Toxicity Profiles
Formal Toxicity Summary for HEPTACHLOR
NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 1. INTRODUCTION
- 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
The toxicity information included in this summary was researched and compiled by R. A. Faust, Ph.D., who is a member of the Chemical Hazard Evaluation Group in the Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory.
Prepared by: Andrew Francis, M.S., D.A.B.T., Chemical Hazard Evaluation and Communication Group, Biomedical Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.
EXECUTIVE SUMMARY
Heptachlor, a cyclodiene insecticide, was extensively used until the 1970s for the control of a variety of insects. At the present time, its only permitted commercial use in the United States is fire ant control in power transformers. Heptachlor is converted to heptachlor epoxide and other degradation products in the environment. The epoxide degrades more slowly and, as a result, is more persistent than heptachlor. Both heptachlor and heptachlor epoxide are bioconcentrated in terrestrial and aquatic organisms. Heptachlor is subject to long-range transport and removal from the atmosphere by wet deposition (ATSDR 1993, Leber and Benya 1994).
Heptachlor is absorbed from the gastrointestinal tract, lungs, and skin. It is distributed to various tissues, with highest levels occurring in adipose tissue. Transplacental transfer to the fetus has been reported (EPA 1986). Metabolism produces primarily heptachlor epoxide, which is more toxic than its parent compound. Heptachlor and its metabolites are eliminated primarily via feces (Tashiro and Matsumara 1978).
The primary adverse health effects associated with heptachlor are central nervous system and liver effects. For humans, acute oral exposure has resulted in abnormal behavior, hyperirritability, tremors, and convulsions (Leber and Benya 1994). Various central nervous system effects such as hyperexcitability, incoordination, tremors, muscle spasms, and seizures have also been reported in animals following acute and subchronic oral exposure (Akay and Alp 1981, Buck et al. 1959, EPA 1985). Oral LD50 values for rabbits, rats, sheep, and calves are 2000, 90 to 160, 50, and 20 mg/kg, respectively (IARC 1979, Leber and Benya 1994). Although hepatic effects have not been reported in humans, chronic dietary exposure of rodents to 10 ppm heptachlor or to 10 ppm of a 25:75 mixture of heptachlor/heptachlor epoxide for 18 months has produced increased liver weights, liver lesions, and decreased body weight gains (Velsicol Chemical Corporation 1955, IRDC 1973).
Other effects reported in humans include blood dyscrasias as a result of exposure to heptachlor during home termite treatment (Epstein and Ozonoff 1987) and increased mortality from cerebrovascular disease in workers manufacturing pesticides. However, cardiovascular effects were not seen in a cohort of pesticide applicators with potentially high exposures to heptachlor (Wang and MacMahon 1979a,b). Reduced fertility, increased resorptions, and decreased survival of offspring was noted in rats fed diets containing 0.25 mg/kg/day for 60 days prior to mating, with treatment continuing through gestation for the females (Green 1970). Reduced fertility and an increased incidence of cataracts, particularly in offspring, was reported in rats fed 6 mg/kg/day over a an 18-month period (Mestitzova 1967).
An oral reference dose (RfD) of 5E-4 mg/kg/day for subchronic (EPA 1995a) and chronic exposure (EPA 1995b) to heptachlor was calculated based on a no-observed-adverse-effect level (NOAEL) of 0.15 mg/kg/day and a lowest-observed-adverse-effect level (LOAEL) of 0.25 mg/kg/day from a 2-year dietary study with rats (Velsicol Chemical Corporation 1955). Increased relative liver weight was identified as the critical effect. An inhalation reference concentration (RfC) for heptachlor has not been derived.
Existing epidemiological studies on heptachlor are inadequate to establish a clear assessment of heptachlor exposure and human risk of developing cancer. Large-scale occupational cohort studies on workers engaged in the manufacture of heptachlor and pesticide applicators have not identified significantly increased cancer deaths (Wang and McMahon 1979a,b). Several bioassays have shown that heptachlor can cause liver cancer in mice. Bioassays with rats were generally negative. Benign liver tumors and hepatocellular carcinomas developed in both sexes of C3H mice fed 10 ppm heptachlor for 2 years; hepatocellular carcinomas developed in both sexes of B6C3F1 mice fed 6-18 ppm technical grade heptachlor for 80 weeks; and nodular hyperplasia benign hepatomas and hepatocellular carcinomas developed in CD-1 mice fed 5 ppm (both sexes) or 10 ppm (males) of a 25:75 heptachlor/heptachlor epoxide mixture for 18 months (Epstein 1976, NCI 1977).
