Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 143-50-0 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • Chlordecone (kepone)
  • KEPONE
  • 1,1A,3,3A,4,5,5A,5B,6-DECACHLOROOCTAHYDRO-1,3,4-METHENO-1H-CYCLOBUTA(CD)PENTALEN-2-OL (9CI)

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: In a study carried out by the Center for Disease Control, 133 employees, including 33 currently employed, were interviewed, examined, had blood samples taken, and completed a standard questionnaire. Of the 133 examined, 76 (57%) had developed clinical illness described as nervousness, tremor, weight loss, opsoclonus, pleuritic and joint pain, and oligospermia. Illness rates were higher for production workers than non-production workers, and the mean blood-chlordecone level for workers with illness was 2.53 mg/L compared with a level of 0.60 mg/L in workers without disease. Laboratory findings from the above study showed an increase in serum alkaline phosphatase activity in several patients and morphological changes in peripheral nervous tissue. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Industrial carelessness during the manufacture of an organochlorine compound chlordecone (Kepone) brought this agent... to the attention of toxicologists in 1975, when 76 of 148 workers in a factory in Hopewell, Virginia, developed a severe neurologic syndrome. This condition, known as the "Kepone shakes," was characterized by tremors, altered gait, behavioral changes, ocular flutter (opsoclonus), arthralgia, headache, chest pains, weight loss, hepatomegaly, splenomegaly, and impotence, the onset of symptoms generally occurring with a latency of approximately 30 days from the initiation of exposure and persisting for many months after the termination of exposure. Laboratory tests showed a reduced sperm count and reduced sperm motility. Routine neurologic studies showed nothing untoward, but microscopic examination of biopsies of the sural nerve revealed relative decreases in the population of small myelinated and unmyelinated axons. With electron microscopy, a number of abnormalities were visible; the significant findings included damage to Schwann cells (membranous inclusions, cytoplasmic folds), prominent endoneural collagen pockets, vacuolization of unmyelinated fibers, focal degeneration of axons with condensations of neurofilaments and neurotubules, focal interlamellar splitting of myelin sheaths, and the formation of myelin bodies and a complex infolding of inner mesaxonal membranes into axoplasm. The involvement of unmyelinated fibers and small myelinated fibers may partially explain the clinical picture. It has been suggested that chlordecone may interfere with metabolic processes in Schwann cells. However, it should be noted that all of these degenerative changes are nonspecific in nature and are commonly seen i other toxic polyneuropathies. Many of the toxic manifestations of chlordecone poisoning in these workers have been confirmed in animal studies, the major target organs being the CNS, liver, adrenals, and testes... . [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 772]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: A group of workers chronically exposed to chlordecone developed tremors, rapid and irregular eye movements, hepatomegaly, and hypospermia. These symptoms dissipated as stores of chlordecone in blood and adipose tissue declined. [Ford MD, Delaney KA, Ling LJ, Erickson T; Clinical Toxicology. W.B. Saunders Company., Philadelphia, PA. 2001, p. 832]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Chemical workers repeatedly exposed to high concentrations of kepone dust developed nervousness and tremors, visual disturbances including rapid erratic eye movement, and occasionally ataxia, chest pain, arthralgia, erythematous skin eruption, and weight loss. Oligospermia was found in some workers. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-287]**PEER REVIEWED**
  • CASE REPORTS: Liver biopsy of workers manufacturing the now banned pesticide Kepone (chlordecone) showed increased fat, numerous dense bodies, and proliferative smooth endoplasmic reticulum, and they also had severe neurologic disease. [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992., p. 639]**PEER REVIEWED**
  • CASE REPORTS: Three patients industrially exposed to chlordecone (kepone) with headache and increased intracranial pressure had elevated blood, serum, and adipose levels of chlordecone. Investigation eliminated intracranial mass or other known causes of pseudotumor cerebri. [Sanborn GE et al; Neurology (Minneap) 29 (9, Part 1): 1222-7 (1979) ]**PEER REVIEWED**
  • CASE REPORTS: In 32 men poisoned by Kepone, 20 showed liver enlargement and 10 showed splenomegaly. Liver biopsy showed increased lipofuscin, minimal fatty metamorphosis, hyperglycogenation of nuclei, and mild portal or lobular inflammatory changes. Exam of liver biopsy showed marked proliferation of smooth endoplasmic reticulum. Urinary excretion of glucaric acid increase and clearance of antipyrine was accelerated when compared to controls. Plasma gamma-glutamyl transpeptidase activity was normal. [Guzelian PS et al; Gastroenterology 78 (2): 206-13 (1980) ]**PEER REVIEWED**
  • CASE REPORTS: In 1975, a number of workers were exposed to excessive amounts of chlordecone. The major manifestations were tremor, opsoclonus, arthralgias, pleural pain, and reduced sperm count. Despite initial high blood concentration, follow up at 6 years indicated that in the re-evaluated workers the chlordecone had been cleared completely from blood, with very low levels remaining in fat. The clinical manifestations abated, and many of the patients returned to work. [Taylor JR; Neurotoxicology 3 (2): 9-16 (1982) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Kepone in drinking water: Upper 95% confidence estimate of lifetime cancer risk per ug/L: 4.4X10-5 /From table/ [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 794]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... MCF-10ATG3B cells cultured on an ECM of Matrigel form lattice-like structures that are disrupted with 0.1 and 1 microM Kepone. E-cadherin protein levels decreased significantly by approximately 23% and approximately 69% following treatment with 0.1 and 1.0 microM Kepone, respectively, relative to solvent-treated cells. Desmoglein and alpha- and gamma-catenin levels did not vary significantly with Kepone. Beta-catenin protein levels decreased significantly by approximately 37%, 36% and 53% at 0.01, 0.1 and 1.0 microM Kepone, respectively. E-cadherin-gamma-catenin association was disrupted with 0.1 and 1.0 microM Kepone. [Starcevic SL et al; In Vivo 15 (4): 289-294 (2001) ]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: Single oral dose of Kepone (72 to 98 mg/kg) was administered to male Sprague-Dawley rats in corn oil. Tremors and abnormal gait were noted within 4 hr, peaking after 2 days and absent after 49 days. Exaggerated startle response followed a similar pattern. Muscle weakness developed during second week and recovery occurred by end of 6 month. [Egle JL et al; Toxicol Appl Pharmacol 48 (3): 533-6 (1979) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Effect of mirex, 2 monohydrogen and 2 dihydrogen mirex derivatives, and chlordecone on several hepatic parameters were studied 2 days following single oral dose of 100 mg/kg in female rats. All compounds increased microsomal cytochrome P450 content, reduced nicotinamide adenine dinucleotide-cytochrome C reductase activity and hepatic ascorbic acid concentration. Microsomal protein concentration was generally increased. All compounds except chlordecone increased relative liver weight and activities of aminopyrine N-demethylase and p-nitroanisole O-demethylase. Hepatic concentration of protein and glutathione were unaltered. [Chambers JE, Trevathan CA; Toxicol Lett (Amst) 16 (1-2): 109-16 (1983) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: In dermal studies on rats and rabbits, no skin irritation was observed when /a single dose of/ chlordecone was administered in oil, but in aqueous solution it produced marked irritation, edema, and scab formation. