National Toxicology Program

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

Names (NTP)

• Chlordane (analytical grade)
• 4,7-METHANO-1H-INDENE,1,2,4,5,6,7,8,8-OCTACHLORO-2,3,3A,7,7A-HEXAHYDRO (9CI)

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: It has been estimated that fatal oral dose for adult lies ... Between 6 & 60 g, with onset of symptoms within 45 min to several hours after ingestion. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-185]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: ... No illness among workers as a result of exposure to chlordane at 5 mg/cu m for from one to three years. Examination of 22 workers for signs and symptoms manifested in exposed animals, loss of weight, anorexia, nervous disorders and disturbances of vision and respiration, revealed none of these conditions during manufacture and formulation at air concentrations exceeding 5 mg/cu m. Moreover, it should be noted that the study was made at a time before newer production methods had refined the technical grade product and reduced its toxicity. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: The fatal human dose is estimated to be around 6 g, and convulsive symptoms have occured with as little as 2.25 g. Topical skin application of about 30 g to an adult resulted in death in 40 minutes ... . [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: To assay and profile chronic neurobehavioral impairment associated with chlordane exposure in symptomatic patients, consecutive evaluations of nine patients were done with sensitive neurophysiologic and neuropsychologic tests for neurobehavioral function. Their visual fields, balance, reaction time, blink, color discrimination, grip strength, cognitive function, recall, memory, and perceptual motor speed were tested, and mood states and frequencies of 35 symptoms were appraised. Prevalences of abnormality were compared test-by-test to predict values with confidence intervals, and mean values for the group were compared with reference values. Testing showed abnormal balance with eyes closed in 7, abnormal color discrimination in 6, verbal recall deficit in 5, and prolonged blink reflex latency, prolonged choice reaction time, and decreased Culture Fair scores in 4 each. Profile of Mood States score was elevated in 5. These observations suggest that chlordane causes protracted neurotoxicity. [Kilburn KH; South Med J 90(3): 299-304 (1997) ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Effects of over-exposure may include: shaking, blurred vision, irritability, confusion, delirium, and staggering, ... cough, vomiting, ataxia, and diarrhea. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 1]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Earliest signs of poisoning are increased sensitivity to stimuli due to hyperexcitability of the central nervous system, generalized hyperactive reflexes, muscle twitching, tremor, incoordination, ataxia, and clonic convulsions with or without coma. Cycles of excitement and depression may be repeated several times. Liver damage as a possible late manifestation. Anorexia and weight loss. Severe gastroenteritis has been described in one of the fatal human poisonings. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-109]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Organochlorines are CNS stimulators that produce apprehension, excitability, paresthesias, dizziness, headache, disorientation, and tremor progressing to stupor, coma, and convulsions in severe cases. Organochlorines may enhance myocardial irritability, leading to cardiac dysrhythmias after heavy exposures. Serious complications involve seizures with resultant hypoxemia, severe metabolic acidosis, and death. Intoxication from acute oral exposures generally begins within 45 minutes to several hours. Subacute toxicity has been reported after the extensive and careless use of chlordane over several weeks. Symptoms included paresthesias, anorexia, nausea, fatigue, and malaise. /Organochlorines/ [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. 1078]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Clinical manifestations following ingestion include apprehension, agitation, vomiting, gastrointestinal upset, abdominal pain, and CNS depression. Convulsions may occur at higher doses and may be preceded by symptoms of ataxia, muscle spasms, and fasciculations. /Chlorinated hydrocarbon insecticides/ [Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991., p. 935]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: The chief acute toxic action of the organochlorine pesticides is on the central nervous system, where these compounds interfere with fluxes of cations across nerve cell membranes, increasing neuronal irritability. This effect is manifest mainly as convulsions, sometimes limited to myoclonic jerking, but often expressed as violent seizures. ... Convulsions may cause death by interfering with pulmonary gas exchange and by generating severe metabolic acidosis. ... High tissue concentrations of organochlorines increase myocardial irritability, predioposing to cardiac arrhythmias. When tissue organochlorine concentrations drop below threshold levels, recovery from the poisoning occurs. Organochlorines are not cholinesterase inhibitors. /Solid organochlorine insecticides/ [U.S. Environmental Protection Agency/Office of Prevention, Pesticides, and Toxic Substances. Reigart, J.R., Roberts, J.R. Recognition and Management of Pesticide Poisonings. 5th ed. 1999. EPA Document No. EPA 735-R-98-003, and available in electronic format at: http://www.epa.gov/pesticides/safety/healthcare, p. 56]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Early use of chlordane often resulted in irritation of the eyes, mucous membranes, and/or skin of industrial and agricultural workers. This does not appear to have been a problem with the product manufactured since 1951. [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 654]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Over 250 adults and children were exposed to chlordane when the wooden building surfaces and soil around an apartment complex were sprayed in 1987. ... Performance of balance, reaction times, Culture Fair, digit symbol, verbal recall, and trail-making were significantly impaired in exposed persons compared to referents. Mood-state scores were elevated, as were the frequencies of respiratory, neurobehavioral, and rheumatic symptoms. In contrast, long-term memory function was similar in both groups. Chlordane exposure was associated with protracted impairment of neurophysiological and psychological functions. [Kilburn KH, Thornton JC; Environ Health Perspect 103 (7-8): 690-694 (1995) ]**PEER REVIEWED**
  
• CASE REPORTS: A 15-month-old girl ingested a mouthful of chlordane suspension and, after 3 h, displayed tremors and incoordination. Repeated seizures developed and she was treated with ethyl chloride, amobarbital, and gastric lavage with magnesium sulfate. The child recovered completely and ataxia and excitability disappeared after 2 - 3 weeks. At 26 years of age, she was in excellent health and appeared not to suffer any consequences from the childhood episode. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• CASE REPORTS: A suicidal person who ingested 6 g (104 mg/kg) of chlordane in talc ... burns of the mouth, severe gastritis, diffuse pneumonia, anuria, mania, and convulsions; Death ... after 9.5 days; Autopsy findings: ... severe necrotizing bronchopneumonia and degeneration of renal tubule epithelium. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 1]**PEER REVIEWED**
  
• CASE REPORTS: ... 25 previously reported cases of blood dyscrasia associated with exposure to chlordane or heptachlor either alone or in combination with other drugs, in conjunction with 3 newly diagnosed cases of aplastic anemia and 3 of acute leukemia associated with prior history of exposure to technical-grade chlordane containing 3-7% heptachlor /were reviewed/. [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 57 (1979)]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: A prospective mortality study was conducted of the 800 employees who worked 3 months or more during the period January 1946 through June 1985, in the only plant in the USA where the termiticide chlordane has been produced. The study covers the entire period of chlordane production to date and includes 7,347 person-years of employment at the chlordane plant and 21,585.5 person-years of follow-up since commencement of employment. All but three former employees considered to be alive at the end of the study period were either contacted directly or were identified as alive by a variety of reliable sources. Death certificates were obtained for 161 of the 181 decendents and reliable causes of death were reported for additional 11 cases. Overall death rate was slightly less than expected but not to the level of statistical significance. Production workers with higher pesticide blood levels had lower standardized mortality ratios for cancer than nonproduction employees, and there appears to be an inverse relationship of cancer mortality to length of employment. An unexplained excess of cerebrovascular deaths was observed, offset by a lesser degree of cardiovascular deaths. [Shindell S, Ulrich S; J Occup Med 28 (7): 497-501 (1986) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: A cohort of 16,124 male pesticide applicators was matched with Social Security Administration and National Death Index files through 31 December 1984. In all, 1,082 deaths were ascertained, and death certificates were obtained for 994 (92%). The standardised mortality ratio for all causes of death was 98. Although a number of specific causes of death showed standardised mortality ratios significantly below 100, one category of cause of death showed a significantly elevated standardised mortality ratio - cancer of the lung, with an standardised mortality ratio of 135. Termite control operators - the group with the greatest likelihood of exposure to chlordane and heptachlor - had an standardised mortality ratio for lung cancer of 97, compared with 158 for other pesticide operators. The excess of lung cancer in the non-termite control workers was limited to operators employed as such for less than 5 yr. [MacMahon B et al; Journal of Occupational Medicine 30 (5): 429-32 (1988) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: The relationship between pesticide use in the home and childhood brain cancer was examined in a case–control study of 45 white children with brain cancer diagnosed between 1985 and 1989, resident in Missouri (USA) and identified through the Missouri Cancer Registry (Davis et al., 1993). The participation rate was 73%, and histological confirmation was made for 89%. Two groups of controls were selected: the first consisted of friends of the children with brain cancer or of children with acute lymphocytic leukemia (85 children; participation rate, 94%), and the second consisted of 108 children with cancer (mostly of the lymphohematopoietic system; 71 children; participation rate, 78%). The adjusted odds ratio associated with living in a home that had been treated for termites within 1 year before residence or during residence from pregnancy to diagnosis was 2.9 (95% CI, 1.3-7.1) when friends were used as controls and 3.0 (1.3-7.4) with cancer controls. Of the 21 patients who reported any termite control treatment, only seven reported specific use of chlordane, giving an odds ratio of 1.5 (0.5-4.9) for friend controls and 1.5 (0.5-5.1) for cancer 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. V79 57 (2001)]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: ... The concentrations of the sum of 38 polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyl-dichloroethylene, hexachlorobenzene (HCB), and chlordanes, /was studied/ in 61 cases with testicular cancer and 58 age-matched controls. ... Among case mothers the sum of PCBs yielded an odds ratio (OR) of 3.8; 95% confidence interval (CI), 1.4-10 was calculated using the median concentration for the control mothers as cutoff value. For HCB, OR = 4.4 (95% CI, 1.7-12); for trans-nonachlordane, OR = 4.1 (95% CI, 1.5-11); for cis-nonachlordane, OR = 3.1 (95% CI, 1.2-7.8); and for sum of chlordanes, OR = 1.9 (95% CI, 0.7-5.0). [Hardell L et al; Environ Health Perspect 111 (7): 930-934 (2003) ]**PEER REVIEWED**
  
