Malarkey et al. (1995) found no H- or K-ras mutations in hepatocellular
tumors from chlordane-exposed B6C3F1 or B6D2F1 mice, whereas H-ras
mutations were found in 4/10 spontaneous hepatocellular tumors examined
from control B6C3F1 mice and in 6/15 liver tumors from control B6D2F1 mice.
This observation of lower H-ras mutation frequency in tumors from exposed
mice than spontaneous tumors from control mice has been observed for other
nongenotoxic agents that cause liver tumors in mice, including dieldrin,
Aroclor, phenobarbital, and chloroform. The majority of neoplastic
hepatocytes and altered hepatocellular foci in exposed mice had acidophilic
cytoplasm, whereas neoplastic hepatocytes and altered hepatocellular foci
in controls had basophilic cytoplasm. Therefore, spontaneous tumors are
different than chlordane-induced tumors in two respects: (1) the occurrence
of H-ras gene mutations and (2) histochemical staining.
Five compounds structurally related to chlordane (aldrin, dieldrin,
heptachlor, heptachlor epoxide, and chlorendic acid) have produced liver
tumors in mice. Chlorendic acid also has produced liver tumors in rats.
_II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL
EXPOSURE
_II.B.1. SUMMARY OF RISK ESTIMATES
_II.B.1.1. Oral Slope Factor -- 3.5E-1 per mg/(kg-day)
_II.B.1.2. Drinking Water Unit Risk -- 1E-5 per (ug/L)
_II.B.1.3. Extrapolation Method -- Linearized multistage procedure,
extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 1E+1 ug/L
E-5 (1 in 100,000) 1E+0 ug/L
E-6 (1 in 1,000,000) 1E-1 ug/L
_II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type: Hepatocellular carcinoma
Test Animals: Mouse/CD-1 (IRDC)
Mouse/B6C3F1 (NCI)
Mouse/ICR (Khasawinah and Grutsch)
Route: Diet
Administered Human Equivalent Carcinoma
Dose (ppm) Dose (mg/kg-day) Incidence Reference
Male IRDC(1973)
0 0 3/33
5 0.1022 5/55
25 0.5137 41/52
50 1.0273 32/39
Female IRDC(1973)
0 0 0/45
5 0.1022 0/61
25 0.5137 32/50
50 1.027 26/37
Male NCI(1977)
0 0 17/92
29.9 0.65187 16/48
56.2 1.1511 43/49
Female NCI(1977)
0 0 3/78
30.1 0.6187 3/47
63.8 1.3093 33/49
Male Khasawinah and
0 0 3/71 Grutsch (1989b)
1 0.0216 3/71
5 0.1079 7/72
12.5 0.2698 9/72
_II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The quantitative estimate is based on the geometric mean of the five
data sets, all hepatocellular carcinomas in mice. The slope factors [units
of mg per (kg/day)] for the individual data sets are as follows: CD-1
males, 0.858; CD-1 females, 0.217; B6C3F1 males, 0.345; B6C3F1 females,
0.114; and ICR males, 0.710. In the calculation of human equivalent dose
from the dietary concentrations, data in the publications were used (where
given) to arrive at the animal dose in mg/kg-day units, and the human
equivalent dose was calculated from the animal dose using the following
equation: human dose = animal dose x (w/70)E1/4, where w is the adult body
weight of the mice. The animal weights were assumed to be 30 g in the
absence of data in the publications; however, the NCI study stated that
males weighed 35 g, and females weighed 30 g, so the actual weights were
used rather than the 30-g default value. In the NCI study, the animal dose
was assumed to be 0.13 times the concentration in the feed (the default
assumption in the absence of animal dose values in the report). Also in
the NCI study, the pooled control tumor incidence data were used instead of
the matched control (not given above) data. None of the studies presented
above, except Khasawinah and Grutsch, reported hepatocellular adenomas, and
the above data are for carcinomas alone. The only other study showing
adenomas is the Barrass et al. (1993) study (not presented here), and that
was for only one dose group. These two studies are not considered
extensive or reliable enough to derive a human estimate of carcinogenic
risk. Neither the male nor the female IRDC data could be fit to the
multistage model, and the procedure of deleting the high-dose group was
used to get an adequate fit. In the case of the females, the best fit was
obtained by a polynomial with all terms zero except Q(6), the sixth degree
in powers of dose. Because the low-dose slope determination for the IRDC
data was judged to be unreliable, the effect of deleting the IRDC data from
the geometric mean was evaluated; the resulting geometric mean was 0.303
per mg/kg-day, which was close enough to the geometric mean of all five
data sets (0.35 per mg/kg-day) so that this difficult data affected the
result to only an insignificant extent. The earlier IRIS summary of the
IRDC data sets used a version of the multistage model in which the degree
of the polynomial was fixed at 3; because that model did not adequately fit
the data, it was not used here.