Based on EPA guidelines, heptachlor was assigned to weight-of-evidence group B2, probable human carcinogen. For oral exposure, the slope factor is 4.5 (mg/kg/day)-1 and the unit risk is 1.3E-4 (µg/L)-1 (EPA 1995b). The inhalation slope factor and unit risk are 4.5 (mg/kg/day)-1 (EPA 1995a) and 1.3E-3 (µg/m3)-1 (EPA 1995b), respectively.
1. INTRODUCTION
Heptachlor (CAS No. 76-44-8) or 1H-1,4,5,6,7,8,8-heptachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene, is a crystalline solid with a molecular weight of 373.35 and a chemical formula of C10H5Cl7 (Budavari et al. 1989). It has a melting point of 95-96C, a vapor pressure of 3 × 10-4 mm Hg @ 25C, and a specific gravity of 1.57 to 1.59 (Leder and Benya 1994). It is practically insoluble in water but is soluble in ethanol, xylene, carbon tetrachloride, acetone, and benzene (IARC 1979). Heptachlor is the chlorination product of chlordane, and technical chlordane may contain from 6% to 30% heptachlor (ATSDR 1993). Heptachlor is not known to occur naturally. Technical grade heptachlor contains approximately 73% heptachlor, 22% trans-chlordane, and 5% nonachlor (Leber and Benya 1994, IARC 1979).
Heptachlor, a cyclodiene insecticide, was extensively used until the 1970s for the control of certain soil-inhabiting insects that attack corn and other field crops, cotton insects, and grasshoppers and for treatment of seeds. Along with other cyclodiene insecticides, heptachlor is uniquely suited for termite control. As of April 1988, it can no longer be used for underground control of termites; its only permitted commercial use in the United States is fire ant control in power transformers (ATSDR 1993, Leber and Benya 1994).
Humans may be exposed to heptachlor/heptachlor epoxide from a variety of sources, including drinking water, food, ambient air, occupational settings, and consumer products (EPA 1985). Heptachlor is converted to heptachlor epoxide and other degradation products in the environment. The epoxide degrades more slowly and, as a result, is more persistent than heptachlor. Both heptachlor and heptachlor epoxide adsorb strongly to sediments, and both are bioconcentrated in terrestrial and aquatic organisms. Biomagnification of both compounds in aquatic food chains is significant. Heptachlor is subject to long-range transport and removal from the atmosphere by wet deposition. The chemical has been identified in at least 129 of 1300 hazardous waste sites on the EPA's National Priorities List (NPL) (ATSDR 1993).
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Heptachlor can be absorbed by the gastrointestinal tract and lungs, and systemic toxicity of heptachlor following topical application is an indication of dermal absorption. Heptachlor administered as a single gavage dose of 120 mg/kg was detected in blood of rats within 0.6 to 1 hour of administration (EPA 1986). Rats retained 77% of heptachlor that they inhaled during a 30-minute period (Hayes 1982). One study examined the respiratory intake in rabbits exposed to a number of pesticides under environmental conditions in the Mississippi Delta area (Arthur et al. 1975). Male and female rabbits were housed in an outdoor area of high pesticide use and a second group was housed inside a building with low pesticide use. During a 3-month period, weekly air sampling revealed concentrations of 1.86 ng/m3 of heptachlor epoxide in the outside air (high-exposure area). The calculated respiratory intake of heptachlor epoxide was 0.002 µg/day. Heptachlor epoxide residues were not identified in the feed.
2.2. DISTRIBUTION
Heptachlor has been found in human fat and in blood and fat of stillborn infants, indicating transplacental transfer to the fetus (IARC 1979). In a group of 45 individuals exposed to contaminated milk products from cattle fed heptachlor-contaminated feed, 23 to 31% were found to have significantly elevated serum levels of heptachlor metabolites (Stehr-Green et al. 1986).
Following a single gavage dose of 120 mg heptachlor, the chemical was detected in blood, liver, kidneys, and adipose tissues of rats within 1 hour (EPA 1986). After 4 hours, the metabolite heptachlor epoxide was detected in blood, liver, and adipose tissue and persisted in adipose tissue for 3 to 6 months. In rats administered dietary concentrations of 30 to 35 ppm heptachlor for 2 months, heptachlor epoxide levels in the adipose tissue of males and females averaged 43 µg/g tissue and 384 µg/g tissue, respectively. Much lower levels of heptachlor epoxide were detected in liver, kidney, and muscle tissue. A similar tissue distribution was seen for dogs that received a daily capsule containing 1 mg heptachlor for 12 to 18 months. Heptachlor epoxide was not detected in the brain of either rats or dogs (EPA 1986).