• BIOMONITORING: Environmental and area air samples were analyzed for chlordane at Lauinger Library, Georgetown University, Washington, DC, in October, 1983. NIOSH was requested to evaluate residual chlordane concentrations following cleanup of an accidental spill that occurred 6 months earlier. Several employees had experienced headaches, nausea, and irritability following the incident. Twelve current and one former employee were interviewed. Blood samples were collected and analyzed for chlordane and the chlordane metabolites heptachlor epoxide and oxychlordane. Air samples contained 0.1 to 0.3 ug/cu m chlordane and wipe samples contained 0.1 to 0.3 ug per sample. The current OSHA standard for chlordane is 500 ug/cu m. Ten employees reported having dermal or inhalation exposure to the spill. Three reported having gastrointestinal and neurological symptoms, while six others had gastrointestinal symptoms alone or isolated neurological symptoms after the incident. No chlordane was found in any of the blood samples. Only one sample had a detectable amount, 2 ppb, of heptachlor epoxide plus oxychlordane. The authors conclude that cleanup of the spill has effectively removed all but trace amounts of chlordane. [Gorman R, Seligman P; Hazard Evaluations and Technical Assistance Branch, NIOSH, U.S. Department of Health and Human Services, Cincinnati, Ohio, Report No. HETA-83-444-1481, 24 pages, 16 references, 19841984 ]**PEER REVIEWED**
  
• BIOMONITORING: Chlordane has been widely used to protect soil and house foundations against termite infestation. Pest control operators are occupationally exposed to chlordane. The relationship between chlordane and its metabolites in blood of pest control operators and spraying conditions were investigated. Chlordane and its metabolites were detected in the blood of some chlordane-exposed pest control operators, but not in that of the controls. Trans-nonachlor and the metabolites oxychlordane and heptachlor epoxide were detected in the blood of pest control operators. Total concentration of chlordane and its metabolites in blood (trans-nonachlor + oxychlordane + heptachlor epoxide) was less than 5.6 ppb (mean: 0.89 ppb). The concentration of chlordane and its metabolites in blood of chlordane-exposed pest control operators was significantly correlated with the number of spraying days and the amount of chlordane sprayed, particularly with a large correlation coefficient (r = 0.81, p< 0.001) with the spraying days in the three months prior to the medical examination. The concentration of chlordane and its metabolites in blood is considered to be a useful indicator of biological monitoring for chlordane exposed workers. [Saito I et al; Int Arch Occup Environ Health 58 (2): 91-7 (1986) ]**PEER REVIEWED**
  
• BIOMONITORING: ... Frequency of SCEs in cultured lymphocyte obtained from infants postnatal of around ten months was examined to evaluate the genotoxic or clastogenic potency of lactational exposures to some organochlorine pesticides such as HCHs, DDT and chlordane in this study. Frequency (median, min.-max.) of SCEs as the control culture treated with the solvent, DMSO, alone (SCE control) was 8.0/cell, 6.5-12.4/cell, that as the culture treated with 7,8-benzoflavone (SCEANF) was 11.8/cell, 9.1-15.6/cell and the difference between SCEANF and SCEcontrol, that is, delta SCEs was 3.9/cell, 0.2:7.2/cell. Lactational exposures (median, min.-max.) to the three organochlorine pesticides were as follows: HCHs; 341 mg/kg body weight, 43-1449 mg/kg body weight, DDT; 272 mg/kg body weight, 33-1361 mg/kg body weight and chlordane; 69 mg/kg body weight, 13-379 mg/kg body weight. The median exposure level to chlordane through the breast milk was one fourth to one fifth times lower than that to HCHs or DDT. ... Frequencies of SCEcontrol and SCEANF showed increasing and decreasing tendencies with the increasing exposure to DDT and also HCHs through the breast milk. In consequence, the frequency of delta SCEs was significantly lowered. [Nagayama J et al; Fukuoka Igaku Zasshi 94 (5): 166-173 (2003) ]**PEER REVIEWED**
  