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Pretreatment of mice with chlordecone (CD) reduced hepatic accumulation of a subsequent dose of [14C]CD without significantly changing [14C]CD biotransformation. ... Total liver or kidney lipid contents were not altered by CD but relative amounts of several hepatic fatty acids were changed. CD caused marked hepatic mitochondrial swelling, increased amounts of endoplasmic reticulum, apparently increased numbers of peroxisome-like structures, and decreased numbers of lipid droplets in cytoplasm of hepatocytes. Numbers of lipid droplets were not decreased in perisinusoidal fat storage cells. In addition, the numbers of cytoplasmic lipoprotein vesicles were apparently increased in some hepatocytes. [Carpenter HM et al; Fundam Appl Toxicol 34 (1): 157-164 (1996) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: ... Biliary excretion of phenolphthalein-glucoronide (PG), a marker of hepatic organic anion transport, and [14C]mannitol, a marker of passive transcellular permeability, was determined. Biliary excretion of PG decreased approximately 25% in rats 24 h after chlordecone (CD) treatment, however rats recovered control PG excretion rates 72 h after CD treatment. Recovery of PG excretion occurred despite higher liver homogenate [14C]CD concentrations at 72 h than at 24 h after [14C]CD treatment. Biliary clearance of [14C]mannitol decreased both 24 h and 72 h after treatment. Even though the amount of [14C]CD retained in the liver was greater at 72 h than at 24 h after treatment, the concentration of [14C]CD in isolated liver plasma membranes (LPM) was the same (3.5-3.9 nmol/mg protein) at both times. There was a significant reduction in 5'-nucleotidase activity of LPM at 24 h but not at 72 h after CD. [Rochelle LG, Curtis LR; Toxicology 86 (1-2): 123-134 (1994) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male, Sprague-Dawley rats treated with different (1, 10, 50, and 100 ppm) concentrations of chlordecone (Cd) in calcium-sufficient (Ca-S) or calcium-deficient (Ca-D) diet for 15 days /showed/ no significant changes in serum total proteins. However, serum nonprotein nitrogen compounds (urea, uric acid, and creatinine) and glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, creatine kinase, and alkaline phosphatase were significantly increased at 50 and 100 ppm of Cd. Chlordecone induced more increase in these serum components of rats fed with Ca-D as compared to Ca-S diet. [Chetty KN et al; Ecotoxicol Environ Saf 26 (2): 248-252 (1993) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Adenosine 3'5'-cyclic monophosphate (cAMP) has been repeatedly shown to mimic some actions of estrogen in the rat uterus. However, the relationship between estrogens and uterine cAMP remains controversial. ... Estradiol benzoate (EB) /and/ chlordecone (Kepone) when administered in doses that provided equal increases in uterine weight, produced equivalent decreases in uterine cAMP content. Although the decrease in cAMP was apparent within 48 hr, it was more pronounced at 72 hr. There was no reduction in cAMP produced in response to direct stimulation of uterine adenylyl cyclase by forskolin [Johnson DC et al; Proc Soc Exp Biol 210 (1): 33-38 (1995) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In an inhalation study reported in a review, male rats were exposed to test and control dusts for 2 h per day for 10 days and killed 2 weeks later. Air flow was maintained at 10 - 12 L/min, and the effective chlordecone concentrations were 3.7 and 15.4 ug/L. The reviewer concluded, contrary to the authors of the actual study, that chlordecone at both dose levels induced toxic effects, including hepatomegaly and histopathological changes in the liver and lungs. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Application of 0.25 and 0.5 g of the active ingredient (in ant bait) to the skin of rabbits (five 24 hr exposures over a 3 week period) produced no signs of local irritation, no effect on body weight, and no significant micropathological organ changes. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male rats fed 10, 50, and 150 ppm kepone in diet for 15 days. Volume of bile flow increased at highest concentration. Inhibition of magnesium(2+) atpase (matpase) was 34% at 50 ppm and 40% at 150 ppm. At 10 ppm no significant inhibition of this enzyme system was noted. [CURTIS LR, MEHENDALE HM; TOXICOL APPL PHARMACOL 47 (2): 295-304 (1979) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Male and female Sherman rats were fed 0 and 25 ppm chlordecone for 3 months. After this, rats were fed control diet for 4.5 months. During this recovery period they were bred twice. Reproduction in females was completely inhibited and hyperplasia of adrenal cortex noted. Livers were enlarged. [CANNON SB, KIMBROUGH RD; TOXICOL APPL PHARMACOL 47 (3): 469-76 (1979) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Groups of 5 male Sprague Dawley rats (150-175 g) were fed a control diet or a diet containing 100 ppm chlordecone for 5, 15, or 20 days. Weight of the period epididymal fat pads was taken as the anatomical marker for the depletion of body fat. The reduction in epididymal fat reached a maximum of 60% in the chlordecone fed animals after 20 days. Circulating ketone bodies were not different in any of the treated animal groups, indicating that chlordecone treatment does not result in metabolic ketosis. It appears that chlordecone induces a depletion of body fat stores as a consequence of altered energy balance of the animal. [Klingensmith JS, Mehendale HM; J Toxicol Environ Health 10 (1): 121-9 (1982) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Male rats were fed diets of 10, 50 or 150 mg/kg chlordecone for 15 days. Studies showed decreased biliary excretion at 10 mg/kg and higher, body weight gain was affected at 50 mg/kg and higher and liver enlargement at all 3 levels of treatment /From table/ [Menedale HM et al; Toxicol Appl Pharmacol 44: 171-80 (1978) as cited in WHO; Environ Health Criteria: Chlordecone p.25 (1984) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: A study has been reported in which chlordecone concentrations equivalent to 5 and 10 mg/kg body weight were tested on groups of 6 male albino rats for 3 weeks, totalling 15 applications; the animals were killed 2 weeks after termination of exposure. Two out of 6 animals in the low-dose group and 1 out of 6 in the high-dose group showed testicular atrophy. Otherwise, there were no consistent or significant pathological changes. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Dogs exposed to Kepone for 17 months at dietary levels of 1, 5, or 25 ppm did not display significant in vivo clinical changes except for a small suppression of body weight gains at 25 ppm. Examination of tissues indicated increased organ weights for the heart, kidneys, and liver at the highest dose level. No other changes were attributable to Kepone administration. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Rats were fed 1, 5, 10, 25, 50, and 80 ppm Kepone for 2 years. All fed 50 and 80 ppm died during 1st 6 months. Depressed growth at 10 ppm for females and 25 ppm for males was noted. Food consumption increased as levels of Kepone increased associated with increased metabolic rate. Proteinuria at 5 ppm and higher. Increased liver-to-body weight ratios were observed. Other organ weight increases were kidney, heart, spleen, and testes, at higher oral concentration of Kepone than required for liver. Pathological findings in liver were fatty degeneration and hyperplasia. [Larson PS et al; Toxicol Appl Pharmacol 48 (1): 29-41 (1979) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 50 male and 50 female B6C3F1 hybrid mice, approx 6 wk of age, were fed technical-grade chlordecone (about 98% pure) at two levels in the diet for 80 wk; there were 20 male and 10 female matched controls and 50 male and 40 female pooled controls. Males received initial levels of 40 mg/kg diet, and females 40 and 80 mg/kg diet; these levels were reduced /later/ ... . Well-differentiated hepatocellular carcinomas were found in over 80% of all treated males: in 39/48 low- and 43/49 high-dose males, compared with 6/19 matched male controls; and 26/50 low- and 23/49 high-dose females, compared with none in female controls. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 70 (1979)]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 50 male and 50 female Osborne-Mendel rats, approx 6 wk of age, were administered chlordecone (about 98% pure) in the diet for 80 weeks; there were 10 male and 10 female matched controls and 105 male and 100 female pooled controls. ... The time-weighted avg dietary concentrations were 8 and 24 mg/kg diet for males and 18 and 26 mg/kg diet for females. ... Hepatocellular carcinomas ... in female rats given the high dose: 10/45 compared with 0/100 pooled controls ... 3/44 hepatocellular carcinomas in high-dose males compared with 0/105 in pooled controls ... neoplastic nodules were dagnosed in 2 low-dose male rats, but none in the controls or in the high-dose group, and in 2 high-dose female rats, with 1 in the controls and none in the low-dose group. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 72 (1979)]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: The administration of chlordecone (Kepone) in feed resulted in a significant increase in hepatocellular carcinomas in both rats and mice. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 1080]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Outbred Sprague Dawley rats of both sexes were exposed to chlordecone in 2 separate expt. In expt 1, male rats (180-198 g) were subjected to 2/3 hepatectomy and 24 hr later were given 20 mg/kg diethylnitrosamine by gavage (initiation treatment). After 10 days, rats began receiving biweekly sc injections of 0.17 to 3.4 mg/kg chlordecone for 44 wk (promotion treatment). Control groups included rats admin diethylnitrosamine only after hepatectomy, as well as those whose livers were not initiated, but who received biweekly injections of either chlordecone or corn oil. One group was also given a single initiation treatment with 30 mg/kg chlordecone in corn oil given by gavage 24 hr after hepatectomy, followed by daily oral sodium phenobarbital (0.05%) treatment for 44 wk. Expt 2 was similar, except that females were also included and promotion treatment was for 27 wk, with chlordecone being admin biweekly by sc injection at 3 and 9 mg/kg body wt. Growth rates of both male and female rats were similarly suppressed by chlordecone when admin at 9.0 mg/kg biweekly. Wt gains for females exposed to 3.0 mg/kg also were affected. Toxicity at doses > or = 3.0 mg/kg biweekly included increased irritability, but no obvious tremors, sporadic dermatologic changes and liver enlargement. There was a dramatic sex difference in the incidence of malignant liver tumors caused by chlordecone promotion in rats. Frank hepatocellular carcinomas were observed only in female rats (11.1% at 3 mg/kg and 62.5% at 9 mg/kg) whose livers were previously initiated with diethylnitrosamine and then promoted for 27 wk. In contrast, none of comparably treated males had malignant liver tumors, even after 44 wk of promotion. Females in the diethylnitrosamine-initiated/chlordecone-promotion groups also contained gamma-glutamyltranspeptidase-positive 'preneoplastic' hepatocellular foci that were more abundant (55.5% and 75.0% of females at 3 and 9 mg/kg) and larger than those observed in comparably treated males. Dose-response expt showed that the hepatocarcinogenic effects of chlordecone admin became undetectable at concn in non-initiated rat liver in the same range (2.5 to 103 ug/g) as those measured in human biopsies taken from exposed workers who exhibited no liver effects (13 to 173 ug/g). Similar levels of chlordecone were measured in the livers of both sexes given only 3 or 9 mg/kg chlordecone (26.6 and 30.4 ug/g liver for males and 18.1 and 22.4 ug/g liver for females, respectively) at the end of the exptl period. [Sirica AE et al; Carcinogenesis 10 (6): 1047-54 (1989) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Female CD-1 mice were exposed to chlordecone for 5 consecutive days for each of 4 consecutive weeks (0.25 mg/day). ...Twice as many medium-sized follicles were found in the estradiol-17 (E-17) beta-treated mice as in both the chlordecone-exposed and sesame oil control groups. Both pesticide- and E-17 beta-exposed mice displayed a much higher percent of atresia in the large follicles; however, there were more actual healthy, large follicles in the E-17 beta group. Thus, both chlordecone and E-17 beta induced increased atresia among large follicles. [Swartz WJ, Mall GM; Reprod Toxicol 3 (3): 203-206 (1989) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The reproductive performance of mice fed 0, 10, 30, or 37.5 mg chlordecone/kg diet was impaired in terms of offspring and litter size. No litters were produced by females fed 40 mg/kg, but litter production did resume within 7 weeks following withdrawal of the chlordecone, although litters were still smaller than those of untreated controls. Histological examination of the testes showed they were normal, but corpora lutea were virtually absent from the ovaries. The authors concluded that reproductive failure was largely due to an effect in females characterized by prolonged FSH and estrogen stimulation, inducing constant estrus, large follicles and absence of corpora lutea but with levels of LH subminimal for ovulation. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Both egg laying and chick survival were reduced in domestic hens fed 75 or 150 mg chlordecone/kg diet for 12 weeks. Only 56% of chicks hatched from hens treated with 75 mg/kg survived for 20 days, no chicks or hens treated with 100 mg/kg survived. Residues were still detectable in eggs laid 3 weeks after treatment ceased. Eggshell deposition was affected by chlordecone. A peculiarly thick spongy layer developed leading to blockage of shell pores and suffocation of the embryo [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: At 6 mo of age female rat offspring exposed prenatally to kepone exhibited persistent vaginal estrus, anovulation and tonic levels of serum estradiol. Reproductive aberrations are probably due to alteration of hypothalamic differentiation during prenatal development. [GELLERT RJ, WILSON C; ENVIRON RES 18 (2): 437-43 (1979) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Adult male rats were fed diets containing 0, 5, 15, & 30 ppm chlordecone for 90 days & then either bred to untreated females or sacrificed. Reproductive performance was unaffected, and no histologic changes in the male sex organs could be attributed to chlordecone treatment. Reversible decreases in the motility & viability of epididymal spermatozoa & decreased sperm reserves in the cauda epididymidis were observed in rats fed 15 or 30 ppm. [Linder RE et al; J Toxicol Environ Health 12 (2-3): 183-92 (1983) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The effects of chlordecone on vaginal estrus and neuroendocrine responses were examined in adult ovariectomized and intact females. Persistent vaginal estrus was seen in females given 50 mg/kg or more of chlordecone. The development of vaginal estrus was similar to that seen in ovariectomized females after treatment with estrogen. Chlordecone increased serum prolactin and decreased serum luteinizing hormone (LH) in ovariectomized females 30 to 36 hr after a single exposure to 50 mg/kg of the pesticide. These results indicate an effect on the hypothalamic pituitary axis by chlordecone treatment and offer a possible explanation for the reduced fertility seen in adult females after chlordecone exposure. Although chlordecone produced peripheral changes in the vaginal smear pattern as well as neuroendocrine alterations, the peripheral changes were not always indicative of the neuroendocrine events. [Uphouse L et al; Toxicol Appl Pharmacol 72 (2): 177-86 (1984) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The effects of chlordecone on fertility were examined in adult, intact female rats. Rats were treated with 25, 50 or 75 mg/kg chlordecone and initial exposure occurred either on the morning before mating or on the morning after mating. When exposure occurred on the morning of proestrus, mating behavior 8 to 9 hours was significantly reduced by 50 or 75 mg/kg chlordecone. Yet, when housed overnight with sexually experienced males, most females showed sperm in the vaginal smear. However, only 23% of the 50 mg/kg group and none of the 75 mg/kg group delivered offspring. Females given 25 mg/kg chlordecone showed behavior and fertility identical to /control vehical/ injected controls. When females were treated with chlordecone after mating, 41% of the females given 50 mg/kg chlordecone produced litters while 33% of the 75 mg/kg females delivered offspring. Under both conditions, fertility was substantially reduced. In previous studies, chlordecone's reduction of the preovulatory luteinizing hormone (LH) surge has been offered as an explanation for the pesticide's reproductive deficits. The present studies indicate that the failure of chlordecone-treated females to ovulate cannot totally account for the decreased fertility. [Uphouse L; Neurobehav Toxicol Teratol. 8(2):121-6 (1986) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Chlordecone was administered by gastric intubation in doses of 2, 6, and 10 mg/kg body weight per day to rats and 2, 4, 8, and 12 mg/kg body weight per day to mice on days 7 - 16 of gestation. In rats, the highest dose caused 19% maternal mortality and fetuses exhibited reduced weight, reduced degree of ossification, edema, undescended testes, enlarged renal pelvis, and enlarged cerebral ventricles. Lower dose levels induced reductions in fetal weight and degree of ossification. Male rats born to treated dams did not show any reproductive impairment. In the mouse, fetotoxicity was observed only at the highest dose level and consisted of increased fetal mortality and clubfoot. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The effect of chlordecone on murine follicular development was examined in female CD-1 mice. Mice were exposed to chlordecone for 5 consecutive days for each of 4 consecutive wk (0.25 mg/day). Controls received sesame oil vehicle or estradiol-17beta (0.1 mg/day) since chlordecone has been ascribed estrogenic activity. Mice were sacrificed 24 hr following the final exposure. Ovaries were removed, serially sectioned, and stained. Follicles were classified as small, medium, or large and were tabulated. Twice as many medium-sized follicles were found in the estradiol-17beta-treated mice as in both the chlordecone-exposed and sesame oil control groups. Both chlordecone- and estradiol-17beta-exposed mice displayed a much higher percent of atresia in the large follicles; however, there were more actual healthy, large follicles in the estradiol-17beta group. [Swartz WJ, Mall GM; Reprod Toxicol 3 (3): 203-6 (1989) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ...Chlordecone... exhibits uterotropic actions in experimental animals. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 676]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Chlordecone was administered to female rats at concentrations of 2.5 mg/kg body weight per day and to mice at 6.0 - 24 mg/kg body weight per day on days 7 - 16 of gestation and also postpartum. Although there were toxic manifestations in the mother (death) and fetuses (litter mortality, decreased litter weight), ophthalmological studies did not reveal cataracts or outlined lenses. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Intraperitoneal injection of chlordecone into adult virgin female Holtzman strain rats before mating, in doses as high as 80 mg/kg, did not prevent fertilization, early development of the embryo to the blastocyst stage, transport of the embryo through the oviduct, or its implantation into the uterus. However, a single dose of 60 or 80 mg/kg, but not 20 or 40 mg/kg, before mating significantly reduced the concentration of progesterone in the serum of rats undergoing normal embryo implantation 5 days later. A dose of 80 mg/kg of chlordecone reduced progesterone levels in the serum by more than 50% within 48 hr in ovariectomized rats with Silastic tubing implants containing crystalline progesterone. ... The minimal effective single dose of chlordecone to initiate implantation of blastocysts in the uteri of hypophysectomized progesterone-primed rats, and to maintain embryo development for at least 5 days, was 50 mg/kg. Daily doses of 20 mg/kg for 3 or 5 days were effective at initiating implantation but did not maintain pregnancy. [Johnson DC et al; Proc Soc Exp Biol Med 195 (1): 44-50 (1990) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Chlordecone treatment led to the presence of vaginal estrus within 2 days, but reduced or eliminated sexual behavior on the evening of predicted proestrus. Of the females that received chlordecone, 20% to 50% showed some behavior on the day after the evening of predicted proestrus and 20% to 35% never showed behavior during the 8-day observation period. [Williams J, Uphouse L; Reprod Toxicol 5 (1): 65-71 (1991) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Levels of norepinephrine, dopamine, serotonin, & the serotonin metabolite, 5-hydroxyindole acetic acid were determined in brains of mice after daily oral administration of 10, 25 or 50 mg/kg of chlordecone until mortality occurred. Significant decreases in whole brain & striated dopamine levels were observed in chlordecone treated mice exhibiting tremors. The serotonin levels were elevated only in animals exhibiting severe tremors. In Mirex treated animals, the norepinephrine levels were not altered by chlordecone. [Fujimori