Toxicity Profiles

Formal Toxicity Summary for CHLORDANE

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
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

December 1994

Prepared by: Carol S. Forsyth, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences 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

Technical grade chlordane is a mixture of structurally related compounds including trans-chlordane, cis-chlordane, -chlordene, heptachlor, and trans-nonachlor (ATSDR, 1994). Chlordane was used extensively as a pesticide in the United States from 1948 to 1988. Because the chemical is persistent in the environment, exposure can still occur from breathing the air of treated homes, consuming shellfish caught in contaminated waters, or eating food produced on contaminated farmlands (ATSDR, 1994). Chlordane is readily absorbed after oral, inhalation, or dermal exposure and is stored in adipose tissue. The chemical is excreted in the feces from the bile (Ewing et al., 1985), but metabolite residues have been detected in 46% of human milk samples from Arkansas/Mississippi, in 68% of samples from Mississippi, and in 100% of samples from Hawaii (ATSDR, 1994).

Death in humans from ingestion of chlordane was accompanied by vomiting, dry cough, agitation and restlessness, hemorrhagic gastritis, bronchopneumonia, muscle twitching, and convulsions (IARC, 1991). Nonlethal, accidental poisoning of children has resulted in convulsions, excitability, loss of coordination, dyspnea, and tachycardia; however, recovery was complete (IARC, 1991). When a municipal water supply was contaminated with chlordane in concentrations of up to 1.2 g/L, 13 persons had symptoms of gastrointestinal and neurological disorders (WHO, 1984). Signs of toxicity from chronic inhalation exposure in chlordane treated homes include sinusitis, bronchitis, dermatitis, neuritis, migraine (Menconi et al., 1988), gastrointestinal distress, fatigue, memory deficits, personality changes, decreased attention span, numbness or paresthesias, disorientation, loss of coordination, dry eyes, and seizures (Spyker et al., 1990). Blood dyscrasias, including production defects and thrombocytopenic purpura, have been described for both professional applicators and for home owners and their families following home termite treatment (Epstein and Ozonoff, 1987). An inhalation reference concentration (RfC) for chlordane is under review by EPA (EPA 1994a).

Liver enlargement occurred in mice exposed to 10 mg/m3 8 hours/day, 5 days/week for 90 days (IARC, 1991). Increased liver weights were found in female rats (5.8 mg/m3), increased liver and kidney weights occurred in male rats (28.2 mg/m3), serum chemistry changes indicative of liver damage and hypersensitivity occurred in females (28.2 mg/m3), and centrilobular hepatocyte enlargement occurred in males and females (28.2 mg/m3) exposed to chlordane by inhalation 8 hours/day, 5 days/week, for 28 days (ATSDR, 1994).

Long-term feeding studies with chlordane in laboratory animals resulted in significantly reduced weight gains in male (203.5 or 407.0 ppm; 80 weeks) and female (120.8 or 241.5 ppm; 80 weeks) rats, a dose-related trend in mortality of female rats and male mice (29.9 or 56.2 ppm; 80 weeks) (NCI, 1977), and liver hypertrophy of female rats (>=5 ppm; 130 weeks) (EPA, 1994a). In a 24-month feeding study with mice, hepatocellular swelling and necrosis occurred in males and increased liver weights occurred in males and females fed 5 ppm (ATSDR, 1994; EPA, 1994a). A chronic oral reference dose (RfD) of 6E-05 mg/kg/day for chlordane was calculated from a no-observed-adverse-effect level (NOAEL) of 0.055 mg/kg/day derived from a chronic feeding study with rats (EPA, 1994a). The subchronic oral RfD is also 6E-05 mg/kg/day (EPA, 1994b).

Altered endocrine (Cranmer et al., 1984) and immune (Shepard, 1983; Theus et al., 1991) functions have been observed in rat pups exposed to chlordane in utero.