• BIOMONITORING: Several components of chlordane ( trans- and cis-chlordane, trans- and cis-nonachlor, heptachlor, gamma-chlordene) were detected in the skin lipids of humans. The samples were taken by swabbing the face with cotton soaked with 70% ethanol 3-4 hours after the face was washed with soap. Because all samples from inhabitants of an area known to be contaminated with chlordane contained chlordane residues, and because the profile of chlordane components in skin lipids closely resembled those in technical chlordane, the authors suggested that skin lipid analysis is a satisfactory indicator of dermal exposure to airborne chlordane, such as occurs in homes treated for termites. Oxychlordane in the skin lipids was positively correlated (correlation coefficient = 0.68, p<0.01) with concentrations in internal adipose tissue. The authors concluded that the concentration of oxychlordane in skin lipids was a satisfactory indicator of body accumulation of chlordane. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• BIOMONITORING: …"Total" chlordane (cis- and trans-chlordane, heptachlor epoxide, oxychlordane and trans-nonachlor) residues in the blood of pest control operators and nonexposed workers in Japan /were measured/. Not all of these residues (e.g., heptachlor epoxide) are specific for exposure to chlordane. Levels in the blood of four of five unexposed workers were below 0.10 ng/g, the limit of detection. A level of 0.13 ng/g was reported for the fifth unexposed worker, who had lived for 2 years in a termite-treated home. Levels in the blood of 21 pest control operators ranged from 0.57 to 83 ng/g, with an average of 12 ng/g, approximately two orders of magnitude greater than levels in unexposed workers. There was no mention or indication of signs of chlordane toxicity in either the unexposed workers or pest control operators. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The toxic effects of the organochlorine insecticide chlordane were /studied/ in man ... . Analysis of blood for chlordane metabolites showed their presence in the descending order of trans-nonachlor, oxychlordane, hepatachlorepoxide and cis-nonachlor. The total range of chlordane and its metabolites in the sera of workers was 9.84 : 4.47 ng/g. Serum levels of triglycerides, creatine phosphokinase and lactate dehydrogenase activities were also found to be higher in pest-control operators... [Ogata M, Izushi F; Toxicol Lett (AMST) 56 (3): 327-38 (1991) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ...A significantly increased frequency of cortical thymocytes in the circulation (CD1) (p less than .001) and a decreased frequency of the suppressor-inducer phenotype CD45RA/T4 (p less than .01) were noted in the exposed group. Both kappa and lambda light-chain frequencies were elevated (p less than 0.01). Proliferative responses to the three mitogens tested, PHA, CONA, PWM, and to allogeneic lymphocytes in the mixed lymphocyte culture assay were significantly lower than in controls (p less than 0.01). Responses in assays of the natural killer function were not significantly different from those of controls, but Fc receptor-associated K cell function was significantly greater than responses in controls. Of 12 individuals tested for evidence of autoimmunity, 11 demonstrated some increased titer of a form of autoantibody. [McConnachie PR, Zahalsky AC; Arch Environ Health 47 (4): 295-301 (1992) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... A total of 426 infants were studied. The exposure rate (based on meconium analysis) and the median concentration of the pollutants in the positive samples were as follows: lead (26.5%; 35.77 microg/ml), cadmium (8.5%; 13.37 microg/ml), mercury (83.9%; 3.17 ng/ml), chlordane (12.7%; 22.48 microg/ml), chlorpyrifos (11.0%; 8.26 microg/ml), diazinon (34.3%; 12.96 microg/ml), DDT (26.5%; 12.56 microg/ml), lindane (73.5%; 2.0 microg/ml), malathion (53.0; 6.80 microg/ml), parathion (32.0%; 2.30 microg/ml) and pentachlorphenol (16.1%; 90.00 microg/ml). [Enrique MO et al; Neurotoxicology 23 (3): 329-339 (2002) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... Chlordane was not toxic for human neutrophils incubated for up to 24 h with concentrations ranging from 0.1 to 50 microg/ml. Chlordane was found to induce neutrophil superoxide production (O2-) in a concentration-dependent fashion and its potency to induce this response was found to be similar to phorbol 12-myristate 13-acetate (PMA), a classical neutrophil agonist. The use of different transduction signal inhibitors (genistein, pertussis toxin, staurosporine, and calphostin C) indicates that, as for PMA, chlordane induces O2- production via protein kinase C (PKC). In this respect, staurosporine and calphostin C were found to inhibit chlordane- and PMA-induced O2- production by 65% and 72%, and by 83% and 85%, respectively. Chlordane was also found to significantly enhance neutrophil phagocytosis of opsonized sheep red blood cells (SRBCs). Chlordane did not alter neutrophil apoptosis as assessed by cytology (Diff-Quick staining) and by flow cytometry (CD-16 expression). In addition, chlordane did not alter neutrophil chemotaxis (48-well Boyden chamber). [Gauthier M, Girard D; Hum Exp Toxicol 20 (5): 229-235 (2001) ]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: Chlordane administered by stomach-tube to sheep at 500 mg/kg body weight induced toxic symptoms (incoordination, partial blindness). Full recovery occurred in 5 to 6 days. A dose of 1000 mg/kg body weight induced severe respiratory and nervous symptoms 16 h after treatment and death after 48 h. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: When given daily oral dose of 10 mg/kg, rabbits died before they had received total dose of about two-thirds of the single lethal dose. Fatal poisoning has been induced experimentally in sheep & goats by 6 to 8 dippings at 4-day intervals in suspension containing 1.5% chlordane. 4 sprayings with suspension containing 2% chlordane wettable powder at fortnightly intervals were fatal in cattle. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 143]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Acute symptoms /mallards/: ataxia, tail up, use of wings for balance in walking, falling, phonation, neck muscle twitches, tremors. Symptoms appeared as soon as 5 min after single oral administration & persisted ... up to 1 or 4 wk. Mortalities occurred between 1 & 8 days. [U. S. Department of the Interior, Fish & Wildlife Service, Bureau of Sport Fisheries & Wildlife. Handbook of Toxicity of Pesticides to Wildlife. Washington, D. C.: U. S. Government Printing Office, 1970., p. 35]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Chlordane ... /produces/ a certain degree of vascular damage. Subcutaneous petechiae & ecchymoses in intestines & myocardium have been described. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 146]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Repeated application of 50 mg/kg to the skin of rats for 3 or 4 days caused 100% fatalities. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ... Rats were administered 100 mg/kg body wt of chlordane by stomach tube once a day for 4 days, whereas 50 mg/kg body wt of chlordane was injected ip once a day for 4 days. The data show that total cholesterol and serum triglycerides as well as creatine phosphokinase and lactate dehydrogenase activities are increased after chlordane treatment. The isoenzyme patterns suggest that an increase in creatine phosphokinase and lactate dehydrogenase is related to skeletal muscle. Furthermore, the hepatotoxicity of chlordane was also studied in rats only. A significant increase in liver weight, its water content, total lipids, triglycerides and phospholipids was recorded. Chlordane induced lipiod peroxidation in the liver, exhibiting a dose-response relationship. Although no appreciable effect on mitochondrial function and latent ATPase activity was observed, 2,4-dinitrophenol-stimulated ATPase activity was inhibited. Histological examination of the liver confirmed fatty infiltration induced by chlordane in rats. [Ogata M, Izushi F; Toxicol Lett (AMST) 56 (3): 327-38 (1991) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ... Prenatal chlordane exposure induced a 36% reduction in ear swelling compared to a 60% reduction following topical treatment at the challenge phase. Topically-applied chlordane also reduced the oxazolone-induced ear swelling by 40% when applied at sensitization. When applied at both sensitization and challenge, ear swelling was reduced by 71%. In a time-course study, it was determined that chlordane must be applied at the time of sensitization, challenge or both or within 1 h post-challenge to significantly reduce ear swelling. A dose-response study showed that the lowest concentration of chlordane resulting in a significantly reduced ear swelling response was 20 micrograms per ear. [Blaylock BL et al; Toxicol Lett 81 (2-3): 205-211 (1995) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: ... Replicating cells were labeled via bromodeoxyuridine delivered by osmotic minipump for 3 days before necropsy. In the thyroid, the peak labeling index (LI) was seen on day 5 (LI = 5.99 +/- 2.90% versus 1.00 +/- 20% in controls), while in the liver the peak was on day 8 (9.0 +/- 1.6% versus 0.5 +/- 0.4% in controls). Both organs had an elevated LI for the first month of dosing, but while the thyroid follicular LI was similar to control at 99 and 190 days, the liver LI was significantly elevated at all time points except in the withdrawal groups. [Barrass N et al; Environ Health Perspect 101 (Suppl 5): 219-223 (1993) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... Rats were administered cis-nonachlor, trans-nonachlor, or technical chlordane by gavage for 28 days at doses of 0.25 to 25 mg/kg body weight. Residue analyses indicated that trans-nonachlor accumulation in adipose was greater than cis-nonachlor. The major metabolite oxychlordane accumulated in adipose tissue. Adipose tissue residue levels of all test chemicals and the major metabolite were higher in female rats. The liver was a target organ in male and female rats [Bondy GS et al; Toxicol Sci 58 (2): 386-398 (2000) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: When male guinea-pigs were exposed to chlordane at 67 mg/kg body weight/day, through dermal painting for 90 days, mild degenerative changes in the skin and testis were evident. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Various toxicological and immunological parameters were assessed after exposure of female B6C3F1 mice to 0.1, 1.0, 4.0, and 8.0 mg/kg gamma-chlordane for 14 days via oral gavage. Variables evaluated included periodic body wt, terminal organ wt, hematology including leukocyte differentials, antibody response to sheep red blood cells, lymphoproliferative responses to the mitogens phytohemaglutinin, concanavalin A, and lipopolysaccharide and allogeneic cells, and the delayed hypersensitivity response to keyhole limpet hemocyanin. When compared to the corn oil (vehicle) controls, chlordane produced a significant, dose-related increase in liver wt. Total leukocytes were significantly increased in chlordane treated groups and seemed to be due to a significant increase in the lymphocyte population. Humoral immunity, as assessed by enumeration of sheep red blood cell-specific IgM antibody forming cells and proliferation of lipopolysaccharide-stimulated spleen cells, was not significantly altered in mice exposed to chlordane. In vitro evaluation of cell-mediated immunity, as measured by proliferation of concanavalin A and phytohemagglutinin-stimulated spleen cells from chlordane treated animals, indicated as significant and dose related increase. The response to allogeneic cells was also enhanced. Results from an in vivo indicator of cell-mediated immune status, the delayed hypersensitivity response to keyhole limpet hemocyanin, did not support chlordane-enhanced T-cell function suggested by mitogen and mixed lymphocyte responses. [Johnson KW et al; Fundam Appl Toxicol 6 (2): 317-26 (1986) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Daily oral doses of chlordane in cottonseed oil of 50 mg/kg for 2 weeks or less resulted in significant mortality, whereas 25 mg/kg during the same period of time was tolerated, suggesting that chlordane effects at higher dosage levels may be cumulative. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: The levels of chlordane congeners in mice were measured after single and repeated oral doses of technical chlordane. Male ddy-strain mice received 0.48 mg of technical chlordane by gavage every other day for a total of from one to 15 doses. Digestive tracts, tails, limbs, and skins were homogenized and purified by organic solvent extraction and florisil column chromatography. trans-Chlordane, cis-chlordane, trans-nonachlor, cis-nonachlor, and oxychlordane were detected by gas chromatography. In the single dose group, maximum levels of cis-chlordane and trans-chlordane occurred at 5 hr after administration, levels of cis-nonachlor and trans-nonachlor reached a plateau at 10 hr post treatment, and oxychlordane levels increased throughout the 24 hr observation period. For mice receiving repeated doses of chlordane, no increases in body content of chlordanes were detected over 29 days, while the trans-nonachlor, cis-nonachlor, and oxychlordane levels increased successively over the entire 29 day period. The authors conclude that the clearance rates for chlordanes and nonachlors differ widely, and recommend that the toxic effect of the high accumulation of nonachlors and oxychlordane in the animal body be studied. [Hirasawa F, Takizawa Y; Toxicology Letters 47: 109-17 (1989) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Tissue chlordane residues following subchronic inhalation exposure to technical chlordane were studied in rats and monkeys. Albino rats and cynomolgus monkeys were exposed to aerosols of technical chlordane at concentrations of 0, 0.1, 1.0, or 10 ug/L, 8 hr per day, 5 days a wk for 90 days. Selected animals were killed after 5, 57, 90, and 180 days and blood, liver, and adipose tissue samples were taken and assayed for total chlordane, oxychlordane, heptachlor epoxide, and trans-nonachlor. Some blood samples were fractionated and the plasma and red blood cells were analyzed separately. Total chlordane residues in the tissue samples of both species of both species were directly proportional to the logarithm of the exposure concentration. The highest residue concentrations were found in the adipose tissue, followed by the liver and blood, in that order. Plasma total chlordane concentrations in monkeys were nearly twice those of the red blood cells. In rats the plasma and red blood cell concentrations were comparable. After exposure ended, the concentrations of total chlordane residues in rats decreased 75 to 90 %. The largest decreases occurred in the liver and blood. Total chlordane concentrations in the tissues of female rats were two to three times those of males. No sex related differences were seen in monkeys. The predominant metabolite in monkeys was trans-nonachlor, accounting for nearly 50% of the chlordane residues. Oxychlordane was the major chlordane residue in rat tissues. During the 90 day recovery period, oxychlordane was the major metabolite present in rat tissues and blood. [Khasawinah AM; Bull Environ Contam Toxicol 43 (3): 459-66 (1989) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ...Female rats were gavaged with oxychlordane at doses ranging from 0.01 to 10 mg/kg body weight/day for up to 28 days. ... 10 mg/kg oxychlordane was acutely toxic and 1 mg/kg oxychlordane caused no measurable effects. Weight loss, reduced feed consumption and thymic atrophy were the hallmarks of acute oxychlordane toxicity. At lower doses rats showed signs of hepatic changes indicative of microsomal enzyme induction. Oxychlordane was more bioaccumulative and was toxic at levels approximately 8 times lower than trans-nonachlor and cis-nonachlor. [Bondy G et al; Food Chem Toxicol 41 (2): 291-301 (2003) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ...In 2-yr chronic feeding study... /with rats/ retardation of growth /was noted/ at concentrations of 150 and 300 ppm in the diet. ...Liver damage was marked at 150 and 300 ppm but slight at 30, minimal at 10, and absent at 5 ppm. ...Marked injury /to kidney/ at 150 and 300 ppm. The lung showed marked damage at 300 ppm, mild injury at 150, and no injury at lower concentrations. [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 651]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Chlordane fed at 56 ppm produced 88.9% hepatocellular carcinoma in male mice, compared with 10% in controls, & 64 ppm produced 69.6% hepatocellular carcinoma in female mice ... with 0% in controls. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 566]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: A long-term study ... was conducted in cohort groups of identically treated mice to determine if prenatal exposure to chlordane had a persistent effect on endocrine function over the lifespan of the exposed offspring as determined by alterations in plasma concentrations of corticosterone at 400 and 800 days of age. Results suggest that prenatal exposure to nonteratogenic doses of chlordane (1) had a significant effect on endocrine funtion (corticosterone control), (2) affected males more than females, and (3) produced changes (increased plasma corticosterone levels) which were detectable at adulthood and persisted into middle age. The mechanisms responsible for these persistent changes in corticosterone metabolism remain to be elucidated. [Cranmer JM et al; Environ Res 35 (1): 204-10 (1984) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: The liver appeared to be the only organ showing either gross or microscopic changes in rats on diets containing 0.008, 0.15 and 0.032% chlordane for 407 days; liver cells, their nuclei and nucleoli, were significantly enlarged, and inclusions were commonly seen in liver cells of male rats at the higher dietary levels. No other organs or tissues, including the blood, showed alterations ascribable to chlordane. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... Feeding study of rats at dietary levels of chlordane 5, 10, 30, 150 and 300 ppm chlordane for 2 years, resulted in marked toxicity at 300 ppm, less marked at 150 ppm and insignificant effects at 5, 10, and 30 ppm. ... Liver damage was the major finding, although myocardial damage was also apparent at the higher dietary levels. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... Chlordane fed in the diets of mice for 80 weeks at an average dietary concentration of 30 or 56 mg/kg (males) and 30 or 64 mg/kg (females) produced a significant incidence of liver cancer. The increased incidence of hepatocellular carcinomas was dose related. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Chlordane (technical, lot B-9129A, 100%); fed /to rats/ in the diet at 0, 1, 5 or 25 ppm for 130 weeks; 80/sex/level with 8/sex/level interim sacrificed at 26 and 52 weeks, with termination at 130 weeks (2.5 years); hepatocellular necrosis ("adenomas") in males with reduced survival beginning after 116 weeks at 25 ppm, NOEL between 1-5 ppm hepatocellular swelling and necrosis. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/toxsumlist.htm on Chlordane (57-74-9) as of June 30, 2004 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ..When chlordane exposure was discontinued for a group of B6C3F1 mice ('stop' group) at 491 days of age, overall tumor multiplicity significantly decreased by 30% from an average of 4.4 per tumor-bearing-animal at 525 days to 3.1 at terminal killing (568 days). Over the same time period the prevalence of hepatocellular carcinomas significantly decreased from 80 to 54% and adenomas from 100 to 93% by terminal killing in B6C3F1 'stop-group' mice. Chlordane induced diffuse hepatocellular centrilobular hypertrophy, frequent multinucleate hepatocytes, toxic change and hepatoproliferative lesions composed predominantly of acidophilic hepatocytes in nearly 100% of both the B6C3F1 and B6D2F1 mice. The development of histological evidence of toxicity closely paralleled the temporal development of hepatocellular neoplasia and decreased in severity when the tumor burden was maximal. No H- or K-ras mutations were detected in the chlordane-induced hepatocellular tumors in B6C3F1 mice (15 adenomas and 15 carcinomas) or B6D2F1 mice (10 adenomas and 10 carcinomas). [Malarkey DE et al; Carcinogenesis 16 (11): 2617-2625 (1995) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 50 male and 50 female, 5-week-old Osborne-Mendel rats were given analytical-grade chlordane in the diet for 80 weeks, at initial levels of 400 and 800 mg/kg for males and 200 and 400 mg/kg for females. The levels had to be reduced during the study because of adverse toxic effects; the time-weighted average dietary concentrations were 407 and 203 mg/kg for males and 241 and 121 mg/kg for females. There were 10 male and 10 female matched controls and 60 male and 60 female pooled controls. Survivors were killed at 80 weeks, at which time approximately 50% of treated and control males and 60% of treated females and 90% of control females were still alive. In all treated animals combined, there was an excess incidence of follicular-cell thyroid neoplasms (10/75 in treated females and 7/65 in treated males versus 0/10, 3/58, 0/6, and 4/51 in matched and pooled female and male controls); there was an excess of malignant fibrous histiocytomas in the treated male groups (8/88 versus 0/8 and 2/58 in matched and pooled male controls). [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: … Groups of 100 male and 100 female Charles River CD-1 mice, 6 weeks of age, were fed technical-grade chlordane (purity not given) at 5, 25, and 50 mg/kg diet, for 18 months. Excluding 10 animals sacrificed from each group for interim study at 6 months, mortality rates at 18 months ranged from 27 - 49%, except in males and females receiving the 50 mg/kg diet, in which the mortality rates were 86 and 75%, respectively. A relatively large number of the deceased animals was lost due to autolysis. A dose- related increased incidence of liver hyperplastic nodules was reported in the 25 and 50 mg/kg diet test groups and a dose-related increased incidence of liver cell hypertrophy was found in all test groups. A significant incidence of hepatocellular carcinomas compared with controls was also reported. In the males receiving chlordane at 0, 5, 25, or 50 mg/kg diet, hepatocellular carcinomas were found in 3/33, 5/55, 41/52, and 32/39 animals, respectively; in females, the respective incidences were 0/45, 0/61, 32/50, and 26/37. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In a two-year feeding study, pure-bred male and female beagle dogs were fed chlordane at levels of 0, 0.3, 3.0, 15, or 30 mg/kg diet. No adverse treatment-related alterations were observed in behaviour, appearance, eye examination, body weight, food consumption, hematology, or plasma biochemistry. Some liver enzyme activities were altered throughout the study at the 15 and 30 mg/kg levels. Relative liver weights were slightly increased after two years in the two highest groups. Treatment-related microscopic changes, observed in dogs fed the two highest levels, consisted of enlargement of centrolobular hepatocytes with margination of coarse cytoplasmic granules. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ...Studies in rodents fed diets containing levels of 12.5 and 25 ppm chlordane were conducted. There were no tumorigenic responses in either rats (dosed for 30 months) or mice (dosed for 24 months). Both chlordane and heptachlor have been shown to cause tumor promotion in mice following initiation with diethylnitrosamine. [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 654]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 50 male and 50 female B6C3F1 hybrid mice, 5 weeks of age, were fed a diet containing technical-grade heptachlor (72 +/- 3% heptachlor, 18% trans-chlordane, 2% cis-chlordane, 2% nonachlor, 1% chlordene, 0.2% hexachlorobutadiene and 10–15 other compounds) for 80 weeks. Males received an initial dietary concentration of 10 or 20 mg/kg and time-weighted average concentrations of 6 and 14 mg/kg; females received an initial concentration of 20 or 40 mg/kg of diet and time-weighted average concentrations of 9 and 18 mg/kg of diet. These concentrations were reduced during the experiment because of adverse toxic effects. Matched controls consisted of 20 males and 20 females. The survivors were killed at 90–91 weeks. The survival rates in all groups were relatively high, with > 70% of treated and control males and 60% of treated and control females still alive at 90 weeks. The survival of treated female mice showed a significant decreasing trend in comparison with 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. V79 53 (2001)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: … Administered analytical grade chlordane in peanut-homogenate at 0, 0.16, or 8.00 mg/kg/day to groups of mice throughout gestation to measure endocrinological performance of adult offspring. Although mice in both treated groups gave birth to approximately equal numbers of viable offspring of "average" body weight that were grossly normal in appearance, 55% of the offspring of the high-dose dams died within the first week of the nursing period. The authors stated only that the cause of death was not apparent from gross necropsy; however, it is possible that exposure to high levels of chlordane and/or metabolites in the dam's milk may have been responsible for these deaths … [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Rats, maintained from weaning on a diet containing a chlordane level of 320 mg/kg, showed reduced rates of mating, of viable litters, and an increased rate of death of progeny prior to weaning. It was concluded that, at this dosage, chlordane interfered with both fertility and litter survival. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Mice fed diets containing chlordane at 25 - 100 mg/kg for 6 generations showed decreased viability in the first and second generations at 100 mg/kg; in the third generation at this level, no offspring were produced. At 50 mg/kg, viability was reduced in the fourth and fifth generations, and at 25 mg/kg no statistically significant effects were observed, even after 6 generations. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant mice were treated with chlordane in order to study the immunological, behavioral, and endocrine effects on the offspring. The offspring were allowed to nurse their dams; therefore, they were exposed to chlordane and metabolites during gestation and nursing. The results of immunological tests suggest that chlordane suppressed cell-mediated immunity. Results of behavioral tests indicate that chlordane depressed the acquisition of avoidance behavior, raised seizure thresholds, and increased exploratory activity. Increased plasma levels of corticosterone were observed in the offspring of mice treated during gestation; the change implies an effect on neuroendocrinological feedback, possibly resulting from the liver's reduced ability to metabolize corticosterone. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 10 male and 20 female rats were used in a 3- generation study at dietary levels of technical chlordane of 0, 0.3, 3, 15, 30, and 60 mg/kg. Two litters in each filial generation were studied. Levels up to and including 30 mg/kg did not have any effect on fertility, number of offspring, or weight, growth, or mortality rate of the young animals to weaning age. Autopsy of animals after weaning did not reveal any gross or microscopic differences between the groups. At 60 mg/kg, there was a high (10.6%) mortality rate in the second F3 generation litters during the latter part of the nursing period; these animals showed gross and microscopic pathological changes, comparable with those characteristic for chlordane intoxication. However, survivors of this generation did not show any tissue changes at all. A third set of F3 litters at 60 mg/kg suffered 17% mortality during the nursing period, with symptomatology and gross and microscopic tissue changes characteristic of chlordane intoxication. Third F3 generation litters from dams removed from the 60 mg/kg group and placed on chlordane-free diets for 30 days prior to re-mating showed no differences in any respect from control litters. No evidence of teratogenicity was found in this study. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Our previous results indicated that prenatal exposure to chlordane resulting in a severe depression of the delayed type hypersensitivity response without measureable effects on lymphocyte function implicating the macrophage population associated with the efferent phase of the delayed type hypersensitivity response. The number of myeloid stem cells is also severely reduced in these animals. In the present study, 2-D gel electrophoresis was used to determine measureable differences between the proteins detectable in resident mphi from 100 day old animals prenatally treated with chlordane or vehicle. 2-D gel analysis revealed 121 significant differences in the 2-D gel patterns. Thiry four of 121 spots were completely absent in chlordane-treated animals that were present in normal animals. 17/121 spots that were present in both groups had significant differences in concentration. The remaining 70/121 were uniquely present in chlordane exposed offspring. These differences could reflect a difference in level of protein synthesis, phosphorylation or the induction of new proteins. [Theus SA et al; FASEB J 4 (7): A1750 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Female mice were treated with either 0, 4 or 8 mg/kg chlordane daily for 18 days during pregnancy. The fetuses of these mice were assayed for fetal liver hematopoietic activity at 18 days gestational age. Hematopoietic activity was evaluated for in vitro granulocyte macrophage colony forming units and in vivo spleen colony forming units. The consistent finding was a significant depression of both the numbers of fetal liver granulocyte macrophage colony forming units and of spleen colony forming units without a change in liver cellularity in fetuses exposed to either 4 or 8 mg/kg chlordane. These data show that the damage to stem cells that persists into adult life as a result of chlordane exposure occurred during the fetal period. [Barnett JB et al; FASEB J 4 (7): A1750 (1990) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Prenatal exposure to chlordane significantly decreased the delayed type hypersensitivity of 100 day old female BALB/c mice. Decreases were also noted in granulocyte macrophage colony forming units colonies in fetal liver and adult bone marrow, however, lymphocyte reactivity was not adversely affected suggesting that chlordane selectively depressed macrophage (Mphi) lineage cells. In the present study, females prenatally exposed to 8 mg/kg chlordane were shown to have a severely depressed macrophage cytoxicity to tumor cells. To examine the effects of chlordane on the macrophage cytokine production, total RNA was extracted from peritoneal macrophage from chlordane-treated and control mice. The RNA was blotted onto nylon membrane and hybridized to a 5'-end labeled synthetic oligonucleotide murine GM-CSF or IL-1 probe. The mGM-CSF signal was reduced by 62% in macrophage RNA from the chlordane-treated mice compared to the control RNA. IL-1 signal also appeared to be reduced. The mechanism for this is presently unknown, however, these data suggest that prenatal exposure to chlordane produces severe defects in macrophage functional capabilities. [Lau KA et al; FASEB J 1990;4(7):A1750 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Oral daily doses of 75 and 275 mg/kg b.w. /of chlordane/ were administered to male mice, for 35 days, animals were sacrificed at the 2nd, 3rd, 4th, and 5th week. The results show that chlordane had a damaging effect on testicular tissues, /causing/ reduction in diameter of the seminiferous tubules, number of spermatogonia, and primary and secondary spermatocytes and spermatids. The effect was remarkably increased by the presence of lead. [Al-Omar MA et al; Toxicol Lett 115 (1): 1-8 (2000) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... There was a significant depression of the numbers of bone marrow colony forming units-granulocyte/macrophage (CFU-GM), CFU-IL-3, and CFU-macrophage (CFU-M) in only the female offspring. Male offspring consistently demonstrated no difference in the CFU-GM, CFU-IL-3, or CFU-M. Prenatal treatment with chlordane did not significantly affect the number of recoverable viable bone marrow cells in either male or female mice. [Blyler G et al; Funam Appl Toxicol 23 (2): 188-193 (1994) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: ... Chlordane-dosed offspring exhibited sex- and dose-dependent effects on testosterone levels, behavioral tests, and body weight conducted between postnatal Days 77 and 85. Chlordane-dosed females, but not males, had significant decreases in testosterone levels, significant improvements in spatial abilities (i.e., decreases in Cincinnati maze errors, navigation times, and failures to escape), and significant increases in body weight and in auditory startle-evoked responses. In two other tests, chlordane-dosed males showed significant increases in male-typical mating behaviors and decreases in 36Cl- uptake into brain microsacs. For all behavioral and body weight measurements, dose-response effects were observed for the 100 and 500 ng/g dosed groups. However, the 5000 ng/g dose group responses were closer to those of control values. [Cassidy RA et al; Toxicol Appl Pharmacol 126 (2): 326-337 (1994) ]**PEER REVIEWED**
  