The 1996 proposed cancer guidelines propose an alternate method of
low-dose extrapolation in which a linear extrapolation to small doses is done
based on the lower 95% confidence limit of the dose giving a 10% incidence
of tumors. Linear extrapolation from this point to zero dose is then
performed. Using this method, the five data sets would have the following
slope values: CD-1 males, 1.136; CD-1 females, 0.699; B6C3F1 males, 0.502;
B6C3F1 females, 0.218; and ICR males, 0.676. The geometric mean of these
values is 0.567, compared with 0.349, the mean of the slopes from the
linearized multistage model. The higher slope values derived from the
alternate method, compared with the low-dose slope estimates derived from
the linear multistage procedure, is a reflection of the positive curvature
(concave upwards) of all of the animal dose-response curves except the ICR
mice data set. The alternate method is not used because the proposed
guidelines are not yet in effect.
The unit risk should not be used if the water concentration exceeds
1000 ug/L, because, above this concentration, the unit risk may not be
appropriate.
_II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Hepatocellular carcinomas were induced by dietary chlordane of
comparable concentrations in five mice strains and in both sexes. The
liver is also the target organ for toxicity in rats. There were an adequate
number of animals in these assays, and the slope values are similar.
Therefore, the confidence is high that chlordane is a mouse liver
carcinogen at dietary concentrations above 10 ppm. Although there is
indication that the dose-response curve is sublinear in the dose region
between 5 and 60 ppm, linearity at low doses cannot be ruled out on
theoretical grounds. Although the evidence for chlordane exposure leading
to cancer in humans is tentative at best, it indicates that the target is
the hematopoietic system rather than the liver. Therefore, it is prudent
to regard mice liver cancer as an indicator of human hazard, and to regard
the extrapolated linear no-threshold dose-response curve as a
health-protective estimate of the doses at which human hazards could occur.
_II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM
INHALATION EXPOSURE
_II.C.1. SUMMARY OF RISK ESTIMATES
_II.C.1.1. Air Unit Risk: 1E-4 per (ug/cu.m)
_II.C.1.2. Extrapolation Method: Linearized multistage procedure, extra
risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 1E+0 ug/cu.m
E-5 (1 in 100,000) 1E-1 ug/cu.m
E-6 (1 in 1,000,000) 1E-2 ug/cu.m
_II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION
EXPOSURE
The air unit risk estimate was derived from the oral slope factor
(Section II.B.1) because no chronic bioassays have been done via the
inhalation route. As discussed in Section 5.3.3 of the toxicological
review (U.S. EPA, 1997), the human air unit risk is estimated assuming 100%
absorption of inhaled chlordane and assuming a breathing rate of 20
cu.m/day.
_II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The inhalation toxicity data indicate that inhaled chlordane causes
systemic effects similar to effects via ingestion exposure. Therefore,
there is no reason to expect effects unique to inhalation, and estimates
for inhalation risk are justified. The unit risk should not be used if the
air concentration exceeds 100 ug/cu.m because above this concentration, the
unit risk may not be appropriate.
_II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
See oral quantitative estimate.
_II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY
ASSESSMENT)
_II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986; Toxicological Review of Chlordane,
U.S. EPA, 1997.
This assessment was peer reviewed by external scientists. Their
comments have been evaluated carefully and incorporated in finalization of
this IRIS summary. A record of these comments is included as an
appendix.(U.S. EPA 1997)
_II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Consensus Review Date -- 11/03/1997.