2.3. METABOLISM
In rats and other animals, some of the absorbed heptachlor undergoes epoxidation to produce heptachlor epoxide, which is more toxic than its parent compound. The epoxide is further metabolized and excreted. Tashiro and Matsumara (1978) studied the metabolic fate of heptachlor in rats. Over a 10-day period following an oral dose of 14C-heptachlor, the relative composition of fecal metabolites (expressed as percent of 14C-compounds) was as follows: unchanged heptachlor, 26.2%; heptachlor epoxide, 13.1%; 1-hydroxychlordene, 19.5%; 1-hydroxy-2,3-epoxychlordene, 17.5%; 1,2-dihydroxydihydrochlordene, 3.5%; and two unnamed metabolites, one of which accounted for 19% of the radioactivity and the other for <0.1%. In an in vitro study, similar metabolites were identified using rat and human liver microsomal preparations. However, rat microsomal preparations were four times more efficient in the metabolic conversion of heptachlor to heptachlor epoxide than were human microsomal preparations.
2.4. EXCRETION
Following administration of a single oral dose of 14C-heptachlor, male rats excreted most of the radioactivity in the feces (Tashiro and Matsumara 1978). One day after dosing, 36% of the dose, and by day 10, approximately 62% of the dose had been eliminated in the feces. Approximately 26% of the radioactivity recovered in the feces was the parent compound, and the remainder was in the form of metabolites. Only 10% of the total dose was excreted in urine in 10 days.
The highest levels of heptachlor epoxide were excreted within 3 to 7 days via milk production by cows that had grazed on pastures immediately following treatment with heptachlor (Gannon and Decker 1960).
3. NONCARCINOGENIC HEALTH EFFECTS
3.1. ORAL EXPOSURES
3.1.1. Acute Toxicity
3.1.1.1. Human
Although uncommon, acute intoxication as a result of heptachlor exposure has occurred in the past. Symptoms include abnormal behavior, hyperirritability, tremors, and convulsions (Leber and Benya 1994).
3.1.1.2. Animal
Oral LD50s for rats range from 90 to 160 mg/kg (Leber and Benya 1994, IARC 1979). LD50 values for rabbits, sheep, and calves are 2000 mg/kg, 50 mg/kg, and 20 mg/kg, respectively (Leber and Benya 1994). The principal toxic responses in rats were tremors, convulsions, paralysis, and hypothermia (EPA 1985). Young calves fed 2.5, 5, or 10 mg/kg/day of a heptachlor formulation for 15, 6, or 3 days, respectively, had muscle spasms in the head and neck region, convulsive seizures, elevated body temperatures, and engorged brain blood vessels (Buck et al. 1959).
Hepatic effects were observed in rats following acute exposures (doses not reported). They included increased liver weights, necrosis, cellular vacuolization, steatosis, and elevated liver enzymes (serum glutamic pyruvate transaminase and alkaline phosphatase), cholesterol, and bilirubin (Leber and Benya 1994). Dietary administration of 10 mg/kg of heptachlor (96%) to rats for 5 or 7 days resulted in alterations in liver function, as evidenced by increased blood glucose, decreased liver glycogen content, and decreased glutamine oxalacetic transaminase and increased acid and alkaline phosphatase levels. Other effects included increased white blood cell counts and serum bilirubin levels (EPA 1985).
3.1.2. Subchronic Toxicity
3.1.2.1. Human
In a group of 45 individuals exposed to contaminated milk products from cattle fed heptachlor-contaminated feed, 23 to 31% were found to have significantly elevated serum levels of heptachlor metabolites, but results of liver function tests and assays for hepatic microsomal induction were negative by comparison with a local non-exposed cohort (Stehr-Green et al. 1986).
3.1.2.2. Animal
Groups of Osborne-Mendel rats and B6C3F1 mice (5/sex/concentration) were administered technical grade heptachlor (73% heptachlor, 22% trans-chlordane, and 5% nonachlor) in the diet for 42 days (NCI 1977). Rats and mice received 0 to 320 ppm and 0 to 80 ppm, respectively. The only criteria of toxicity examined were food consumption, body weight gain, and mortality. At 80 ppm, female rats had reduced body weights during the first week. Four female rats died at 160 ppm, and two males and five female rats died at 320 ppm. In mice, all males and two females died at 80 ppm. No deaths and no effects on food consumption or body weight gain occurred in either species at the lower doses. Daily oral administration of 2 or 5 mg/kg heptachlor for 78 to 86 days to pigs, sheep, and rats produced liver necrosis and induced synthesis of smooth endoplasmic reticulum, with rats being the most sensitive species (IARC 1979).