• GENOTOXICITY: Chlordane was negative in the Salmonella assay and in cultured Chinese hamster ovary cells for an increased frequency of chromosomal aberrations, but was positive for in the chinese hamster ovary assay for increased frequency of sister-chromatid exchanges. Technical grade chlordane was positive in the Salmonella and mouse lymphoma assays. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  
• GENOTOXICITY: Chlordane induced mitotic gene conversion in Saccharomyces cerevisiae in the presence, but not the absence, of metabolic activation; and in prophage in Escherichia coli, regardless of metabolic activation. Chlordane induced forward mutation in mouse lymphoma L5178Y cells without metabolic activation, and also induced sister chromatid exchange in human lymphoid cells. Dermal application of chlordane to mice induced micronuclei formation in the bone marrow cells and nuclei aberrations in the hair follicles. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• GENOTOXICITY: It was established that chlordane-treated cells did not (for the most part) re-enter mitosis. They were, instead, arrested somewhere between the G1 and G2 phases of the cell cycle. Studies involving DNA synthesis were undertaken to determine more precisely at which phase (G1, S, G2) the cells are blocked. The data showed that the treated cells were as competent in DNA replication as the control cells. In both control and treated cultures, 25 - 30% of total DNA persisted as light-density material indicating that some of the pre-existing DNA never engaged in DNA synthesis. Either a large fraction of cells failed to complete DNA synthesis or 25 - 30% of the cells did not enter phase S. In any case, treated and control cells behaved the same in terms of DNA synthesis, indicating that treatment of the cells with chlordane blocked the cells at the G2 stage of the cell cycle. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• GENOTOXICITY: Chlordane induced neither DNA damage nor point mutations in bacteria. It caused SOS repair and prophage induction in Escherichia coli and gene conversion in Saccharomyces cerevisiae. In cultured mammalian cells, it did not induce unscheduled DNA synthesis but did induce gene mutations at the Tk and Na+/K+ ATPase loci. It inhibited gap-junctional intercellular communication in cultured mammalian cells. In single studies with cultured human cells, evidence was obtained for the induction of unscheduled DNA synthesis and sister chromatid exchange, but not for the induction of gene mutations. Sister chromatid exchange was induced in intestinal cells of Umbra limi (mud minnow) in vivo. Chlordane caused micronucleus formation and chromosomal aberrations in the bone marrow of mice treated in vivo, and nuclear aberrations (micronucleated and apoptotic cells) in hair follicle cells of these mice. No evidence was found of adduct formation with chlordane in liver DNA of mice treated in vivo. No dominant lethal mutation was found in mice. [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. V79 467 (2001)]**PEER REVIEWED**
  