K et al; Neurotoxicology 3 (2): 143-8 (1982) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: A single injection of chlordecone (1 mg/pup on day 4 of age) reduced the level of (Met5)-enkephalin at 70 & 120 days of age in male rats but not in females. The same treatment caused a transient reduction in the hypothalamic beta-endorphin level in both male & female rats without affecting the levels of other neuropeptides in the hypothalamus & other brain regions. These results suggest that the hypothalamo-pituitary axis may be the primary neural target to the chlordecone-elicited decrease in pituitary (Met5)-enkephalin level. [Hong JS, Ali SF; Neurotoxicol 3 (2): 111-8 (1982) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Chlordecone was administered orally to young (4-6 wk old) and old (6 mo old) mice in a dose of 25 mg/kg/day in 10 mL/kg corn oil. Age matched control mice received 10 mL/kg/day corn oil. The acute (24 hr after a single dose) and subchronic (24 hr after 8 daily doses) effects of chlordecone on content & subcellular distribution of calcium in the brain were studied. Significant differences in calcium content and subcellular distribution were found between the young and old control mice. Acute exposure to chlordecone (no signs of neurotoxicity) increased significantly total brain, protein bound, nuclear, mitochondrial, and myelin calcium in brains from young mice. However, old mice had significantly decreased total brain, protein bound, & mitochondrial calcium with significantly increased nuclear calcium content. When young mice received chlordecone for 8 days and were suffering severe chlordecone induced tremors, at the times of sacrifice, their brains were found to have decreased total, protein bound, myelin, and synaptosomal calcium. Nuclear calcium was increased. Tremors induced by chlordecone might be due to chlordecone induced calcium deficiency in brain synaptosomes. [Hoskins B, Ho IK; J Toxicol Environ Health 9 (4): 535-44 (1982) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Male Sprague Dawley rats were fed with chlordecone by gastric intubation at 10, 25, and 50 mg/kg/day for 3 days. Control rats received 0.3 mL of corn oil. Complete body movements (including tremors) were monitored for a period of 12 hr, and at 24, 48, & 72 hr after treatment. Rats receiving chlordecone showed an increased tremor activity which was significant and dose dependent. The brain synaptosomal sodium-potassium ion and oligomycin sensitive magnesium ion ATPases were significantly decreased in chlordecone treated rats. A linear relationship was observed between the decreases in ATPase activities and tremor activity. These results suggest that the inhibition of the ATPase system in the brain may be related to the production of the neurotoxic symptoms. [Jordan JE et al; Neurotoxicol 2 (2): 355-64 (1981) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Male and female Fischer 344 rat pups were exposed to kepone by subcutaneous injection on day 4 postnatally. Kepone had transient effects on body weights and resulted in precocial vaginal opening. At approx 100 days of age, one half of the animals were trained on a variable interval (VI) 15 sec schedule of food reinforcement. Rates of free operant activity differed during training of the variable interval and chlordecone treated females had lower baselines than controls following establishment of baseline responding. Baselines of males were not affected. Chlordecone exposed rats were affected the same as controls by amphetamine and apomorphine. The remaining rats were trained to make a visually cued nose poke response for food in a discrete trial discrimination task over a 3 wk period. Marked alterations in responding were observed during 2 wk of reversal. These data indicate that a single postnatal injection of chlordecone can produce subtle, long lasting neurobehavioral changes in rats. The nature of these changes appear to be alterations in their reactivity to novel or changing conditions. [Tilson HA et al; Neurotoxicol 3 (2): 45-57 (1982) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: The brain and plasma levels of chlordecone were monitored after daily oral admin of chlordecone at 10 or 50 mg/kg/day to mice. At a low dose, the plasma level of chlordecone increased steadily and the brain level showed a steady increase and then a plateau. At the higher dose the brain and plasma concentration of chlordecone decayed biphasically. The chlordecone-induced neurotoxicity correlated closely with both brain and plasma concn of chlordecone. This study established the threshold levels of chlordecone in plasma and brain for motor incoordination and mortality in the mouse. [Wang TP et al; Neurotoxicology 2 (2): 373-81 (1981) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: ...Proestrous treatment with chlordecone attenuated the increase in 5-HT and in 3H-5-HT binding but had no effect on 5-HIAA. ... The 5-HT1A agonist, 8-OH-DPAT, was an inefficient competitor for 3H-5-HT binding in frontal cortex of females treated with chlordecone. [Williams J et al; Neurotoxicology 9 (4): 597-610 (1988) ]**PEER REVIEWED**
  • GENOTOXICITY: Kepone did not revert Salmonella strains Ta 1535, Ta 1537, Ta 98, or Ta100 when tested with or without metabolic activation. [Schoeny RS et al; Mutat Res 68 (2): 125-32 (1979) ]**PEER REVIEWED**
  • GENOTOXICITY: Cytological and cytotoxic effects of kepone on Chinese hamster cells (M3-1) were investigated. Cells treated with 2 ug, 4 ug, or 6 ug/ml of kepone did not show any morphological abnormalities. Cytological observations showed that chromosome breaks, chromatid breaks, dicentric chromosomes, and chromosome interchanges were produced by these treatments. Cell toxicity was greater at the 30 ug/ml concn, producing 100% cell death within 24 hr. [Bale SS; J Hered 74 (2): 123-4 (1983) ]**PEER REVIEWED**
  • GENOTOXICITY: Chlordecone was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Chlordecone was tested at doses of 0.03, 0.10, 0.30, 1.0, 3.3, 10, 33, and 100 ug/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9. Chlorodecone was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 100 ug/plate. At this dose, slight clearing of the background bacterial lawn occurred in 3 strains. [Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) ]**PEER REVIEWED**
  • GENOTOXICITY: ... Kepone is negative when tested as a mutagen in the point mutation assay in the Ames test or in the DNA repair test in rat liver cells. This is in keeping with the fact that several other organochlorine pesticides which cause liver cancer in rodents are nevertheless negative or only weakly positive when examined in mutagenesis tests. Thus, one may speculate that such agents may not be directly carcinogenic, but may serve as promoters for other endogenous or environmental carcinogens. [Haddad, L.M. and Winchester, J.F. Clinical Management of Poisoning and Drug Overdosage. Philadelphia, PA: W.B. Saunders Co., 1983., p. 354]**PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: In vitro, chlordecone was a remarkably potent inhibitor of brain mitochondrial oxidative phosphorylation and associated calcium ion transport. At a high concn of chlordecone (1x10-5 M), destabilization of biological membranes was observed. [End DW et al; J Toxicol Environ Health 8 (5-6): 707-18 (1981) ]**PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: ... Chlordecone (CD) in vitro inhibited (45)Ca-uptake by sarcoplamic reticulum (SR) in a concentration