_II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions
concerning this assessment or IRIS, in general, at (513)569-7254 (phone),
(513)569-7159 (FAX), or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_III. (Reserved)
_IV. (Reserved)
_V. (Reserved)
_VI. BIBLIOGRAPHY
Chlordane
CASRN 12789-03-6
Last Revised 02/07/1998
_VI.A. ORAL RfD REFERENCES
Adeshina, F. and E.L. Todd. 1991. Application of biological data in
cancer risk estimations of chlordane and heptachlor. Regul. Toxicol.
Pharmacol. 14: 59-77.
Al-Hachim, G.M. and A. Al-Baker. 1973. Effects of chlordane on
conditioned avoidance response, brain seizure threshold and open-field
performance of prenatally-treated mice. Br. J. Pharmacol. 49: 480-483.
Alvarez, W.C. and S. Hyman. 1953. Absence of toxic manifestations in
workers exposed to chlordane. Arch. Ind. Hyg. Occup. Med. 8: 480- 483.
Barnett, J.B., D. Holcomb, J.H. Menna, and L.S.F. Soderberg. 1985a. The
effect of prenatal chlordane exposure on specific anti-influenza
cell-mediated immunity. Toxicol. Lett. 25(3): 229-238.
Barnett, J.B., L.S.F. Soderberg, and J.H. Menna. 1985b. The effect of
prenatal chlordane exposure on the delayed hypersensitivity response of
BALB/C mice. Toxicol. Lett. 25(2): 173-183.
Barnett, J.B., B.L. Blaylock, J. Gandy, J.H. Menna, R. Denton, and L.S.
Soderberg. 1990a. Long-term alteration of adult bone marrow colony
formation by prenatal chlordane exposure. Fundam. Appl. Toxicol. 14(4):
688-695.
Barnett, J.B., B.L. Blaylock, J. Gandy, J.H. Menna, R. Denton, and L.S.
Soderberg. 1990b. Alteration of fetal liver colony formation by prenatal
chlordane exposure. Fundam. Appl. Toxicol. 15(4): 820-822.
Cassidy, R. A., C.V. Vorhees, D. J. Minnema, and L. Hastings. 1994. The
effects of chlordane exposure during pre- and postnatal periods at
environmentally relevant levels on sex steroid-mediated behaviors and
functions in the rat. Toxicol. Appl. Pharmacol. 126(2): 326-337.
Dearth, M.A. and R. A. Hites. 1991. Complete analysis of technical
chlordane using negative ionization mass spectrometry. Environ. Sci.
Technol. 25(2): 245-254.
Fleming, L. E. And W. Timmeny. 1993. Aplastic anemia and pesticides:
An etiologic association? J. Occup. Med. 35:1,106-1,116.
Fishbein, W. I., J. V. White, and H. J. Isaacs. 1964. Survey of workers
exposed to chlordane. Ind. Med. Surg. 33:726-727.
Grutsch, J.F. and A. Khasawinah. 1991. Signs and mechansims of chlordane
intoxication. Biomed. Environ. Sci. 4(3): 317-326.
ICF-Clement. 1987. Pathology peer review of chlordane in F344 rats.
Pathology review participants: Goodman, D.G., A.W. Mackin, R.R. Maronpot,
J.A. Popp, R.A. Squire, J.M. Ward, and M.R. Anver.
Infante, P., S.S. Epstein, and W.A. Newton, Jr. 1978. Blolod dyscrasias
and childhood tumors and exposure to chlordane and heptachlor. Scand. J.
Work Environ. Health 4: 137-150.
IRDC (International Research and Development Corporation). 1973.
Eighteen-month oral carcinogenic study of chlordane in mice. Unpublished
report to Velsicol Chemical Corporation. MRID No. 00067568. Available
from the U. S. Environmental Protection Agency.
Khasawinah, A. 1989. Chlordane residues in rat and monkey tissues
following subchronic inhalation exposure to technical chlordane. Bull.
Environ. Contam. Toxicol. 43: 459-466.