Neurological effects were reported in several studies. Mice that received 13 mg/kg/day heptachlor for 10 weeks had difficulty walking and standing and lost their righting reflex. Tremors and self-mutilation also occurred (Akay and Alp 1981). Significant changes were seen in the electroencephalogram (EEG) of female rats administered 1 or 5 mg/kg/day in the diet for three generations (Formanek et al. 1976). Minks fed 6.19 mg/kg/day heptachlor for 28 days exhibited hyperexcitability and incoordination; one had paralysis of the hind legs (Aulerich et al. 1990).
3.1.3. Chronic Toxicity
3.1.3.1. Human
Information on the chronic toxicity of heptachlor in humans following oral exposure was not available.
3.1.3.2. Animal
Several long-term feeding studies with heptachlor were designed as carcinogenicity studies and a few provide noncarcinogenic toxicity data as well. In an NCI (1977) study, groups of B6C3F1 mice and Osborne-Mendel rats (50 animals/sex/concentration) were fed a diet containing technical grade heptachlor (73% heptachlor, 22% trans-chlordane, and 5% nonachlor) for 80 weeks. Time-weighted-average concentrations were 38.9 or 77.9 ppm for male rats; 25.7 or 51.3 ppm for female rats; 6.1 ppm or 13.8 ppm for male mice; and 9 or 18 ppm for female mice. The body weights of rats treated with the high dose were consistently lower than those of untreated controls while the body weights of low-dose rats and low- and high-dose mice were unaffected. A dose-related increased mortality was observed for female rats and mice, but not for males of either species. Except for an increased tumor incidence in mice (see Sect. 4.1.2.), no other systemic toxic effects were reported.
Groups of male and female CF rats were administered dietary concentrations of 0, 1.5, 3, 5, 7, or 10 ppm of heptachlor for 2 years (Velsicol Chemical Corporation 1955). Mortality was high (but not dose-related) in all groups, ranging from 50% to 75% for treated animals and 40% for controls. Significant other findings included loss of body weight, decreased food consumption, and increased liver weight at the highest dose. Liver lesions, described as "chlorinated hydrocarbon type," were seen in 30% of animals at 7 ppm and in 17% of animals at 10 ppm. No liver lesions developed in the other treated groups or in controls.
A 25:75 mixture of heptachlor:heptachlor epoxide was administered to groups of 100 male and 100 female CD-1 mice in the diet at a concentration of 0, 1, 5, and 10 ppm for 18 months (IRDC 1973). At the 6-month interim sacrifice, decreased body weights were seen in high-dose females but not in other treated groups. Significantly increased liver weights and an increased incidence of hepatocytomegaly were seen in both sexes at 6 and 18 months. The increases were dose-related and more marked in males (liver weight).
3.1.4. Developmental and Reproductive Toxicity
3.1.4.1. Human
A study was conducted on women of child-bearing age from Hawaii who ingested milk containing heptachlor for 27 to 29 months (Le Marchand et al. 1986). During this time (1980 to 1982), milk fat levels of heptachlor ranged from 0.12 to 5 ppm. Based on birth certificate and hospital discharge data, no adverse developmental or reproductive effects were apparent.
3.1.4.2. Animal
Male and female rats were fed diets containing 0.25 mg/kg/day heptachlor for 60 days prior to mating and treatment continued for the females through gestation (Green 1970). Reduced fertility and increased resorptions were observed in the treated group and postnatal survival of the F1 generation was reduced.
Administration of heptachlor in the feed at a dose of 6 mg/kg/day over an 18-month period reduced fertility of rats and survival of young during the first postnatal weeks by about one third. There was an increased incidence of cataracts, particularly in offspring of treated mothers (Mestitzova 1967). Similar reproductive effects were reported for doses of 5 and 10 mg/kg/day (duration not specified). In addition, some fetal abnormalities (unspecified) as well as resorptions were observed. No reproductive effects were observed at a dose of 1 mg/kg/day (Rosival et al. 1972).
Rats were fed diets containing 1 or 5 ppm heptachlor for 3 generations (Cerey et al. 1973). There was a statistically significant increase in the number of resorbed fetuses in both generations compared with controls. Bone marrow cells of the F1 and F2 generations had an increased incidence of abnormal mitosis. However, oral administration of a single gavage dose of 7.5 mg/kg of a 25:75 heptachlor:heptachlor epoxide mixture to male mice that were then mated with untreated females sequentially for 6 consecutive weeks, provided no evidence of an increase in dominant lethality as measured by pregnancy rates, early deaths, and number of live implants/female (Arnold et al. 1977).
Male and female mice fed 4.5 to 26 mg/kg/day of heptachlor for 10 weeks failed to produce offspring (Akay and Alp 1981).