dependent manner with an IC50 value of 7 microM and SR (45)Ca-uptake was totally inhibited at 20-30 microM CD. Both high affinity and low affinity Ca2(+)-ATPases were also inhibited by CD in a concentration dependent manner with IC50 values of 0.7 and 3.2 microM respectively. Both Ca2(+)-ATPase and (45)Ca-uptake by cardiac SR were significantly lower in rats treated with CD (25, 50 or 75 mg/kg) when compared to control rats. cAMP as well as calmodulin (CaM) significantly elevated the 32P-binding to SR proteins in vitro to about 70-80%. [Kodavanti PR et al; Pharmacol Toxicol 67 (3): 227-234 (1990) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... Primary cultures of rat hepatocytes were treated with phenobarbital (PB) or one of several organochlorine pesticides, including Mirex, there was co-induction of cytochrome P450 2B1 and 2B2 mRNAs and immunoreactive proteins, whereas Kepone selectively induced 2B2. Indeed, Kepone treatment actively suppressed induction of 2B1 and 2B2 mRNAs in hepatocytes cotreated with phenobarbital. Because Kepone differs chemically from Mirex only in the replacement of 2 chlorine atoms with a ketone group, which exists in aqueous solution as a gem-diol and appears to confer weak estrogenic properties, we treated hepatocyte cultures with one of 3 potent estrogens, beta-estradiol, 17 alpha-ethinylestradiol or diethylstilbestrol. Treatment with each of these estrogens induced 2B1 and 2B2 mRNA only at very high doses (10(-4) M). Beta-Estradiol (10(-4) M) treatment also induced 2B1/2 mRNA in hepatocyte cultures prepared from a prepubescent female rat. The anti-estrogen tamoxifen failed to reverse 2B1/2 mRNA induction following beta-estradiol or Kepone treatment of adult hepatocyte cultures. High doses of beta-estradiol or 17 alpha-ethinylestradiol failed to induce 2B1/2 mRNA in treated rats. We also examined the effects of chloral hydrate, a simple gem-diol, on 2B1/2 mRNA induction in the hepatocyte cultures. Treatment with chloral hydrate (3 x 10(-3) M), like Kepone (10(-5) M), suppressed 2B1/2 mRNA induction following phenobarbital (10(-4) M) treatment, while Kepone alcohol (10(-5) M), which is not a gem-diol, produced less suppression. Our results suggest that selective induction by Kepone of 2B2 is unlikely related to its effects as a weak classical estrogen, while the ability of Kepone to suppress induction of 2B1 and 2B2 by PB may be related to its properties as a gem-diol. [Kocarek TA et al; Toxicol Lett 71 (2): 183-196 (1994) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... Mice treated intraperitoneally with low (6 mg/kg) and high (30 mg/kg) doses of chlordecone in corn oil for 2 days ... significantly increased the hepatic microsomal P-450 content over that of controls. [Lewandowski M et al; J Biochem Toxicol 4 (3): 195-199 (1989) ]**PEER REVIEWED**
  • GENOTOXICITY: ... Whereas carbon tetrachloride alone was not genotoxic, chlordecone or chlordecone in combination with carbon tetrachloride was genotoxic. [Ikegwuonu FI, Mehendale HM; J Appl Toxicol 11 (4): 303-310 (1991) ]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 95 mg/kg [Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. Park Ridge, NJ: Noyes Data Corporation. 1980., p. 172]**PEER REVIEWED**
  • LD50 Dog oral 250 mg/kg [Larson, L.L., Kenaga, E.E., Morgan, R.W. Commercial and Experimental Organic Insecticides. 1985 Revision. College Park, MD: Entomological Society of America, 1985., p. 22]**PEER REVIEWED**
  • LD50 Rabbit subcutaneous 345-475 mg/kg [Larson, L.L., Kenaga, E.E., Morgan, R.W. Commercial and Experimental Organic Insecticides. 1985 Revision. College Park, MD: Entomological Society of America, 1985., p. 22]**PEER REVIEWED**
  • LD50 Rabbit oral 65 mg/kg [WHO; Environ Health Criteria: Chlordecone p.24 (1984)]**PEER REVIEWED**
  • LD50 Chicken oral 480 mg/kg [WHO; Environ Health Criteria: Chlordecone p.24 (1984)]**PEER REVIEWED**
  • LD50 Pig oral 2550 mg/kg (approx) [WHO; Environ Health Criteria: Chlordecone p.24 (1984)]**PEER REVIEWED**
  • LD50 Rat (male) oral 132 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • LD50 Rat (female) oral 126 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • LD50 Rabbit (male) oral 71 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • LD50 Rabbit (male) percutaneous 410 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • LD50 Rat (female) dermal 2000 mg/kg /in xylene vehicle/ [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • LD50 Rat (male) dermal 2000 mg/kg /in xylene vehicle/ [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • ... Green neon shrimp (Neocaridina denticulata) were exposed to chlordane and lindane to estimate the 96-h LC(50)(96-h median lethal concentration). Then, levels of testosterone and vitellogenin in hemolymph of N. denticulata after exposure to sublethal concentrations of chlordane (1 ng/L and 10 ng/L) and lindane (0.1 microg/L and 1 microg/L) were also examined. The 96-h LC(50) values obtained from the results of acute exposure were 127.03 (130.11-122.35) ng/L and 9.36 (8.00-10.96) microg/L for chlordane and lindane, respectively. Furthermore, reductions of testosterone concentration were observed in both chlordane- and lindane-treated shrimps, whereas induction of vitellogenin-like protein was only apparent in chlordane-treated shrimps. [Huang DJ, Chen HC; Int J Toxicol 23 (2): 91-95 (2004) ]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Kepone is absorbed from the GI tract and by way of the lungs and skin. It is retained primarily in the liver but also in the brain, kidneys, and fat. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 663]**PEER REVIEWED**
  • Tissue-to-blood ratios for the liver, fat, muscle, and gallbladder bile were 15, 6.7,2.9, and 2.5, respectively. The high concentration in blood as compared to its concentration in fat (1 versus 6.7) may be explained by the fact that chlordecone is bound specifically by the proteins in plasma, particularly high-density lipoproteins (HDLs), unlike most organochlorine pesticides which distribute among tissues in direct proportion to the concentration of tissue fat. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • Chlordecone was present in high concentrations in the liver (mean and range) (75.9 mg/kg; 13.3 - 173 mg/kg), whole blood (5.8 mg/L, 0.6 - 32 mg/L), and subcutaneous fat (21.5 mg/kg, 2.2 - 62 mg/kg) of 32 male workers. … In occupationally-exposed workers, serum chlordecone concentrations ranged from 120 to 2109 µg/L. Six to 7 months later, the concentration dropped to 37 - 486 µg/L. [WHO; Environmental Health Criteria Document No. 43: Chlordecone (143-50-0). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  • In rats, chlordecone was absorbed and distributed to various tissues, with the highest concentrations being found in the liver. Chlordecone was detected in the liver (125.8 mg/kg), adipose tissue (27.3 mg/kg), kidney (25.2 mg/kg), and plasma (4.9 mg/L) of rats 8 days following a single oral dose of 50 mg/kg. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • Chlordecone accumulates in maternal tissues, readily crosses the placenta of rats, and accumulates in fetal tissues. Four hours following a single oral dose of 5 mg/kg, maximal concentrations of chlordecone in the placenta ranged from 3.5 to 4 ppm. Concentrations of chlordecone in the placenta remained steady for up to 48 hours postdosing. Chlordecone levels in the fetus were generally highest in the liver, followed by the brain, heart, and kidney. Concentrations increased during the first 24 hours after dosing and declined in the second 24-hour period, regardless of gestation age at the time of dosing. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • The preferential distribution of the relatively non-polar pesticide chlordecone (CD) to liver rather than to fat tissues in humans suggests that it may be transported in plasma differently from other organochlorine pesticides. The plasma binding of (14)carbon-CD is investigated in vitro in human, rat, and pig plasma and in vivo rat plasma. Protein and lipoprotein fractions were separated by serial ultracentrifugation. Heparin-manganese precipitation and agarose gel electrophoresis were also carried out to determine whether separation techniques altered CD binding to plasma components. In human plasma, the distribution of (14)carbon-CD among proteins and high density, low density, and very low density lipoproteins (HDL, LDL, and VLDL) was 46, 30, 20, and 6%, respectively. [Guzelian PS et al; J Toxicol Environ Health 9 (1): 107-11 (1982)]**PEER REVIEWED**