• IMMUNOTOXICITY: ... Adult male and female Sprague-Dawley rats were randomly assigned to six experimental groups: cis-nonachlor, females; trans-nonachlor, females; technical chlordane females; cis-nonachlor, males; trans-nonachlor, males; technical chlordane, males. The immunologic endpoints included: quantification of the total serum immunoglobulin (Ig) levels and subclasses and flow cytometric analysis of peripheral blood leukocytes and T-lymphocyte subsets, evaluation of the lymphoproliferative activity of splenocytes in response to concanavalin A (Con A) and Salmonella typhimurium (STM) mitogens, and natural killer (NK) cell activity of splenocytes. Satellite experiments to examine the delayed-type hypersensitivity (DTH) response to oxazolone, and resistance to Listeria monocytogenes were set up for female rats treated with cis- or trans-nonachlor. Statistically significant (P<0.05) effects included: increased serum immunoglobulin M (IgM) levels in the chlordane-treated females at the 25 mg/kg dose (pairwise comparison); increased serum IgG(1) and IgG(2c) in the cis-nonachlor-treated males at the 2.5 and 25 mg/kg doses and increased serum IgG(2a) levels at all doses; increased serum IgG(2b) at the 25 mg/kg dose and decreased (dose-related) serum IgM levels in the cis-nonachlor-treated male rats; increased (linear trend) IgG(1) and IgG(2a) in the cis-nonachlor-treated females with effects on IgG(2a) significant at the 25 mg/kg dose compared with control; increased serum IgG(2a) in the trans-nonachlor-treated male and female rats at the 2.5 mg/kg dose; increased absolute numbers (linear trend) of peripheral white blood cells, B lymphocytes, natural killer (NK) cells, T-suppressor/cytotoxic lymphocytes, and the double positive (T-helper/inducer, T-suppressor/cytotoxic) cells in the trans-nonachlor-treated females; increased (non-linear trend) lymphoproliferative activity in the Con A-stimulated splenocytes and decreased (linear trend) activity in the S. typhimurium mitogen-stimulated splenocytes of the cis-nonachlor-treated females; reduced resistance to L. monocytogenes in the cis-nonachlor (day 3, P=0.034)- and trans-nonachlor (day 2, P=0.0001)-treated females, and reduced (linear trend) NK cell activity in the cis-nonachlor-treated males. [Tryphonas H et al; Food Chem Toxicol 41(1): 107-118 (2003) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: Purified chlordane at a concentration of 100 ug/L was reported to induce cytotoxic effects in human HeLa cell cultures including growth inhibiting and alteration of cell morphology. [Gabliks J; Proc Soc Exp Biol Med 120: 168 (1965) as cited in USEPA; Ambient Water Quality Criteria Doc: Chlordane p.C-8 (1980) EPA 600/5-80-027 ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: Immunosuppression by gamma-chlordane was examined by the direct addition of chlordane to cultured spleen cells from untreated B6C3F1 mice. Both cell-mediated and humoral immune responses were markedly suppressed upon in vitro exposure. The mixed lymphocyte response and the proliferative response to both B- and T-cell mitogens were significantly suppressed at uM concentrations of chlordane. The antibody response to sheep erythrocytes was suppressed 90% at 10 uM chlordane. The kinetics of the sheep erythrocytes response were not altered by chlordane. Addition of chlordane to the antibody cultures on various days indicated an effect at the early stages of the response. Previous studies with chlordane failed to demonstrate immunosuppression following in vivo exposure. The possibility that chlordane was metabolized in vivo to a less immunosuppressive form was studied by examining the effect of the major metabolite, oxychlordane, on the in vitro antibody response and by incubating splenocytes with chlordane and a liver S9 preparation prior to culture with sheep erythrocytes. Oxychlordane was immunosuppressive by itself, and the activity of chlordane was unaltered in the co-culture experiments. The association of chlordane with serum components was evaluated in vitro in cultures of mouse bone-marrow cells. The chlordane-induced suppression of (3)H thymidine incorporation by bone-marrow cells was reversed by the addition of mouse or human serum. In summary, chlordane produces marked suppression of in vitro immune responses via an apparent antiproliferative action. The failure of chlordane to produce in vivo immunosuppression may be related to extensive association of chlordane with serum components. [Johnson KW et al; J Toxicol Environ Health 22 (4): 497-516 (1987) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: The cyclodiene pesticides endosulfan, chlordane and heptachlor have been reported to be non-genotoxic rodent hepatocarcinogens. These three compounds ... were examined for their effects on gap junctional intercellular communication in primary cultured male F344 rat hepatocytes and B6C3F1 mouse hepatocytes. ... Chlordane and heptachlor inhibited both mouse and rat hepatocyte gap junctional intercellular communication at concentrations of 50-200 uM. The inhibition of gap junctional intercellular communication by the cyclodienes showed similar dose-response relationships and kinetics of onset of inhibition and reversibility for both mouse and rat hepatocytes. Concomitant treatment of the cells with inhibitors of cytochrome P450 monooxygenases (SKF-525A, piperonyl butoxide or carbon monoxide) did not alter the inhibition of gap junctional intercellular communication by the cyclodienes, suggesting that cytochrome P450 metabolism was not involved in the inhibitory mechanism. Dibutyryl cyclic AMP (0.5 mM), however, decreased the inhibition of gap junctional intercellular communication by the cyclodienes and may indicate that these compounds inhibit intercellular communication through a cAMP-dependent process. The inhibition of mouse and rat hepatocyte gap junctional intercellular communication by the cyclodienes correlated with previous reports indicating that these compounds are non-genotoxic rodent liver carcinogens. [Ruch R et al; Carcinogenesis (Lond) 11 (7): 1097-102 (1990) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: The effect of chlordane and chlordane related compounds on guinea-pig leukocyte function was studied in vitro. Polymorphonuclear leukocytes obtained from male guinea pigs were incubated with 0 to 80 uM cis-chlordane, trans-chlordane, heptachlor, and heptachlor epoxide . The effects on superoxide anion generation, membrane potential, intracellular and membrane bound calcium ion (calcium (+2)), and protein kinase activity were determined. All compounds stimulated superoxide anion formation. cis-Chlordane showed the greatest activity, followed in order by heptachlor epoxide, trans-chlordane, and heptachlor. Heptachlor epoxide had the greatest depolarizing effect on polymorphonuclear leukocyte membrane potentials, followed by cis-chlordane, trans-chlordane, and heptachlor. All compounds increased intracellular and membrane bound calcium (+2) concentrations. No definite trends in terms of molecular structure were discernible. None of the compounds affected protein kinase activity. The /results indicate/ that chlordane and chlordane related compounds exert stimulative effects on polymorphonuclear leukocytes in vitro. The lack of an effect on polymorphonuclear leukocyte protein kinase suggests that phospholipase-C may play a role in accelerating superoxide anion generation induced by these compounds. [Suzaki E et al; Toxicol Appl Pharmacol 93 (1): 137-45 (1988) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: In order to clarify the cytotoxicity of chlordane, an industrial product used as an insecticide, its effect on oxidative phosphorylation in rat hepatic mitochondria was studied. The respiration rate, RCI and ADP/O ratios were inhibited by chlordane related compounds; the degree of inhibition was in the descending order of trans-chlordane, cis-chlordane, heptachlor and heptachlorepoxide. Of the indices indicating various respiratory activities, state 3 respiration was the most sensitively inhibited by these compounds, suggesting that they inhibit energy transfer. However, electron transport was inhibited also by high concentrations of chlordane constituents. The inhibitory effect of the chlordane constituents on respiratory activity varied depending on the species of respiratory substrate, suggesting site-specificity of these compounds. The release of potassium (+) ions paralleled the results of the respiratory activity study. Heptachlorepoxide, a metabolic product of heptachlor, had less effect on mitochondria than heptachlor. [Ogata M et al; Toxicol Lett 48 (1): 67-74 (1989) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: ... Phenobarbital (PB), PCBs, and chlordane (CLD) were tested for DNA adduct formation in the liver of male and female B6C3F1 mice after either single or 2-week dietary exposures. Single gavage dose levels were as follows: PB, 200 mg/kg; PCBs, 50 mg/kg; and CLD, 50 mg/kg. Dietary dose levels were as follows: PB, 1000 ppm; PCBs, 200 ppm. ... None of the three test compounds produced DNA adducts detected by 32P-postlabeling. Similar negative results were obtained for DNA from the livers of both male and female mice receiving either single or 2-week exposures. [Whysner J et al; Toxicol Appl Pharmacol 148 (1): 14-23 (1998)... ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: ... Macrophages (m phi) from chlordane-treated animals required a 48 hr in vitro period of induction with interferon-gamma and lipopolysaccharide (IFN/LPS) before they could kill P815 targets. Similarly, m phi from chlordane-treated animals also failed to produce an immediate H2O2 burst upon perturbation. Moreover, levels of inositol triphosphate (IP3), were significantly delayed in chlordane-treated animals following interaction with IFN/LPS. When nitrate/nitrite production was analyzed as an alternate mechanism for killing tumors, stimulated m phi from both normal and chlordane-treated animals responded equally. [Theus SA et al; Agents Actions 37 (1-2): 140-146 (1992) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... After inhalation of 4.22-11.36 micrograms/m3 chlordanes (total of 5 compounds) in air for 1-6 months, high levels of chlordanes (4.19-11.63 ppm, total of 5 compounds and 2 metabolites) were found in the adipose tissue of mice. Transnanochlor, which accounted for only 14% of the total chlordane in the inhaled air, showed a high percentage (50%) in the adipose tissue, followed by 2 metabolites, i.e., oxychlordane (25%) and heptachlorepoxide (22%). Little transchlordane, cis-chlordane, or heptachlor, which accounted for high percentages of the total chlordane inhaled, was detected in the adipose tissue. A low level of cis-nonachlor was observed in the adipose tissue, and its percentage was similar to that in the air (2%). [Asakawa F et al; Nippon Koshu Eisei Zasshi 41 (11): 1084-1089 (1994) ]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat (female) percutaneous 690 mg/kg [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 564]**PEER REVIEWED**
  