3.1.5. Reference Dose
3.1.5.1. Subchronic
ORAL RfD: 5E-4 mg/kg/day (EPA 1995a)
NOAEL: 0.15 mg/kg/day
LOAEL: 0.25 mg/kg/day
UNCERTAINTY FACTOR: 300
PRINCIPAL STUDY: Velsicol Chemical Corporation 1955
COMMENTS: The chronic oral RfD (Section 3.1.5.2.) was adopted as the subchronic oral RfD.
3.1.5.2. Chronic
ORAL RfD: 5E-4 mg/kg/day (EPA 1995b)
NOAEL: 0.15 mg/kg/day
LOAEL: 0.25 mg/kg/day
UNCERTAINTY FACTOR: 300
CONFIDENCE:
Study: Low
Data Base: Low
RfD: Low
VERIFICATION DATE: 4/16/87
PRINCIPAL STUDY: Velsicol Chemical Corporation 1955
COMMENTS: The chronic RfD is based on liver weight increases in male rats exposed to heptachlor in the diet for 2 years. An uncertainty factor of 10 each was applied for inter- and intraspecies variation, and an additional factor of 3 was applied because of a lack of chronic toxicity data in a second species. The deficiencies would normally warrant a 10-fold factor for this area of uncertainty; however, toxicity data for other cyclodiene insecticides suggest that rats and dogs do not differ significantly in sensitivity to the effects of this class of compounds. Furthermore, liver toxicity is fairly well established for this class of compounds.
3.2. INHALATION EXPOSURES
3.2.1. Acute Toxicity
Information on the acute toxicity of heptachlor in humans or animals following inhalation exposure was not available.
3.2.2. Subchronic Toxicity
3.2.2.1. Human
The incidence of deaths due to cerebrovascular disease was significantly increased in 1403 white male workers engaged for at least 3 months in the manufacture of chlordane, heptachlor, and endrin between 1946 and 1976 (Wang and MacMahon 1979b) but was not increased in a larger cohort of 16,124 male pesticide applicators employed for at least 3 months during the same time period that were thought to have the potential for high level exposures to the pesticides (MacMahon et al. 1988, Wang and MacMahon 1979a). These studies were limited because specific dose and exposure information and controls for confounding variables such as preexisting cardiovascular disease and other risk factors were not provided.
Blood dyscrasias (production defects and thrombocytopenic purpura) were reported in 25 individuals exposed for an unspecified duration to heptachlor and chlordane following home application for termite treatment (Epstein and Ozonoff 1987).
3.2.2.2. Animal
Information on the subchronic toxicity of heptachlor in animals following inhalation exposure was not available.
3.2.3. Chronic Toxicity
Information on the chronic toxicity of heptachlor in humans or animals following inhalation exposure was not available.
3.2.4. Developmental and Reproductive Toxicity
Information on the developmental or reproductive toxicity of heptachlor in humans or animals following inhalation exposure was not available.
3.2.5. Reference Concentration
An inhalation RfC for heptachlor has not been derived.
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Information on the acute toxicity of heptachlor in humans by other routes of exposure was not available.
3.3.1.2. Animal
The dermal LD50 for rats is 195-250 mg/kg (Gaines 1969) and the intravenous LD50 for mice is about 20 mg/kg (IARC 1979). Female rats with carotid artery cannulation were injected (route not given) with a single dose of 13 mg/kg of heptachlor in peanut oil-lecithin (St. Omer and Ecobichon 1971). Mild tremors progressing to severe tremors were seen in 2 to 26 minutes. Within 10 to 20 minutes, there were episodes of running, rolling, and leg-paddling, followed by mild tonic-clonic seizures and inactivity. Death occurred within 2 hours.
3.3.2. Subchronic Toxicity
Daily intramuscular injections of 3 or 15 mg/kg heptachlor administered to rats for 45 days resulted in decreased liver size and dose-related increases in hepatic and gluconeogenic enzymes but had no effect on other tissues. Similar results were reported following intraperitoneal injections (EPA 1985).
3.3.3. Chronic Toxicity
3.3.3.1. Human
Information on the chronic toxicity of heptachlor in humans or animals by other routes of exposure was not available.
3.3.4. Developmental and Reproductive Toxicity
3.3.4.1. Human
Information on the developmental and reproductive toxicity of heptachlor in humans by other routes of exposure was not available.
3.3.4.2 Animal
Male mice that received a single intraperitoneal injection of 15 mg/kg of a 25:75 heptachlor:heptachlor epoxide mixture were mated with untreated females sequentially for 6 consecutive weeks (Arnold et al. 1977). No increase in dominant lethality as measured by pregnancy rates, early deaths, and number of live implants/female was evident.
3.4. TARGET ORGANS/CRITICAL EFFECTS
3.4.1. Oral Exposures
3.4.1.1. Primary Target Organ(s)
1. Liver: Increased liver weight and hepatocellular changes were seen in rats and mice following subchronic and chronic exposure.
