Heptachlor

This CICAD1 on heptachlor was prepared by the Fraunhofer Institute of Toxicology and Experimental Medicine, Hanover, Germany. It is an update of the Environmental Health Criteria document on heptachlor (IPCS, 1984) and includes data from the IARC (2001) and JMPR (1992) reports. A comprehensive literature search of relevant databases was conducted from 2000 up to February 2004 to identify any relevant references published subsequent to those incorporated in these reports. Information on the source documents is presented in Appendix 2. Information on the peer review of this CICAD is presented in Appendix 3. This CICAD was considered and approved as an international assessment at a meeting of the Final Review Board, held in Hanoi, Viet Nam, on 28 September - 1 October 2004. Participants at the Final Review Board meeting are presented in Appendix 4. The International Chemical Safety Card on heptachlor (ICSC 0743), produced by the International Programme on Chemical Safety (IPCS, 2003), has also been reproduced in this document. Heptachlor (CAS No. 76-44-8) is a chlorinated dicyclopentadiene insecticide that is persistent in the environment and accumulates in the food-chain. Although its use has been banned or severely restricted in many countries since the 1980s, it is still detected as a contaminant in some food commodities. This is due to its persistence, but it also suggests the illegal use of this pesticide in the recent past or present (or maybe its permitted use in some countries). Heptachlor is one of several organochlorine pesticides that are persistent in the environment. Concentrations in body tissues and in the environment of all these compounds together are several times greater than those of heptachlor and/or heptachlor epoxide (a persistent heptachlor metabolite) alone. Heptachlor released into the environment can be transformed by abiotic processes, such as the transformation by photochemically produced hydroxyl radicals, and it is transformed in the presence of water to compounds such as 1-hydroxychlordene or heptachlor epoxide (such as, for example, in moist soils). In addition, it can be removed to some extent from aquatic systems by evaporation and has a limited potential to leach from soil into groundwater due to its elevated soil sorption coefficient. It is not readily biodegraded, but it is transformed biologically (i.e. by bacteria, fungi, plants, animals), mainly to the stable heptachlor epoxide. The data available on the bioconcentration potential of this lipophilic chlorinated hydrocarbon indicate that it and its stable epoxide will bioaccumulate, which can be shown from the extent of heptachlor/heptachlor epoxide still detected in environmental samples. The main exposure routes for heptachlor are probably via application-related inhalation or skin penetration, from extended exposure to dusts containing heptachlor in, for example, homes treated with this compound to control termites, and indirectly by uptake from food contaminated with heptachlor from crops or from other foods via the food-chain. However, heptachlor is a component of technical chlordane as well as a metabolite of chlordane, and thus identification of heptachlor or heptachlor epoxide does not always signify unequivocally that the primary exposure was to heptachlor (or heptachlor epoxide) per se. A survey of recent studies shows that heptachlor and/or heptachlor epoxide are found in all environmental compartments - air, water, soil, and sediment - as well as in plants (vegetables), fish and other aquatic organisms, amphibians and reptiles, birds and bird eggs, and aquatic and terrestrial mammals. They are found particularly in adipose tissues, where they accumulate. They pass up the food-chain. They are detected in human serum, adipose tissue, including breast tissue, and human breast milk. Heptachlor is readily absorbed via all routes of exposure and is readily metabolized. The major faecal metabolites include heptachlor epoxide, 1-hydroxychlordene, and 1-hydroxy-2,3-epoxychlordene. In liver microsomes incubated with heptachlor, 85.8% was metabolized to heptachlor epoxide in rats, but only 20.4% in humans. Other metabolites identified in the human liver microsome system were 1-hydroxy-2,3- epoxychlordene (5%), 1-hydroxychlordene (4.8%), and 1,2-dihydroxydihydrochlordene (0.1%). Heptachlor epoxide is metabolized slowly and is the most persistent metabolite; it is stored mainly in adipose tissue, but also in liver, kidney, and muscle. Females appear to store more heptachlor epoxide than males. A period of 12 weeks was required for complete disappearance from the fat after discontinuing heptachlor feeding in rats. In humans and laboratory animals, placental transfer of heptachlor and/or heptachlor epoxide has been shown. Acute oral LD50s for heptachlor for the rat and mouse are 40-162 and 68-90 mg/kg body weight, respectively. The acute toxicity of heptachlor in animals is associated with central nervous system disturbances, such as hyperexcitability, tremors, convulsions, and paralysis. The acute toxicity of heptachlor epoxide is greater than that of heptachlor, whereas that of the other metabolites is much less. In animals fed heptachlor/heptachlor epoxide by diet, gavage, or subcutaneous injection, there is a sharp dose-response curve for mortality. Usually, no marked differences were seen between the treated animals and the controls with respect to body weights and food consumption. However, liver enlargement has been described, associated with accentuated lobulation, and histopathological findings showed enlargement of centrilobular and midzonal hepatocytes. Fertility studies in rats injected with heptachlor subcutaneously resulted in LOAELs of 5 mg/kg body weight per day for suppression of reproductive hormone levels, disruptions in female cyclicity, and delays in mating behaviour. In developmental toxicity studies, there were usually no clinical signs of maternal toxicity (dose-related alterations in weight gain) until mortality occurred [NOAEL for maternal toxicity = 3 mg/kg body weight per day]. In one study, reduced litter sizes were noted, but postnatal