  • Studies show that pretreatment with an inducer (phenobarbital) or inhibitor (SKF-525A) of P-450 causes an alteration in the distribution of chlordecone in rats. Following a single oral dose of chlordecone alone, the liver had the highest levels of chlordecone, followed by the adrenal gland, lung, kidney, and spinal cord. Pretreatment with Phenobarbital (particularly with multiple phenobarbital doses) caused an increase in the accumulation of chlordecone in the liver compared to animals given no pretreatment. This hepatic increase resulted in a significant decrease of chlordecone levels in other tissue (e.g., brain, kidney, muscle) as well as significantly reduced excretion. Pretreatment with SKF-525A caused a nonsignificant reduction in chlordecone levels in the liver and significant increases in the digestive system tissues. The results of the chlordecone distribution following SKF-525A pre-dosing must be interpreted with caution, since the effects may have resulted partly from SKF-525A-mediated decreases in absorption of the chlordecone. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • In expt 1, C57BL/6N (B6) and DBA/2N (D2) male mice received by ip injection a pretreatment of unlabeled chlordecone (5 mg/kg) in corn oil or corn oil alone (control). 1, 3, 7, or 14 days after pretreatment, (14)C-labeled chlordecone (5 mg/kg) was admin by ip injection. 16 hr later the mice were killed, and blood and tissues were analyzed. In a second set of expt, B6 and D2 mice received either corn oil or chlordecone in corn oil ip 3 days before the admin of a 1-uCi tracer dose chlordecone. Mice were killed 1, 3, 8 or 16 hr after the tracer. In the third expt, B6 and D2 mice received a pretreatment of corn oil or 1, 5, 15, or 40 mg/kg chlordecone in corn oil 3 days before the admin of a 5 mg/kg tracer dose of chlordecone. 6 hr after admin of tracer, the mice were killed. In the fourth expt, B6 and D2 mice were injected ip with chlordecone (5 mg/kg) in corn oil, or corn oil alone. Three days after pretreatment, (14)C chlordecone doses of 1, 5, 15, or 40 mg/kg were admin by ip injection. Mice were killed and tissues were examined 16 hr after the tracer dose. Hepatic levels of (14)C in the B6 mice were higher than those in any of the other tissues examined, but there were no apparent differences in (14)C content between the pretreatment and control groups until 7 days after treatment. Here, (14)C levels were lower in the pretreated group (78% of controls). In contrast, amounts of (14)C in the lung, kidney, and fat of the pretreated group were higher (134, 144, and 190% respectively) than controls 3 days after chlordecone. Although hepatic levels of (14)C were also higher in the D2 mice, response to pretreatment was different. Livers were rapidly affected, exhibiting decreased (14)C levels 1 day after pretreatment (72% of controls). Admin of chlordecone to mice caused a time-dependent alteration in the pattern of distribution of the subsequently admin dose of tracer. [Carpenter HM, Curtis LR; Drug Metab Dispos 17 (2): 131-8 (1989)]**PEER REVIEWED**
  • ... The levels of Kepone residues /were assayed/ in the gonads of male and female mice by feeding them a daily diet containing 40 ppm for an extended period. /The/ ... data indicate that the levels of Kepone in the gonads remain constant and slightly lower than those found in the brain, or at levels rather comparable to those in muscle. [Matsumura, F. Toxicology of Insecticides. 2nd ed. New York, NY: Plenum Press, 1985., p. 372]**PEER REVIEWED**
  • ... Pregnant mice /were fed/ 40 ppm of Kepone in the diet and ... on the avg 5 ppm accumulated in seven embryos weighing 0.3 g. This is a comparable level to that in the maternal brains but is considerably lower than the levels found in their livers (45 ppm) and fat (13 ppm). [Matsumura, F. Toxicology of Insecticides. 2nd ed. New York, NY: Plenum Press, 1985., p. 369]**PEER REVIEWED**
  • Male sprague-dawley rats received (14)carbon labeled kepone in corn oil by gastric intubation. Radioactivity detected in adrenal gland, blood, and liver. 12.7% of radioactive kepone was excreted by feces of rats during first 24 hr, 2.9% 2nd 24 hr, & 3.3% 3rd 24 hr. Total of 29.5% excreted by end of 1st wk. Rate then steadily declined & after 182 days total excretion was 69.8%. Urinary excretion by 84 days was only 1.6%. [EGLE JL JR ET AL; DRUG METAB DISPOS 6 (1): 91-5 (1978) ]**PEER REVIEWED**
  • Workers excreted larger amount in bile than in stool, which suggests that it may undergo enterohepatic recirculation. In one person, equal amounts of chlordecone and its reduced metabolite, chlordecone alc, excreted in bile at a rate 4 times as great as in stool. When biliary contents diverted from intestines through t-tube, fecal excretion of chlordecone alcohol was abolished. It was concluded that chlordecone enters intestinal lumen from nonbiliary source, probably gut, and that net excretion of chlordecone can be increased by cholestyramine. (14)carbon chlordecone treated rats in which bile flow exteriorized through cannula showed that excretion of radioactivity in feces was in same range when bile was reinfused in duodenum or was completely diverted. [BOYLAN JJ ET AL; CLIN PHARMACOL THER 25 (5): 579-85 (1979) ]**PEER REVIEWED**
  • Metabolites of chlordecone have not been found in human tissues. The compound is primarily eliminated in bile, but is largely reabsorbed, so that the overall elimination rate is only 0.075% of the total body burden per day. Negligible amounts are excreted in urine and sweat. A single oral dose administered to rats was slowly excreted over a period of 84 days in feces (66%) and urine (1.6%), apparently as unchanged chlordecone. [Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 76 (1980)]**PEER REVIEWED**