2. Nervous system: Various neurological effects such as hyperexcitability, incoordination, tremors, muscle spasms, and seizures were seen in animals following acute and subchronic exposure. Acute intoxication of humans has resulted in abnormal behavior, hyperirritability, tremors, and convulsions.
3. Reproduction and Development: Reduced fertility, increased resorptions, and decreased survival of offspring was seen in rats fed heptachlor.
3.4.1.2. Other Target Organ(s)
Eyes: Cataracts developed in dams and offspring of exposed rats.
3.4.2. Inhalation Exposures
3.4.2.1. Primary Target Organ(s)
No primary target organs were identified.
3.4.2.2. Other Target Organ(s)
1. Hematopoietic system: Blood dyscrasias were reported in individuals exposed to heptachlor during home termite treatment.
2. Cardiovascular system: Increased mortality from cerebrovascular disease was seen in workers manufacturing pesticides including heptachlor. However, this effect was not seen in a cohort of pesticide applicators with potentially high exposures to heptachlor.
3.4.3 Other Routes of Exposure
3.4.3.1 Primary target organs
Liver: Intramuscular injection produced increased liver weights in rats.
3.4.3.2 Other target organs
No other target organs by other routes of exposure were identified.
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
Information on the carcinogenicity of heptachlor in humans following oral exposure was not available.
4.1.2. Animal
Groups of B6C3F1 mice and Osborne-Mendel rats (50 animals/sex/concentration) were fed a diet containing technical grade heptachlor (73% heptachlor, 22% trans-chlordane, and 5% nonachlor) for 80 weeks (NCI 1977). Time-weighted-average concentrations were 38.9 or 77.9 ppm for male rats; 25.7 or 51.3 ppm for female rats; 6.1 ppm or 13.8 ppm for male mice; and 9 or 18 ppm for female mice. The rats and mice were observed for an additional 30 and 10 weeks, respectively. The body weights of rats treated with the high dose were consistently lower than those of untreated controls while the body weights of low-dose rats and low- and high-dose mice were unaffected. A dose-related increased mortality was observed for female rats and mice but not for males of either species. No hepatic tumors were found in rats treated with heptachlor. In mice, a significantly (p<0.01) increased incidence of hepatocellular carcinomas was seen in males (5/19, controls; 11/46, low dose; 34/37, high dose) and females (2/10, controls; 3/47, low dose; 30/42, high dose).
Epstein (1976) reviewed several unpublished long-term feeding studies with rats and mice. These studies are discussed in the following text.
In an unpublished study by Kettering Laboratories, carried out in 1955, groups of 20 male and 20 female CF rats were administered dietary concentrations of 1.5, 3, 5, 7, or 10 ppm heptachlor (produced by spraying alcoholic solutions on feed) for 100 weeks. Mortality was high in all groups, ranging from 50% to 75% for treated animals and 40% for controls. Liver cell abnormalities were reported in both sexes at 7 and 10 ppm, and an excess of heterogenous, multiple-site tumors was reported for all females, particularly for those given 5 and 7 ppm. Subsequent statistical analysis revealed a significantly (p>0.01) increased incidence of all tumors combined in females given the higher levels of heptachlor.
In an unpublished study by the Food & Drug Administration conducted in 1965, groups of 100 female C3H mice were fed heptachlor at a concentration of 0 or 10 ppm for 24 months. The numbers still alive at 24 months were 62 controls and 60 animals treated with heptachlor. The incidence of hepatic hyperplasia and benign hepatomas in heptachlor-treated mice was doubled by comparison with controls. The incidence of hepatic carcinomas (diagnosed on the basis of metastases) was the same in both groups. However, following histological reevaluation, a significant (p<0.01) excess of liver carcinomas was found in males and females treated with heptachlor.
Epstein (1976) also evaluated an unpublished study by the International Research and Development Corporation conducted in 1973. A 25:75 mixture of heptachlor:heptachlor epoxide was administered to groups of 100 male and 100 female CD-1 mice in the diet at concentrations of 0, 1, 5, and 10 ppm for 18 months. Mortality in all groups ranged from 34 to 49%, with the exception of males and females given the 10 mg/kg diet that had mortalities of approximately 70%. A dose-related increased incidence of compound-related liver masses and nodular hyperplasia was reported in the treated groups. Histological reevaluation revealed an excess of liver carcinomas in both sexes at 10 ppm and in males at 5 ppm.