mortality of the pups was the most obvious finding [NOAEL for pre- or postnatal survival of pups = 6 mg/kg body weight per day]. No teratological effects were observed. There is accumulating evidence that the nervous system and its development are influenced by cyclodiene pesticides. The profile of effects produced by repeated heptachlor administration to female rats consisted of altered activity, hyperexcitability, and autonomic effects [NOAEL = 2 mg/kg body weight per day]. Neurotoxicological studies on perinatal heptachlor exposure in the rat (0.03, 0.3, or 3 mg/kg body weight per day) suggested developmental delays, alterations in GABAergic neurotransmission, and neurobehavioural changes, including cognitive deficits at all doses. Immunological studies in rats indicate the suppression of the primary IgM and secondary IgG anti-sheep red blood cell responses following perinatal exposure to all tested doses (0.03, 0.3, or 3 mg/kg body weight per day) of heptachlor. Heptachlor, technical-grade heptachlor, heptachlor epoxide, and a mixture of heptachlor and heptachlor epoxide have been tested for carcinogenicity by oral administration in several strains of mice and rats. Heptachlor/heptachlor epoxide and technical-grade heptachlor were shown to be carcinogenic in male and female mice but not in rats. In an initiation-promotion assay, heptachlor was active as a promoter after initiation by N-nitrosodiethylamine. Heptachlor shows mostly negative responses in in vitro and in vivo genotoxicity testing. Heptachlor causes in vitro inhibition of gap junctional intercellular communication, also suggesting a non-genotoxic carcinogenic mechanism. Available epidemiological data do not show a clear relationship between adverse health effects and exposure to heptachlor. A tolerable intake was therefore developed from experimental studies. As hepatic tumours induced by heptachlor in mice are likely to be induced by a nongenotoxic mechanism and as non-neoplastic effects were observed at doses 1/20th of those inducing tumours, nonneoplastic effects (i.e. histopathological effects in the liver, neurotoxicological effects, and immunotoxicological effects) were used to derive the tolerable intake. The NOAEL for hepatic effects observed in dogs was 25 ?g/kg body weight per day, and that for neurotoxicity and immunotoxicity observed in studies in rats was 30 ?g/kg body weight per day. Applying an uncertainty factor of 10 for each of inter- and intraspecies variation and an additional factor of 2 for inadequacy of the database to the NOAEL in dogs gives a tolerable intake of 0.1 ?g/kg body weight per day for the non-neoplastic effects. Daily dietary intakes of heptachlor and heptachlor epoxide in Poland were estimated at 0.51-0.58 ?g per person (about 0.01 ?g/kg body weight, assuming a mean weight of 64 kg). This value is 10-fold less than the tolerable intake of 0.1 ?g/kg body weight. However, if food is contaminated with heptachlor, such as fish from contaminated rivers (e.g. concentrations in fish in the 0.1-1 mg/kg range reported recently in some areas), vegetables from fields contaminated with heptachlor (up to 16 mg/kg), or contaminated milk (e.g. in the microgram per kilogram to milligram per kilogram range in some regions), then the dietary intake of this chemical would be much higher, and there would be a likely health risk if the contaminated food is ingested for a long period of time. For breast-fed children, taking the highest reported values for heptachlor epoxide in human breast milk and assuming a daily milk consumption of 150 g/kg body weight and an average milk fat content of 3.1%, a mean intake of 1.5 ?g/kg body weight can be calculated. This value is more than 10-fold higher than the tolerable intake of 0.1 ?g/kg body weight per day and, if the concentrations reported are correct, should be a cause of concern. The acute toxicity of heptachlor was tested using a variety of aquatic species from different trophic levels. Heptachlor was shown to be toxic to fish and other aquatic species. However, there is a great deal of variability in the levels of toxicity reported, possibly due to evaporation of heptachlor, thereby reducing the actual concentration of the test compound from the nominal test concentration over time. For the freshwater environment, 23 toxicity values were chosen to derive a guidance value. A guidance value for heptachlor, based on the species sensitivity distribution, for the protection of 99% of species with 50% confidence was derived at 10 ng/l. In many locations, freshwater heptachlor concentrations exceed the guidance value; the highest reported heptachlor concentration measured in fresh surface water, 62 000 ng/l, exceeds it more than 1000-fold. For the marine environment, 18 toxicity values were chosen to derive a guidance value. A guidance value for heptachlor, based on the species sensitivity distribution, for the protection of 99% of species with 50% confidence was derived at 5 ng/l. For seawater, the highest reliable value for heptachlor present is about 0.15 ng/l, so the guidance value is not exceeded, suggesting a low risk for the marine environment. From the few data available, heptachlor appears to exhibit moderate toxic effects upon terrestrial vertebrates. None of the studies appears reliable enough to serve as a basis for a quantitative risk characterization. It should be remembered that heptachlor is used as a termiticide. In studies on rats, heptachlor has been shown to be neurotoxic and immunotoxic at 0.03 mg/kg body weight per day. The Göksu Delta, Turkey, which is one of the most important breeding and wintering areas for birds in the world, is contaminated by organochlorine pesticides from soils from agricultural areas that have been transported to the delta by the Göksu River. From this region, levels of heptachlor/heptachlor epoxide have been detected in birds and bird eggs in the lower milligram per kilogram range. The effect of such concentrations of heptachlor on the bird populations can only be speculated at present due to lack of data; however, there is a potential risk for the terrestrial environment in this location.