Exposure of humans from chlordane treated homes has been associated with leukemia (Epstein and Ozonoff, 1987), skin neoplasms (Menconi et al., 1988), and neuroblastoma in children (IARC, 1991). An increased risk of non-Hodgkin's lymphoma has been found among farmers exposed to chlordane 20 or more days per year (Hoar Zahm et al., 1988). Hepatic carcinomas and hepatocellular adenomas have been described for several strains of male and female mice and male rats given chlordane in the diet (NCI, 1977; EPA, 1994a). EPA (1994a) has classified chlordane as group B2, probable human carcinogen. The carcinogenicity slope factor (q1*) for oral exposure is 1.3E+0 (mg/kg/day)-1 based on an increase of hepatocellular carcinomas in mice and hepatocellular adenomas in rats. A drinking water unit risk of 3.7E-5 (µg/L)-1 was calculated based on the q1* (EPA, 1994a). The q1* for inhalation exposure is 1.3E+0 (mg/kg/day)-1 (EPA, 1994b), and the inhalation unit risk value is 3.7E-4 (µg/m3)-1 (EPA, 1994a). The inhalation risk estimates were calculated from the oral data.

1. INTRODUCTION

Chlordane (C10H6Cl8; CAS registry number 57-94-9) is a viscous, amber-colored liquid with a molecular weight of 409.8 (Budavari et al., 1989). Technical grade chlordane is a mixture of many structurally related compounds including trans-chlordane, cis-chlordane, -chlordene, heptachlor, and trans-nonachlor (ATSDR, 1994). The man-made chemical was used as a broad-spectrum pesticide in the United States from 1948 to 1988 and is often referred to by the trade names Octachlor and Velsicol 1068 (ATSDR, 1994). Uses included termite control in homes; pest control on agricultural crops such as maize and citrus; and pest control on home lawns and gardens, turf, and ornamental plants (IARC, 1991).

In the environment, chlordane is persistent and not readily degraded in water or soil. The chemical can volatilize from surface waters into the atmosphere but adsorbs strongly to soils. Chlordane accumulates in the fat of fish, birds, mammals, and humans (ATSDR, 1994).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Chlordane is readily absorbed after oral, inhalation, or dermal exposure. Blood levels in children after ingestion of unknown amounts have been measured at 2.71 to 3.4 mg/L (ATSDR, 1994). Peak blood levels in rats (81 ng/mL) and mice (113 ng/mL) occurred 2 and 8 hours, respectively, following oral administration of 1 mg/kg (Ewing et al., 1985). Data from humans exposed to chlordane in the air of treated homes indicates that blood or tissue levels increase with duration of exposure (ATSDR, 1994). Absorption through the skin of monkeys accounted for 4.2% of the dose in soil (ATSDR, 1994). Chlordane has been detected more frequently in the blood (mean of 2.2 ppm) of pesticide applicators who wore respirators than those not wearing respirators, indicating that dermal absorption is important because applicators wearing respirators tended to spray much larger amounts of the chemical (Saito et al., 1986).

2.2 DISTRIBUTION

In rats, one day after a single oral dose of chlordane ranging from 0.05-1.0 mg/kg, the greatest concentration of the chemical was found in adipose tissue, followed by liver, kidney, brain, and muscle (ATSDR, 1994). Because of its lipophilicity, chlordane accumulates in fat with the amount of accumulation dependent on duration of exposure (ATSDR, 1994). Rats fed chlordane at 1, 5, or 25 mg/kg for 56 days had fat residues 3 times higher than the dietary concentrations (WHO, 1984). Ewing et al. (1985) determined tissue concentrations of chlordane in mice and rats treated orally with 1 mg/kg. Peak concentrations in mice occurred at 4 hours and were 808, 1180, 349, 68, and 164 ng/g for fat, liver, kidney, brain, and muscle, respectively. Rats had peak tissue concentrations of 1239 and 729 ng/g for fat and kidney, respectively, at 4 hours and of 1959, 221, and 130 ng/g for liver, brain, and muscle, respectively, at 2 hours. Chlordane concentrations of 0.005-0.137 mg/kg have been measured in human placenta (Al-Omar et al., 1986) indicating that distribution to the fetus is possible. Chlordane has also been detected in human milk (Giroux et al., 1992).