4.2. INHALATION EXPOSURES
4.2.1. Human
Exposures in the studies discussed in the following text are presumed to be predominantly by inhalation with contributions by the dermal route. Several case reports suggest a relationship between exposure to heptachlor or chlordane (either alone or in combination with other compounds) and acute leukemia. An association between pre- and post-natal exposure to technical grade chlordane containing heptachlor and the development of neuroblastoma in children has also been suggested (EPA 1985). According to IARC (1979), these case reports do not allow an evaluation of the carcinogenicity of heptachlor to humans.
A large-scale occupational mortality study of 16,124 male pesticide applicators has not shown an increased risk of cancer mortality. The standard mortality ratio (SMR) for bladder cancer was of borderline significance, but no information on smoking history was obtained (Wang and McMahon 1979a). One retrospective mortality study conducted with 1403 white male workers employed for >3 months in the production of chlordane, heptachlor, and endrin found a slight excess of lung cancer, but the increase was not statistically significant (Wang and McMahon 1979b). Because of methodological deficiencies, carcinogenicity could not be attributed to work exposure in these studies (ATSDR 1993).
4.2.2. Animal
Information on the carcinogenicity of heptachlor in animals following inhalation exposure was not available.
4.3. OTHER ROUTES OF EXPOSURE
Information on the carcinogenicity of heptachlor in humans or animals by other routes of exposure was not available.
4.4. EPA WEIGHT-OF-EVIDENCE
Classification: Group B2, probable human carcinogen (EPA 1995a,b).
Basis: Inadequate human data, but sufficient evidence from studies in which benign and malignant liver tumors were induced in three strains of mice of both sexes. Several structurally related compounds are liver carcinogens.
4.5. CARCINOGENICITY SLOPE FACTORS
4.5.1. Oral
SLOPE FACTOR: 4.5 (mg/kg/day)-1 (EPA 1995b)
UNIT RISK: 1.3E-4 (µg/L)-1 (EPA 1995b)
PRINCIPAL STUDIES: Davis, 1965; NCI 1977
COMMENT: The estimated slope factor is the geometric mean of the slope factors for four mouse data sets using two strains of mice (C3H and B6C3F1). Although the magnitude of the responses differed somewhat, a combined risk estimate was chosen because the two strains are related.
4.5.2. Inhalation
SLOPE FACTOR: 4.5 (mg/kg/day)-1 (EPA 1995a)
UNIT RISK: 1.3E-3 (µg/m3)-1 (EPA 1995b)
PRINCIPAL STUDY: Davis 1965, NCI 1977
COMMENT: The risk estimates were calculated from oral data.
5. REFERENCES
Akay, M. T. and U. Alp. 1981. The effects of BHC and heptachlor on mice. Hacette Bull. Nat. Sci. Eng. 10:11-22 (cited in ATSDR 1993).
Aulerich, R. J, G. J. Bursian, and A. C. Napolitano. 1990. Subacute toxicity of dietary heptachlor to mink (Mustela vison). Arch. Environ. Contam. Toxicol. 19:913-916 (cited in ATSDR 1993).
Arnold, D. W., G. L. Kennedy, Jr., M. L. Keplinger, and J. C. Calandra. 1977. Dominant lethal studies with technical chlordane, HCS-3260, and heptachlor:heptachlor epoxide. J. Toxicol. Environ. Health 2:547-555.
Arthur, R. D., J. D. Cain, and B. F. Barrantine. 1975. The effect of atmospheric levels of pesticides on pesticide residues in rabbit tissue and blood sera. Bull. Environ. Contam. Toxicol. 14:760-764.
ATSDR (Agency for Toxic Substances and Disease Registry). 1993. Toxicological Profile for Heptachlor/Heptachlor Epoxide. Prepared by Clement International Corporation, under Contract No. 205-88-0608. U.S. Public Health Service, TP-92/11.
Buck, W. B., R. D. Radeleff, J. B. Jackson, et al. 1959. Oral toxicity studies with heptachlor and heptachlor epoxide in young calves. J. Econ. Entomo. 52:1127-1129 (cited in ATSDR 1993).
Budavari, S., M. J. O'Neil, and A. Smith. 1989. The Merck Index. Merck & Co., Rahway, NJ, p. 736.
Cerey, K., V. Izakovic, and J. Ruttkay-Nedecka. 1973. Effect of heptachlor on dominant lethality and bone marrow in rats (Abstract. No. 10). Mutat. Res. 21:26.
Davis, K. 1965. Pathology Report on mice fed Aldrin, Dieldrin, Heptachlor and Heptachlor Epoxide for Two Years. Internal FDA memorandum to Dr. A. J. Lehman, July 19 (cited in EPA 1995a).
EPA (U.S. Environmental Protection Agency). 1985. Drinking Water Criteria Document for Heptachlor, Heptachlor Epoxide and Chlordane (Final Draft). ECAO-CIN-406; EPA-600/X-84-197-1; PB86-117991. Prepared by the Office of Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water.