Khasawinah, A.M. and J.F. Grutsch. 1989a. Chlordane: 24-month
tumorigenicity and chronic toxicity test in mice. Regul. Toxicol.
Pharmacol. 10: 244-254.
Khasawinah, A.M. and J. Grutsch. 1989b. Chlordane: thirty-month
tumorigenicity and chronic toxicity test in rats. Regul. Toxicol.
Pharmacol. 10(2): 95-109.
Kilburn, K.H. and J.C. Thornton. 1995. Protracted neurotoxicity from
chlordane sprayed to kill termites. Environ. Health Perspect. 103(7-8):
690-694.
Mussalo-Rauhamaa, H. 1991. Partitioning and levels of neutral
organochlorine compounds in human serum, blood cells, and adipose and liver
tissue. Sci. Total Environ. 103: 159-175.
NCI (National Cancer Institute). 1977. Bioassay of chlordane for possible
carcinogenicity. Technical Report Series No. 8. U.S. Department of
Health, Education and Welfare; National Institutes of Health. PB 271 977.
Nomeir, A.A. and N.P. Hajjar. 1987. Metabolism of chlordane in mammals.
Rev. Environ. Contam. Toxicol. 100: 1-22.
R ani, B.E., N.G. Karanth, and M.K. Krishnakumari. 1992. Accumulation and
embryotoxicity of the insecticide heptachlor in the albino rat. J.
Environ. Biol. 13(2): 95-100.
Satoh, A. and H. Kikawa. 1992. Metabolic fate of cis- and trans-chlordane
in mice. Nippon Eiseigaku Zasshi 47(4): 818-825.
Sipes, I.G. and A.J. Gandolfi. 1991. Biotransformation of toxicants. In:
Casarett and Doull's Toxicology, 4th Ed. (Klassen, C.D., M.O. Amdur, and J.
Doull, eds.). McGraw-Hill; pp. 88-126.
Solleveld, S.P., J.K. Haseman, and E.E. McConnell. 1984. Natural history
of body weight gain, survival and neoplasia in the F344 rat. J. Natl.
Cancer Inst. 72: 929-940.
Spyker-Cranmer, J.M., J.B. Barnett, D.L. Avery, and M.F. Cranmer. 1982.
Immunoteratology of chlordane: Cell-mediated and humoral immune responses
in adult mice exposed in utero. Toxicol. Appl. Pharmacol. 62(3): 402-408.
Stromberg, P.C. and L.M. Vogtsberger. 1983. Pathology of the mononuclear
cell luekemia of Fischer rats. I. Morphologic studies. Vet. Pathol. 20:
698-708.
Taguchi, S. and T. Yakushiji. 1988. Influence of termite treatment in the
home on the chlordane concentration in human milk. Arch. Environ. Contam.
Toxicol. 17: 65-72.
U. S. EPA. 1979. Acceptable Common Names and Chemical Names for the
Ingredient Statement on Pesticide Labels. EPA 540/9-77-017. Washington,
DC: Office of Pesticide Programs.
U.S. EPA 1986. Carcinogenicity Assessment of Chlordane and
Heptachlor/Heptachlor Epoxide. Washington, DC: Office of Health and
Environmental Assessment. NTIS, PB87-208757.
U.S. EPA. 1997. Toxicological Review of Chlordane. Available online from:
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Velsiocol Chemical Corporation. 1983. Twenty-four month chronic toxicity
and tumorigenicity test in mice by chlordane technical. Unpublished study
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Japan. MRID No. 00144312, 00132566. Available from U. S. Environmental
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__VI.B. INHALATION RfC REFERENCES
Adeshina, F. and E.L. Todd. 1991. Application of biological data in
cancer risk estimations of chlordane and heptachlor. Regul. Toxicol.
Pharmacol. 14: 59-77.
Al-Hachim, G.M. and A. Al-Baker. 1973. Effects of chlordane on
conditioned avoidance response, brain seizure threshold and open-field
performance of prenatally-treated mice. Br. J. Pharmacol. 49: 480-483.