2.3 METABOLISM

Four metabolic pathways have been proposed for the metabolism of chlordane: 1) hydroxylation followed by dehydration to form the precursor of oxychlordane; 2) dehydrochlorination to form heptachlor with the subsequent formation of heptachlor epoxide; 3) dechlorination, and; 4) replacement of chlorine atoms by hydroxyl groups to form metabolites that are excreted or conjugated with glucuronic acid (IARC, 1991). The major metabolite of chlordane in humans is oxychlordane, which has been detected in the blood of pesticide applicators (Saito et al., 1986). Dearth and Hites (1991) determined that the nonachloro- and pentachlorocyclopentene components of chlordane were preferentially accumulated in human adipose tissue suggesting that people are unable to metabolize these isomers.

2.4 EXCRETION

The major route of chlordane excretion is in the feces; however, of more importance is elimination in human milk. Chlordane had been detected in the urine and feces of humans following accidental ingestion of the chemical (ATSDR, 1994). Mice and rats given a single oral dose of 1 mg/kg, eliminated 34% and 7%, respectively, in the feces by 12 hours; by 3 days, both species had eliminated 83% of the dose in the feces. Biliary excretion appears to be the source of fecal excretion (Ewing et al., 1985). Oxychlordane residues have been detected in 46% of human milk samples from Arkansas/Mississippi, in 68% of samples from Mississippi, and in 100% of samples from Hawaii (ATSDR, 1994). Al-Omar et al. (1986) monitored chlordane residues in human milk over a 5-month period. Concentrations of the chemical varied from below the limit of detection to a high of 0.310 mg/kg whole milk throughout the entire study.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

The acute lethal dose of chlordane to humans has been estimated to be 25-50 mg/kg (WHO 1984). A woman died 9.5 days after ingestion of about 6 g of a 5% formulation (104 mg/kg). Signs of toxicity included vomiting, dry cough, agitation and restlessness, hemorrhagic gastritis, bronchopneumonia, muscle twitching, and convulsions (IARC, 1991). Accidental poisoning of children by ingestion of nonlethal amounts of chlordane has resulted in convulsions, excitability, loss of coordination, dyspnea, and tachycardia; however, recovery was complete (IARC, 1991). When a municipal water supply was contaminated with chlordane at concentrations of up to 1.2 g/L, 13 persons had symptoms of gastrointestinal and neurological disorders (WHO, 1984).

3.1.1.2 Animal

Oral LD50 values for technical grade chlordane in the rat range from 137 to 590 mg/kg (ATSDR, 1994). However, the LD50 for the rabbit is 1720 mg/kg (WHO, 1984). Signs of acute chlordane intoxication include ataxia, convulsions, and cyanosis followed by death due to respiratory failure (WHO, 1984). Rats treated by gavage with 100 mg/kg once a day for 4 days had increased absolute liver weights; fatty infiltration of the liver; and increased serum triglycerides, creatine phosphokinase, and lactic acid dehydrogenase (Ogata and Izushi, 1991). Sheep treated by stomach tube with 500 mg/kg showed signs of intoxication but recovered fully within 5-6 days; a dose 1000 mg/kg resulted in death after 48 hours (WHO, 1984).

3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of chlordane in humans was not available.

3.1.2.2 Animal

Male and female rats and mice were given chlordane in the diet for 6 weeks (NCI, 1977). All male rats fed 1600 ppm died after 2 weeks but no effects were seen at 800 ppm; however, 4 of 5 female rats died at 800 ppm with no effects seen at 400 ppm. Two of 5 male mice and all females died when fed 320 ppm; no effects were seen in either sex of mice at 80 ppm.

3.1.3 Chronic Toxicity

3.1.3.1 Human

Information on the chronic oral toxicity of chlordane to humans was not available.

3.1.3.2 Animal

Male and female rats and mice were given chlordane in the diet for 80 weeks (NCI, 1977). Doses were calculated as time-weighted averages with male rats receiving 203.5 or 407.0 ppm, female rats receiving 120.8 or 241.5 ppm, male mice receiving 29.9 or 56.2 ppm, and female mice receiving 30.1 or 63.8 ppm. All treated animals were in generally poor physical condition at the end of the study with significantly reduced weight gains measured in both sexes of rats. For female rats and male mice, there was a dose-related trend in mortality. No effect on mortality was observed in male or female rats fed chlordane at concentrations of 1, 5, or 25 ppm for 130 weeks but females had liver hypertrophy at >=5 ppm (EPA, 1994a). In a 24-month feeding study with mice, hepatocellular swelling and necrosis occurred in males and increased liver weights occurred in males and females fed 5 ppm (ATSDR, 1994; EPA, 1994a). Dogs fed chlordane at doses of 0.3, 3, 15, or 30 mg/kg for 2 years had abnormal clinical liver function tests (not defined) at the two highest concentrations and a dose-related increase in liver weight (WHO, 1984).