EPA. 1986. Carcinogenicity Assessment of Chlordane and Heptachlor/Heptachlor Epoxide. EPA-600/6-87/004. Carcinogen Assessment Group, Office of Health and Environmental Assessment, Washington, D.C.
EPA. 1995a. Health Effects Assessment Summary Tables. Annual FY-95. Prepared for the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, D.C.
EPA. 1995b. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
Epstein, S. S. 1976. Carcinogenicity of heptachlor and chlordane. Sci. Total Environ. 6:103.
Epstein, S. S. and D. Ozonoff. 1987. Leukemias and blood dyscrasias following exposure to chlordane and heptachlor. Teratogen. Carcinog. Mutagen. 7:527-540.
Formanek, J., M. Vanickova, J. Plevova, et al. 1976. The effect of some industrial toxic agents on EEG frequency spectra in rats. Adverse Effects of Environmental Chemicals and Psychotropic Drugs 2:257-268 (cited in ATSDR 1993).
Gaines, T. B. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol. 14:515-534.
Gannon, N. and G. D. Decker. 1960. The excretion of dieldrin, DDT, and heptachlor epoxide in milk of dairy cow fed on pasture treated with dieldrin, DDT, and heptachlor. J. Econ. Entomol. 53:411-415 (cited in ATSDR 1993).
Green, V. A. 1970. Effects of pesticides on rat and chick embryo. In: Trace Substance Environmental Health 3. Proceedings of the 3rd Annual Conference, University of Missouri, pp. 183-209 (cited in ATSDR 1993).
Hayes, W. J. 1982. Heptachlor. In: Pesticides Studied in Man. Williams @ Wilkins, Baltimore, pp. 233-234.
IARC (International Agency for Research on Cancer). 1979. Heptachlor and heptachlor epoxide. In: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some Halogenated Hydrocarbons, Vol. 20. World Health Organization, Lyon, France, pp. 129-154.
IRDC (International Research and Development Corporation). 1973. Unpublished Report to Velsicol Chemical Corporation, Eighteen Month Oral Carcinogenic Study in Mice, September 26 (cited in Epstein 1976).
Leber, A. P. and T. J. Benya. 1994. Chlorinated hydrocarbon pesticides. In: Patty's Industrial Hygiene and Toxicology, 4th ed., Volume II, Part E. G. D. Clayton and F. E. Clayton, Eds. New York, John Wiley & Sons, pp. 1540-1545.
Le Marchand, L., L. N. Kolonel, B. Z. Siegel, and W. H. Dendle, III. 1986. Trends in birth defects for a Hawaiian population exposed to heptachlor and for the United States. Arch. Environ. Health 41:145-148.
MacMahon, B., R. R. Monson, H. H. Wang, et al. 1988. A second follow-up of mortality in a cohort of pesticide applicators. J. Occup. Med. 30:429-432 (cited in ATSDR 1993).
Mestitzova, M. 1967. On reproduction studies on the occurrence of cataracts in rats after long-term feeding of the insecticide heptachlor. Experientia 23:42-43.
NCI (National Cancer Institute). 1977. Bioassay of Heptachlor for Possible Carcinogenicity, CAS No. 76-44-8. NCI-CG-TR-9, DEWH Publ. No. 77-809.
Rosival, L., M. Ravera, G. Repetti, et al. 1972. Recent achievements in pesticide toxicology studies. Egeszsegtudomany 16:63-69 (cited in Hayes 1982).
St. Omer, V. V., and D. J. Ecobichon. 1971. The acute effect of some chlorinated hydrocarbon insecticides on the acetylcholine content of the brain. Can. J. Physiol. Pharmacol. 49:79 (cited in EPA 1985).
Stehr-Green, P. A., R. J. Schilling, V. W. Burse, et al. 1986. Evaluation of persons exposed to dairy products contaminated with heptachlor. JAMA 256:3350-3351.
Tashiro, S. and F. Matsumara. 1978. Metabolism of trans-nonachlor and related chlordane components in rat and man. Arch. Environ. Contam. Toxicol. 7:113-117.
Velsicol Chemical Corporation. 1955. MRID No. 00062599. Available from EPA. FOI, EPA, Washington, D.C.
Wang, H. H. and B. MacMahon. 1979a. Mortality of pesticide applicators. J. Occup. Med. 21:741-744 (cited in ATSDR 1993).
Wang, H. H. and B. MacMahon. 1979b. Mortality of workers employed in the manufacture of chlordane and heptachlor. J. Occup. Med. 21:745-748 (cited in ATSDR 1993).
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