Alvarez, W.C. and S. Hyman. 1953. Absence of toxic manifestations in
workers exposed to chlordane. Arch. Ind. Hyg. Occup. Med. 8: 480- 483.
Barnett, J.B., D. Holcomb, J.H. Menna, and L.S.F. Soderberg. 1985. The
effect of prenatal chlordane exposure on specific anti-influenza
cell-mediated immunity. Toxicol. Lett. 25(3): 229-238.
Barnett, J.B., B.L. Blaylock, J. Gandy, J.H. Menna, R. Denton, and L.S.
Soderberg. 1990a. Long-term alteration of adult bone marrow colony
formation by prenatal chlordane exposure. Fundam. Appl. Toxicol. 14(4):
688-695.
Barnett, J.B., B.L. Blaylock, J. Gandy, J.H. Menna, R. Denton, and L.S.
Soderberg. 1990b. Alteration of fetal liver colony formation by prenatal
chlordane exposure. Fundam. Appl. Toxicol. 15(4): 820-822.
Cassidy, R.A., C.V. Vorhees, D.J. Minnema, and L. Hastings. 1994. The
effects of chlordane exposure during pre- and postnatal periods at
environmentally relevant levels on sex steroid-mediated behaviors and
functions in the rat. Toxicol. Appl. Pharmacol. 126(2): 326-337.
Dearth, M.A. and R.A. Hites. 1991. Complete analysis of technical
chlordane using negative ionization mass spectrometry. Environ. Sci.
Technol. 25(2): 245-254.
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etiologic association? J. Occup. Med. 35: 1106-1116.
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_VII. REVISION HISTORY
Chlordane (Technical)
CASRN 12789-03-6
Date Section Description
09/30/1997 II. Carcinogenicity section added
03/01/1988 I.A.l. Dose conversion clarified
03/01/1988 I.A.2. Text clarified in paragraph 3
03/01/1988 II.A.1. Basis for classification clarified
03/01/1988 III.A. Health Advisory added
04/01/1989 I.A. Withdrawn, new RfD verified (in preparation)
06/01/1989 I.A. Revised oral RfD summary added
06/01/1989 VI. Bibliography on-line
07/01/1989 I.A.2. Reference clarified in paragraph 2
07/01/1989 II. Velsicol (1993) references clarified
07/01/1989 VI.C. Carcinogen references added
03/01/1990 I.B. Inhalation RfD now under review
08/01/1990 III.A.5. DWEL changed reflecting change in RfD
08/01/1990 III.A.10. Primary contact changed
08/01/1990 IV.F.1. EPA contact changed
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global
change)
01/01/1992 IV. Regulatory actions updated
07/01/1993 II.D.3. Secondary contact's phone number changed
02/07/1998 I.A.,I.B.,II.,VI. Revised RfD and cancer assessments, new
RfC added
_VIII. SYNONYMS
Chlordane (Technical)
CASRN 12789-03-06
Last Revised 03/31/1987
57-74-9
Belt
CD 68
Chlordane
Chlorindan
Chlor Kil
Corodan
Dowchlor
ENT 9, 932
HCS 3260
Kypchlor
M 140
M 410
4,7-Methanoindan, 1,2,4,5,6,7,8,8-Octachloro-3a,4,7,7a-Tetrahydro-
4,7-Methano-1H-Indene, 1,2,4,5,6,7,8,8-Octachloro-2,3,3a,4,7,7a-Hexahydro-
NCI-C00099
Niran
Octachlorodihydrodicyclopentadiene
1,2,4,5,6,7,8,8-Octachloro-2,3,3a,4,7,7a-Hexahydro-4, 7-Methano-indene
1,2,4,5,6,7,8,8-Octachloro-3a,4,7,7a-Hexahydro-4,7-Methylene Indane
Octachloro-4, 7-Methanohydroindane
Octachloro-4, 7-Methanotetrahydroindane
Octa-Klor
Oktaterr
Ortho-Klor
Synklor
TAT Chlor 4
Topiclor
Toxichlor
Velsicol 1068
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Last updated: 16 July 1998
URL: http://www.epa.gov/iris/SUBST/0142.HTM
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