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

Information on the developmental or reproductive toxicity of chlordane to humans following oral exposure was not available.

3.1.4.2 Animal

No histopathological lesions were observed in reproductive tracts of male (407 ppm) or female (241.5 ppm) rats or in male (56.2 ppm) or female (63.8 ppm) mice given chlordane in the diet for 80 weeks (NCI, 1977).

No malformations or fetal toxicity were seen in offspring from rats administered up to 80 mg/kg/day chlordane by gavage during gestation (ATSDR, 1994). Rats fed 150 to 300 ppm chlordane during and after gestation gave birth to normal offspring. If maintained with their birth mothers during lactation, the pups developed excitability and tremors, but when foster nursed to dams on control diets, the pups developed normally (Shepard, 1983). Defects in macrophage function at 100 days of age (Theus et al., 1991) and cell mediated immunity (Shepard, 1983) have been demonstrated in offspring of mice treated with 8 mg/kg during gestation. Significant depression of the numbers of fetal liver granulocyte-macrophage colony-forming units and spleen colony-forming units has been demonstrated in fetuses from mice treated with 8 mg/kg throughout gestation (Barnett et al., 1990). Cranmer et al. (1984) treated mice with 0.16 or 8 mg/kg/day throughout gestation and monitored corticosterone levels in the offspring. At birth there was no difference in the numbers of viable offspring, but during the first week 55% of the offspring born to dams receiving 8 mg/kg died. At 400 days of age, male offspring exposed in utero to both levels of chlordane and high dose female offspring, had elevated corticosterone levels; these differences were resolved by 800 days of age.

3.1.5 Reference Dose

3.1.5.1 Subchronic

  • ORAL RfD: 6E-5 mg/kg/day (EPA, 1994b)
  • NOAEL: 0.055 mg/kg/day
  • UNCERTAINTY FACTOR: 1000
  • PRINCIPAL STUDY: Velsicol Chemical Co., 1983
  • COMMENTS: The chronic oral RfD was adopted as the subchronic oral RfD (EPA, 1994b).

3.1.5.2 Chronic

  • ORAL RfD: 6E-5 mg/kg/day (EPA, 1994a)
  • NOAEL: 0.055 mg/kg/day
  • LEL: 0.273 mg/kg/day
  • UNCERTAINTY FACTOR: 1000
  • CONFIDENCE: Study: Medium Data Base: Low RfD: Low
  • VERIFICATION DATE: 3/22/89
  • PRINCIPAL STUDY: Velsicol Chemical Co., 1983
  • COMMENTS: The RfD is based on the results of a 30-month chronic feeding study in rats. The critical effect was regional liver hypertrophy in females. An uncertainty factor of 100 was used to account for inter- and intraspecies variability. An additional factor of 10 was used to account for the lack of a reproduction study and a chronic study in another mammalian species and the generally inadequate sensitive endpoints studied in existing studies, particularly since chlordane is known to bioaccumulate (EPA, 1994a).

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Gastrointestinal disorders and neurological symptoms were reported in workers within 4 days of an accidental spill of 1% chlordane. Exposure was from inhalation and/or dermal contact with most affected individuals being involved in the cleanup (ATSDR, 1994).

3.2.1.2 Animal

Death occurred in all rats exposed for 8 hours/day to either 413 mg/m3 for 2 days or to 154 mg/m3 for 5 days (ATSDR, 1994). Animals had evidence of respiratory tract and liver damage.

3.2.2 Subchronic Toxicity

3.2.2.1 Human

Information on the subchronic toxicity of chlordane to humans by inhalation was not available.