• LD50 Rat (new-born) 539 mg/kg (pretreatment with 40 mg/kg sodium phenobarbital). [Harbinson RD; Toxicol Appl Pharm 32: 443 (1975) as cited in USEPA; Ambient Water Quality Criteria Doc: Chlordane p.C-9 (1980) EPA 440/5-80-027]**PEER REVIEWED**
  
• LD50 Rat oral 590 mg/kg [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  
• LD50 Mouse oral 430 mg/kg [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  
• LD50 Rabbit oral 300 mg/kg [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  
• LD50 Rat dermal 590-840 mg/kg [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  
• LD50 Rat (male) ip 343 mg/kg [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 358]**PEER REVIEWED**
  
• LD50 Rat dermal 780 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 711]**PEER REVIEWED**
  
• LD50 Rabbit oral 100 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 711]**PEER REVIEWED**
  
• LC50 Cat inhalation 100 mg/cu m/4 hours [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 711]**PEER REVIEWED**
  
• LD50 Hamster oral 1720 mg/kg [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LD50 Goat oral 180 mg/kg [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LD50 Sheep oral 500 - 1000 mg/kg [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LD50 Chicken oral 220 - 230 mg/kg [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LD50 Mallard oral 1200 mg/kg [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• LD50 Cow oral 25 - 90 mg/kg [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• ...Absorbed through skin, more readily via the lungs, and from ... /gastrointestinal/ tract. [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 652]**PEER REVIEWED**
  
• In a child, fat concentration ... after single dose continued to rise through 8th post-ingestion day, and after 3 months fat-serum partition was 1470:1. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-185]**PEER REVIEWED**
  
• The chief route of excretion is biliary, although nearly all organochlorines yield measurable urinary metabolites. ... Many of the unmetabolized pesticides are efficiently reabsorbed by the intestine (enterohepatic circulation) substantially retarding fecal excretion. /Solid organochlorine insecticides/ [U.S. Environmental Protection Agency/Office of Prevention, Pesticides, and Toxic Substances. Reigart, J.R., Roberts, J.R. Recognition and Management of Pesticide Poisonings. 5th ed. 1999. EPA Document No. EPA 735-R-98-003, and available in electronic format at: http://www.epa.gov/pesticides/safety/healthcare, p. 55]**PEER REVIEWED**
  
• ... Wistar rats that received iv ... (14)C-alpha-chlordane showed that 29% of total injected radioactivity was excreted within 60 hr in feces and only 1% was excreted in urine. /cis-isomer/ [Menzie, C.M. Metabolism of Pesticides. U.S. Department of the Interior, Bureau of Sport Fisheries and Wildlife, Publication 127. Washington, DC: U.S. Government Printing Office, 1969., p. 84]**PEER REVIEWED**
  
• 1700 mg of 14C-labeled alpha and gamma isomers of chlordane /was fed/ to four male rabbits, in four doses each. In this study, 77% of the alpha isomer and 84% of the gamma isomer were excreted in the feces and urine. The alpha isomer was retained primarily in body fat, and successively less in kidney, muscle, liver, and brain; the highest concentrations of the gamma isomer were found in the kidney, followed by fat, liver, muscle, and brain. The concentrations of oxychlordane in the tissues (primarily in fat) were higher than those of the parent compound. [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 652]**PEER REVIEWED**
  
• Studies using radio-labelled chlordane showed that after oral administration, the radioactivity was well distributed in tissues of rats and rabbits. Rats, whether being treated with single oral doses of chlordane or fed diets containing this compound, retained the highest levels of residues in adipose tissue, followed by the liver, kidney, brain, and muscle. More of the gamma-isomers was retained than of the alpha-isomer. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• Rats orally administered 1, 5, or 25 mg/kg (14)C-labeled chlordane for 56 days had levels of chlordane in the fat 3 times the concentration in the diet. Distribution in the liver, kidney, brain, and muscle were 12, 10, 4, and 2%, respectively. [Barnett JR, Dorough HW; J Agric Food Chem 22: 612 (1974)]**PEER REVIEWED**
  
• Elimination of radiolabelled chlordane (3:1 alpha- and gamma- chlordane) and the individual isomers was studied in rats. Single oral doses of 0.05, 0.2, and 1 mg/kg body weight in corn oil were almost completely eliminated after 7 days; 24 h after administration, 70% of alpha-chlordane and 60% of the gamma-isomer were excreted. Female rats excreted more of the dose in the urine than the males. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• Dermal application of 50 mg chlordane/kg was more toxic to rats when the chemical was applied in cottonseed oil rather than in ethyl alcohol indicating greater absorption with a lipophilic vehicle. [Ambrose AM et al; Fed Proc Am Soc Exp Biol 12: 298 (1953) as cited in USEPA/CAG; Carcinogenicity Risk Assessment for Chlordane and Heptachlor/Heptachlor Epoxide (Draft) p.4-2 (1985)]**PEER REVIEWED**
  
• Toxicokinetic parameters of gamma-chlordane after oral administration of various doses of radio labelled gamma-chlordane (50 ug/kg - 10 mg/kg) were compared. Absorption of gamma-chlordane were about 80% in both 0.1 and 1.0 mg/kg groups. Distributions of gamma-chlordane (50 ug/kg and 10 mg/kg) into the liver and kidney were rapid and those into adipose tissues were relatively slow. Concentrations of gamma-chlordane in adipose tissues became highest at 16 hr after administration and became about 10 times more than those in the liver. The initial concentrations of gamma-chlordane calculated by two-compartment open model in high dose group (10 mg/kg) were about 200-300 times higher than those in low dose group (50 ug/kg). ... [Ohno Y et al; J Toxicol Sci 11 (2): 111-23 (1986) ]**PEER REVIEWED**
  
• The absorption, distribution, and elimination of chlordane were determined in male rats and mice. Male Sprague-Dawley rats and C57BL/6JX mice received 1.0 mg/kg of (14) carbon labeled chlordane in a single oral dose. Feces and urine were collected at 12 hr intervals for 3 days and at 24 hr intervals thereafter. Animals were killed at various times after treatment and sample of tissue and blood were taken for radioassay. Urine was counted directly whereas feces, tissue, and blood were combusted and the trapped carbon-dioxide was counted. The initial absorption of chlordane was similar in rats and mice although the concentrations were consistently higher in rats. Peak blood concentrations occurred after 2 hr in rats and after 8 hr in mice. Rates of clearance of chlordane residues from blood and tissues were higher in rats than in mice. In rats the major tissue residue was the metabolite oxychlordane. Mice fell into two groups, low and high excretors. After 14 days the low excretors had eliminated 71% of the original chlordane dose and the high excretors essentially 100%; the rats essentially excreted 100% of the original dose. The difference in excretion pattern among the mice was not related to feed/water intake, amount of excreta produced, liver weight, or to any visual observation of disease state. It was concluded that the fate of chlordane appears to be different in rats and mice. [Ewing AD et al; Toxicology Letters 26 (2-3): 233-9 (1985)]**PEER REVIEWED**
  
• The metabolism of the components of chlordane and the lipophilicity of the components and metabolites influence their distribution. Initial distribution to the liver and kidneys is more rapid than to fat, probably reflecting differences in vascularity of these sites. Subsequently, redistribution results in higher levels in the fat than other tissues. Low levels of cis- and trans-chlordane in fat and relatively higher levels of oxychlordane (a metabolite) and trans-nonachlor (a component) reflect the relative lability of the chlordane isomers and stability of the latter two compounds. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• While cis- and trans-chlordane have not been identified in human milk, chlordane metabolites and related chemicals present in commercial products (eg, oxychlordane, trans-nonachlor and heptachlor epoxide) have been identified in human milk. Oxychlordane residues were detected in 46% of 57 human milk samples in Arkansas/Mississippi, in 68% of 6 samples in low pesticide usage areas of Mississippi, and in 100% of 50 samples in Hawaii. On a whole milk basis, mean concentrations of oxychlordane ranged from 0.002 to 0.005 mg/L. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• Excretion of radioactivity in the urine of rats given a single oral dose of radiolabeled chlordane accounted for /approximately/ 2-8.5% of the administered dose. The chlordane doses used in this study were 0.05-1.0 mg/kg of a 3:l mixture of cis- and trans-chlordane, or 0.2 mg/kg of each isomer separately. Based on these urinary excretion data, EPA stated that chlordane absorption from the gastrointestinal tract of rats was at least 28.5% of the administered dose. More recent information, however, indicates that absorption from the gastrointestinal tract of rats and mice may be substantially higher than previously estimated. Biliary excretion of chlordane (and/or its metabolites) played a significant role in the elimination of this compound in both species, suggesting that a large amount of the radioactivity found in the feces following oral administration of radiolabeled chlordane represents absorbed material. A first-order absorption model suitably described the experimental data in rats. The extent of chlordane absorption after oral exposure was estimated by comparing areas under the plasma concentration versus time curves (AUC) of radioactive equivalents of chlordane after oral or intravenous dosing at 0.1-1.0 mg/kg. Absorption was estimated to be /approximately/ 80% of the administered dose in rats, and this percentage did not vary significantly over the dose range tested. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• In rabbits, the estimated absorption of chlordane following various repeated oral dosing regimens with radiolabeled compound has been between 30% and 50% of the cumulative 14C dose, based on radioactivity eliminated in the urine. The various dosing regimens used in these studies included: radiolabeled trans-chlordane given to male rabbits at /approximately/ 3.8 mg/kg/day for 10 weeks,25 ppm of a mixture of cis- and trans-chlordane fed to a male rabbit for 2 days (/approximately/ 1.22 mg/kg/day), and cis- or trans-chlordane (30 and 67 mg/kg/day, respectively) given in gelatin capsules to male rabbits for 4 days. Biliary excretion was not studied in the rabbit, and the estimation of 30-50% absorption (based on urinary excretion) must be considered a minimum estimate. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• Tropical freshwater cichilds, cichlasoma species, weighing 300 g each, were individually placed in 16 L of water with 80 mug of cis-(14)C-chlordane for 72 hr. Fish absorbed the compound rapidly, accumulating 2.8 ppm in visceral fat, 1.2 ppm in bile, & 1.1 ppm in gall bladder. Recovery of radioactivity added to water at end of 72 hr was estimated to be 64.8 & 6.1% in fish & exposure water, respectively. Rate of elimination of absorbed radioactivity was about 2.9%/wk. 12.5% was accounted for by metabolites and remainder was unchanged cis-chlordane. [FEROZ M, KHAN MAQ; J AGRIC FOOD CHEM 27 (6): 1190-7 (1979) ]**PEER REVIEWED**
  