  • Chlordecone and chlordecone alcohol (chlordecol) are excreted in the bile and eliminated via the feces of humans occupationally exposed to chlordecone. However, a substantial enterohepatic recirculation of chlordecone exists that curtails its excretion. Only 5-10% of the biliary chlordecone entering the lumen of the duodenum appeared in the feces. Similarly, the rate of chlordecone excretion in the bile was on the average 19 times greater than the rate of elimination of chlordecone in the stool. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • In rats, chlordecone is slowly eliminated in the feces. Rats given a single oral dose of 40 mg/kg 14C-chlordecone excreted 65.5% of the administered dose in the feces and 1.6% of the dose in the urine by 84 days. Less than 1% of the administered dose was expired as radiolabeled carbon dioxide (14 C-CO2). Rats fed 14C-chlordecone (0.2 mg/kg/day for 3 days) excreted 52.16% of the radioactivity in the feces and 0.52% in the urine 25 days post-dosing. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • Hens were fed 75 or 150 mg/kg diet chlordecone in their feed for 16 wk. After 5 wk of treatment, the chlordecone content of egg yolk was 163 and 336 mg/kg, respectively, for the two dosage levels. By the 13th wk, it was 100 and 214 mg/kg, respectively ... 3 week after treatment ... the chlordecone content was 26 and 70 mg/kg, respectively ... [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 75 (1979)]**PEER REVIEWED**
  • ... Cows fed 5.0 ppm in diet for 60 days excreted 90 ppb of kepone in milk 35 days after cessation of treated feeding ... [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 593]**PEER REVIEWED**
  • When chlordecone was fed to dairy cows in concentrations of 0.25-5.0 mg/kg in hay and in feed-concentrate for 60 days, the highest residue level in milk recorded from an individual cow was 0.44 mg/L. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 74 (1979)]**PEER REVIEWED**
  • In /rats, rabbits, and dogs/, the outstanding sign of intoxication was the development of severe DDT-like tremors. These reached maximum intensity (in surviving animals) 2-3 days following treatment. The tremors gradually subsided over a period of a week or longer. Exacerbation of the tremors occurred whenever an animals became excited, for example when handled. It was also noted that rats and pigs can develop a muscular weakness the second week after treatment that progresses through the seventh week, with a final phase of recovery within 6 months. Hyperexcitability and tremors were noted in mice the day following one oral dose of 50 mg Kepone/kg; mortality occurred on the fifth day. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 662]**PEER REVIEWED**
  • In 1978, white-footed mice were collected at Jamestown Island, Virginia, approximately 50 km downstream from Hopewell, Virginia, the site of a major industrial environmental contamination event involving kepone (chlordecone) in 1975. Concentrations of kepone in livers of mice from two sites on the Island were 2.74 and 0.80 mg/kg, compared to 0.16 mg/kg from an inland forest site located 4.8 km from the Jamestown Island. [Shore R.F., Rattner BA. Ecotoxicology of Wild Mammals. Ecological & Environmental Toxicology Series 2001. John Wiley & Sons, New York, N.Y. 2001, p. 224]**PEER REVIEWED**
  • ... [14C]Chlordecone (0.286 umol/sq cm) was applied to dorsal skin (2. 3% BSA) and radioactivity was quantified in selected tissues and excreta up to 120 hr. ... In vivo percutaneous absorption over 120 h was 14.4+/-0.99 and 14.2+/-1. 5% dose in young and adults, respectively. Organ and tissue content increased over time (carcass>liver>kidney). Statistical differences between young and old were found for liver, skin, and urine, but not for absorption. Excretion occurred primarily in feces, but also in urine. [Heatherington AC et al; Environ Res 79 (2): 138-155 (1998) ]**PEER REVIEWED**
  • When Kepone was fed to dairy cows in concentrations of 0.25-5.0 mg/kg in hay and in feed-concentrate for 60 days, the highest residue level in milk recorded from an individual cow was 0.44 mg/L. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20: 74 (1979)]**PEER REVIEWED**

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Metabolism/Metabolites

  • The fate of chlordecone in humans involves uptake by the liver, enzymatic reduction to chlordecone alcohol, conjugation with glucuronic acid, partial conversion to unidentified polar forms, and excretion of these metabolites mainly as glucuronide conjugates into bile. Of the total chlordecone measured in bile of occupationally exposed workers, the predominant portion (72%) was unconjugated, with only a small portion conjugated with glucuronic acid or sulfate (9%). The remaining fraction (19%) of total chlordecone measured in the bile was stable polar metabolites which were resistant to ß-glucuronidase. Following treatment of bile with ß-glucuronidase plus sulfatase, the ratio of total chlordecone to total chlordecone alcohol was 1:3 in human bile. [DHHS/ATSDR; Toxicological Profile for Mirex and Chlordecone (PB/95/264354) (August 1995). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  • In seeking a practical animal model only in gerbils was this organochlorine pesticide converted to chlordecone alcohol, a reduced metabolite found in the stool of chlordecone poisoned humans. Gerbils eliminated chlordecone alcohol exclusively in stool with none being detected in urine. Gerbils excreted chlordecone alcohol in bile in an amount more than twice that of chlordecone and in the form of a glucuronide conjugate. The ratio of chlordecone to chlordecone alcohol in gerbil stool was 10 times higher than the ratio in human stool. This suggests that the newly recognized nonbiliary mechanism(s) for entry of chlordecone into the intestinal lumen may be extremely active in the gerbil. Incubation of the cytosolic fraction of gerbil liver homogenate in the presence of reduced nicotinamide adenine dinucleotide and chlordecone produced chlordecone alcohol. Bioreduction of chlordecone is catalyzed in gerbil liver by a species-specific reductase. The livers of these (3)H-chlordecone alcohol treated animals also contained chlordecone in amounts eight times (rat) and 14 times (gerbil) higher than the respective amounts of chlordecone alcohol. From this result, the existence of a separate enzyme(s) catalyzing dehydrogenation of chlordecone alcohol to chlordecone may be inferred. [Houston TE et al; Fundam Appl Toxicol 1 (3): 293-8 (1981)]**PEER REVIEWED**
  • Induction patterns of rat hepatic microsomal mixed-function oxidases by pesticides and related chemicals were compared. Drug metabolizing activity of phenobarbital, DDT, chlordane, mirex, and kepone inducing liver microsomes was similar. [MADHUKAR BV, MATSUMURA F; PESTIC BIOCHEM PHYSIOL 11 (1-3): 301-8 (1979) ]**PEER REVIEWED**
  • ...The conjugate of decachlorooctahydro 1,3,4-metheno-2H-cyclobuta(c,d)pentalen-2-ol (chlordecone alcohol) in fecal specimens from patients diagnosed as suffering from Kepone poisoning. This metabolite is a result of reduction of the ketonic group by an aldo-keto reductase enzyme that was identified in the gerbil, rabbit, and human but not in rodents. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V5 663]**PEER REVIEWED**
  • Pigs were administered chlordecone by intraperitoneal injection. Plasma, gall bladder bile, hepatic bile, liver, and feces were collected and analyzed by gas chromatography for chlordecone metabolites. Chlordecone alcohol was present in bile and feces with up to 85% conjugated in the bile but only 15% was conjugated in the feces. Up to 20% of the chlordecone in plasma and bile and less than 3% in feces was in the conjugated form. Both reduction and conjugation of chlordecone in the pig are similar to those in man. [Soine PJ et al; Toxicol Lett 17 (1-2): 35-41 (1983)]**PEER REVIEWED**
  • Mirex is probably oxidized to chlordecone. The main metabolite of chlordecone is chlordecone alcohol, which appears in human bile as glucuronic acid conjugates. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1891]**PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008