3.2.2.2 Animal

Rats and monkeys were exposed to chlordane by inhalation at concentrations of 0.1, 1, and 10 mg/m3 8 hours/day, 5 days/week for 90 days (IARC, 1991). While no effects were seen in monkeys at any dose, mice had liver enlargement at the highest dose. Increased liver weights were found in female rats (5.8 mg/m3), increased liver and kidney weights occurred in male rats (28.2 mg/m3), serum chemistry changes indicative of liver damage and hypersensitivity occurred in females (28.2 mg/m3), and centrilobular hepatocyte enlargement occurred in males and females (28.2 mg/m3) exposed to chlordane by inhalation 8 hours/day, 5 days/week, for 28 days (ATSDR, 1994).

3.2.3 Chronic Toxicity

3.2.3.1 Human

No increase in mortality rate has been found for workers employed in the manufacture or use of chlordane (ATSDR, 1994; Shindell and Ulrich, 1986). An epidemiological study on the health status of individuals whose homes had been treated with chlordane 1-24 years ago showed a positive correlation between indoor air levels (<1 µg/m3, 1-5 µg/m3, or >5 µg/m3) and the incidence of sinusitis, bronchitis, dermatitis, neuritis, and migraine (Menconi et al., 1988). Another survey reported headache, gastrointestinal distress, fatigue, memory deficits, personality changes, decreased attention span, numbness or paresthesias, disorientation, loss of coordination, dry eyes, and seizures from chlordane exposure in the home (indoor air levels were not measured) (Spyker et al., 1990). Blood dyscrasias, including production defects and thrombocytopenic purpura, have been described for professional applicators and for home owners and their families following home termite treatment with chlordane and heptachlor (Epstein and Ozonoff, 1987).

3.2.3.2 Animal

Information on the chronic inhalation toxicity of chlordane to animals was not available.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

The incidence of ovarian and uterine disease was significantly elevated in women in chlordane-treated homes (Menconi et al., 1988).

3.2.4.2 Animal

No histopathological abnormalities were observed in the reproductive organs of rats exposed to 28.2 mg/m3 for 28 days or in rats or monkeys exposed for 90 days to 10 mg/m3, 8 hours/day, 5 days/week (ATSDR, 1994).

3.2.5 Reference Concentration

3.2.5.1 Subchronic

Contact the Superfund Health Risk Technical Support Center, (513) 569-7300, concerning the subchronic inhalation RfC for chlordane (EPA, 1994b).

3.2.5.2 Chronic

A risk assessment for chlordane is under review by an EPA working group (EPA 1994a).

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Humans

Dermal application of about 30 g of chlordane to an adult resulted in death within 40 minutes (ACGIH, 1991). Gastrointestinal disorders and neurological symptoms were reported in workers within 4 days of an accidental spill of 1% chlordane. Exposure was from inhalation and/or dermal contact with most affected individuals being involved in the cleanup (ATSDR, 1994).

3.3.1.2 Animals

The dermal LD50 of chlordane in rabbits is 1100-1200 mg/kg (WHO, 1984). Rats injected intraperitoneally with 50 mg/kg once a day for 4 days had increased liver weights and increased lipid content of the liver (Ogata and Izushi, 1991). Gerbils injected intramuscularly with 2.5 mg/kg had hyperproteinemia, hyperglycemia, and increased serum alkaline and acid phosphatase activity (WHO, 1984).

3.3.2 Subchronic Toxicity

Information on the subchronic toxicity of chlordane to humans or animals by other routes of exposure was not available.

3.3.3 Chronic Toxicity

3.3.3.1 Human

Serum triglycerides, creatine phosphokinase, and lactic acid dehydrogenase activities were shown to be higher in pesticide applicators who wore masks. This would suggest that the effects were from dermal exposure, but the biological significance is unknown (Ogata and Izushi, 1991).

3.3.3.2 Animal

Information on the chronic toxicity of chlordane to animals by other routes of exposure was not available.

3.3.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of chlordane to humans or animals by other routes of exposure was not available.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary Target Organs

  1. Liver: In a 24-month feeding study with mice, hepatocellular swelling and necrosis occurred in males and increased liver weights occurred in males and females fed 5 ppm. Dogs fed chlordane at 0.3, 3, 15, or 30 mg/kg for 2 years had abnormal clinical liver function tests (not defined) at the two highest concentrations and a dose-related increase in liver weight.
  2. CNS: Accidental poisonings by chlordane in humans has caused convulsions, agitation and restlessness, loss of coordination, and tachycardia. Death has been attributed to respiratory failure. In addition, tremors developed in rat pups nursing from dams treated with 150-300 ppm in the diet.

3.4.1.2 Other target organs

Gastrointestinal disorders have been reported in humans after accidental poisoning with chlordane. Following prenatal exposure to chlordane, rats have shown altered endocrine and immune functions.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target organs

  1. Liver: Increased liver weights were found in female (5.8 mg/m3) and in male (28.2 mg/m3) rats, serum chemistry changes indicative of liver damage and hypersensitivity occurred in females (28.2 mg/m3), and centrilobular hepatocyte enlargement occurred in males and females (28.2 mg/m3) exposed to chlordane by inhalation 8 hours/day, 5 days/week, for 28 days.
  2. CNS: Headache, fatigue, memory deficits, personality changes, decreased attention span, numbness or paresthesias, disorientation, loss of coordination, and seizures have been described from chlordane exposure in the home.

3.4.2.2 Other target organs

Gastrointestinal distress, dermatitis, sinusitis, and bronchitis have been associated with inhalation exposure to chlordane in treated homes.

3.4.3 Other Routes of Exposure

3.4.3.1 Primary target organs

  1. Liver: Serum triglycerides, creatine phosphokinase, and lactic acid dehydrogenase activities were shown to be higher in pesticide applicators who wore masks suggesting that the effects were from dermal exposure to chlordane.
  2. CNS: Neurological symptoms were reported in workers within 4 days of an accidental spill of 1% chlordane in which exposure was a combination of dermal and inhalation.

3.4.3.2 Other target organs

Gastrointestinal distress occurred in workers from a combination of dermal and inhalation chlordane exposure.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

Information on the carcinogenicity of chlordane to humans following oral exposure was not available.

4.1.2 Animal

Hepatic carcinomas and hepatocellular adenomas have been described for several strains of male and female mice and in one strain of male rat given chlordane in the diet. Male and female B6C3F1 mice were fed chlordane in the diet for 80 weeks; males received 29.9 or 56.2 ppm and females received 30.1 or 63.8 ppm (NCI, 1977). A dose-related increase (statistical significance, p < 0.001) in hepatocellular carcinomas was observed in both sexes in both treated male groups and high-dose females. No tumors were reported for male or female Osborne-Mendel rats fed 203.5 or 407.0 ppm and 120.8 or 241.5 ppm, respectively (NCI, 1977). In an unpublished report by the International Research and Development Corporation under contract to Velsicol Chemical Corporation, male and female CD-1 mice were fed chlordane at concentrations of 0, 5, 25, or 50 ppm for 18 months (Howard and Epstein, 1976; EPA, 1994a). The original report described a dose-related increase in liver nodular hyperplasia at the two highest doses. However, histological reanalysis by several pathologists diagnosed the lesions as hepatocarcinomas. Male and female ICR mice were fed chlordane in the diet at doses of 0, 1, 5, or 12.5 mg/kg for 104 weeks (IARC, 1991). High-dose males had a significant increase in hepatocellular adenomas often with associated hemangiomas. A significant increase in liver adenomas was observed in male F344 rats, but not females, given 25 ppm chlordane in the diet for 130 weeks (EPA, 1994a).

4.2 INHALATION EXPOSURES

4.2.1 Human

Information on the carcinogenicity of chlordane by inhalation in humans comes from case reports and epidemiology studies. Mortality due to cancer was found to be lower in workers employed in the manufacture of chlordane (Shindell and Ulrich, 1986; Brown, 1992). Fewer lung cancers were found in termite control operators (who are more likely to be exposed to chlordane) than in other pesticide control operators (MacMahon et al., 1988); however, in another study, an increase in respiratory cancers was associated with chlordane exposure (Brown, 1992). Exposure from treated homes has been associated with leukemia (Epstein and Ozonoff, 1987), skin neoplasms (Menconi et al., 1988), and neuroblastoma in children (IARC, 1991). An increased risk of non-Hodgkin's lymphoma has been found among farmers exposed to chlordane 20 or more days per year (Hoar Zahm et al., 1988).

4.2.2 Animal

Information on the carcinogenicity of chlordane by inhalation exposure to animals was not available.

4.3 OTHER ROUTES OF EXPOSURE

4.3.1 Human

Information on the carcinogenicity of chlordane in humans by other routes of exposure was not available.

4.3.2 Animal

Chlordane (2 µM), applied 3 times weekly for 20 weeks, failed to promote tumors in DMBA-initiated mouse skin (Moser et al., 1993).

4.4 EPA WEIGHT-OF-EVIDENCE

4.4.1 Oral

Classification: Group B2 -- Probable Human Carcinogen (EPA, 1994a)

Basis: Benign and malignant liver tumor induction in four strains of male and female mice and in male rats treated with chlordane in the diet; chlordane is structurally related to other liver carcinogens (EPA, 1994a).

4.4.2 Inhalation

Classification: Group B2 -- Probable Human Carcinogen (EPA, 1994a)

Basis: Benign and malignant liver tumor induction in 4 strains of male and female mice and in male rats treated with chlordane in the diet; chlordane structurally related to other liver carcinogens (EPA 1994a).

4.5 CARCINOGENICITY SLOPE FACTORS

4.5.1 Oral

  • SLOPE FACTOR: 1.3E+0 (mg/kg/day)-1 (EPA, 1994a)
  • DRINKING WATER UNIT RISK: 3.7E-5 (µg/L)-1 (EPA, 1994a)
  • VERIFICATION DATE: 4/1/87
  • PRINCIPAL STUDIES: Velsicol Chemical Co., 1973; NCI, 1977
  • COMMENTS: Slope factors were developed based on an increase in hepatocellular carcinomas in mice and hepatocellular adenomas in rats treated with chlordane in the diet (EPA, 1994a).

4.5.2 Inhalation

  • SLOPE FACTOR: 1.3E+0 (mg/kg/day)-1 (EPA, 1994b)
  • INHALATION UNIT RISK: 3.7E-4 (µg/m3)-1 (EPA, 1994a)
  • VERIFICATION DATE: 4/1/87
  • PRINCIPAL STUDIES: Velsicol Chemical Co., 1973; NCI, 1977
  • COMMENTS: The inhalation risk estimates were calculated from the oral data (EPA, 1994a).

5. REFERENCES

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Chlordane. Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed. ACGIH, Inc., Cincinnati, OH, pp. 244-246.

Al-Omar, M.A., F.H. Abdul-Jalil, N.H. Al-Ogaily, S.J. Tawfiq, and M.A. Al-Bassomy. 1986. A follow-up study of maternal milk contamination with organochlorine insecticide residues. Environ. Pollut. Ser. A 42:79-91.

ATSDR (Agency for Toxic Substances and Disease Registry) 1994. Toxicological Profile for Chlordane (Update). Prepared by Clement International Corporation, under Contract No. 205-88-0608 for ATSDR, Public Health Service, U.S. Department of Health and Human Services.

Barnett, J.B., B.L. Blaylock, J. Gandy, J.H. Menna, R. Denton, and L.S.F. Soderberg. 1990. Alteration of fetal liver colony formation by prenatal chlordane exposure. Fundam. Appl. Toxicol. 15:820-822.

Brown, D.P. 1992. Mortality of workers employed at organochlorine pesticide manufacturing plants - an update. Scand. J. Work Environ. Health 18:155-161.

Budavari, S., M.J. O'Neil, A. Smith, and P.E. Heckelman, Eds. 1989. The Merck Index, 11 ed. Merck and Co., Rahway, NJ. p.321.

Cranmer, J.M., M.F. Cranmer, and P.T. Goad. 1984. Prenatal chlordane exposure: effects on plasma corticosterone concentrations over the lifespan of mice. Environ. Res. 35:204-210.

Dearth, M.A. and R.A. Hites. 1991. Chlordane accumulation in people. Environ. Sci. Technol. 25:1279-1285.

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Last Updated 8/29/97