• Bluegill fish rapidly absorbed cis(14)C-chlordane or (14)C-photochlordane during a 48 hr exposure to 5 ppb. Elimination of chlordane was linear but slow during the 6 wk period; photochlordane was biphasic, being rapid in early phase (first 3 wk). Less than 7% of radioactivity retained in chlordane-treated fish was in the form of 2 conjugates, which on acid hydrolysis yielded at least 8 hydroxylated products. [SUDERSHAN P, KHAN MAQ; J AGRIC FOOD CHEM 28 (2): 291-7 (1980) ]**PEER REVIEWED**
  
• Ten vegetable crops were monitored for chlordane residues following soil treatment at 1.4, 2.8, 5.6 and 11.2 kg/hectare of chlordane. Maximal residues (0.15 and 0.11 mg/kg of tissue) found in beets and cucumbers grown in soil treated at the 11.2 kg/hectare rate. Chlordane levels in remaining crops were between 0.01 mg/kg - 0.1 mg/kg of tissue. [USDA, Agric Research Service; Chlordane Residue in Crops (1965)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• In mice treated orally every other day for 28 days with technical chlordane, cis- and trans-chlordane reached peak levels in the whole body on the first day and declined to lower levels in spite of repeated dosing; cis- and trans-nonachlor and oxychlordane increased during the entire study period. The ratio of cis- to trans-chlordane and cis- to trans-nonachlor in the test sample (6:7 and 1:4, respectively) and in the mouse body at termination of the experiment (5:3 and 1:7, respectively) suggests that trans-chlordane is metabolized more readily than cis-chlordane and that cis-nonachlor is metabolized more readily than trans-nonachlor. The decreasing content of the chlordane isomers and the increasing content of oxychlordane with repeated dosing suggests that chlordane induces its own metabolism. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• The metabolism of trans-chlordane (chlordane) and oxychlordane by rat liver microsomes was studied in vitro. Liver microsomes prepared from male Sprague-Dawley rats were incubated with 12.3 nmol chlordane in the presence or absence of a reduced NADPH generating system under air or atmospheres of nitrogen or carbon monoxide for 15 min at 37 degrees C. Rat liver microsomes were incubated with 11.8 nmol oxychlordane in air with NADPH and in the presence or absence of 0.2 mM 1,1,1-trichloropropene-2,3-oxide for 15 min at 37 degrees C. Approximately 11% of the chlordane was metabolized in the presence of NADPH and under air. No metabolism occurred when NADPH was absent from the reaction mixture. Degradation of chlordane was decreased by 67% when nitrogen was substituted for air. No chlordane metabolism occurred under the carbon-monoxide atmosphere. Oxychlordane was metabolized to an appreciable extent when 1,1,1-trichloropropene-2,3-oxide was absent from the incubation mixture. When present, 1,1,1-trichloropropene-2,3-oxide caused a sharp decrease in the amount of oxychlordane that was metabolized. The authors conclude that oxidative degradation of chlordane is catalyzed by hepatic microsomal cytochrome P-450. Oxychlordane, an oxidized metabolite of chlordane, is metabolized further by hepatic epoxide-hydrolase. [Kawano M et al; Chemosphere 19 (12): 1829-33 (1989)]**PEER REVIEWED**
  
• Metabolism appears to be largely oxidative, involving hepatic microsomal cytochrome P-450. Epoxide hydrolase is probably the predominant enzyme involved in further degradation of oxychlordane, but the process appears to be slow in animals and humans. In addition, reductive dehalogenation, probably resulting in the formation of reactive free radical intermediates, may be important in the toxicity of chlordane. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• Metabolism for the chlordane molecule involves four routes … The first proposed metabolic route starts with hydroxylation at position three of the molecule to form 3-hydroxychlordane. This reaction is thought to be mediated by the microsomal mixed-function oxidase (MFO) system. Dehydration of 3-hydroxychlordane leads to 1,2-dichlorochlordene and eventually to other metabolites such as oxychlordane and l-hydroxy-2-chlorochlordene. Alternatively, 3-hydroxychlordane may undergo replacement of chlorines by hydroxyl groups to form monochlorodihydroxylated and -trihydroxylated derivatives. The second pathway starts with dehydrochlorination to form heptachlor. The mechanism of this reaction is not completely understood but is thought to be mediated by the cytochrome P-450 system and/or by glutathione-S-transferase type enzymes. Further metabolism of heptachlor leads to 1-hydroxychlordene, heptachlor epoxide, or eventually to 1-chloro-2,3-dihydroxydihydrochlordene. The third pathway starts with dehalogenation of chlordane to form l-chlorodihydrochlordene, probably mediated by microsomal MFO systems. Further reactions probably involve hydrolysis and conjugation with glucuronic acid. The fourth metabolic pathway, and probably the least understood, involves hydrolytic removal of a chlorine atom and its replacement by a hydroxyl group to form l-chloro-2-hydroxychlordene chlorohydrin. This product may undergo further metabolism to form monochlorodihydroxy- and trihydroxy- derivatives of dihydrochlordene. Studies with rat hepatic microsomes suggest that cytochrome P-450 may be the most important enzyme to catalyze degradation of trans-chlordane. Epoxide hydrolase is probably the predominant enzyme to catalyze degradation of oxychlordane. Reductive dehalogenation, with the production of free radicals, may also be important in the toxicity of chlordane. [DHHS/ATSDR; Toxicological Profile for Chlordane (Update) PB/95/100111/AS (May 1994). Available from: http://www.atsdr.cdc.gov/toxprofiles/tp77.html as of July 7, 2004. ]**PEER REVIEWED**
  
• In vivo and in vitro studies in rats have revealed /several/ routes of biotransformation of chlordane and shown that the metabolites include: trans-chlordane, 1,2-dichlorochlordene, oxychlordane, 1-hydroxy-2-chlorochlordene, 1-hydroxy-2-chloro-2,3-epoxy chlordene, chlordene chlorohydrin, and 1,2-trans-dihydroxy dihydrochlordene, as well as metabolites of heptachlor. In vitro studies showed that the liver of rat and man have almost identical capacity to degrade chlordane except that human liver has little capacity to convert trans-nonachlor to trans-chlordane. [Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982., p. 230]**PEER REVIEWED**
  
• Oxychlordane has been isolated from the fat of dogs, rats, pigs, and cattle. It has also been isolated from human fat. /Investigators/ indicated that the fecal extracts of rats fed 14C-chlordane showed the presence of eight radioactive areas on the TLC plate. Although the structures of the metabolites were not fully elucidated, they were tentatively identified as mono-, di-, and tri-hydroxylated products of chlordane. [WHO; Environmental Health Criteria Document No. 34: Chlordane (57-74-9). Available from http://www.inchem.org/pages/ehc.html as of July 7, 2004. ]**PEER REVIEWED**
  
• Tropical freshwater cichilds, cichlasoma species, weighing 300 g each, were individually placed in 16 L of water with 80 ug of cis-(14)C-chlordane for 72 hr. Dichlorochlordene, oxychlordane, chlordene chlorohydrin, dihydroxy heptachlor, dihydroxyl dihydrochlordene plus 4 unidentified compounds accounted for 12.5% of radiocarbon recovered from fish and water. Remainder was unchanged cis-chlordane. [FEROZ M, KHAN MAQ; J AGRIC FOOD CHEM 27 (6): 1190-7 (1979) ]**PEER REVIEWED**
  
• Aspergillus niger can utilize chlordane from nutrient solutions, with more than 90% loss found in 48 hr for chlordane concentrations initially below 38 ppm. [Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979., p. 22-8]**PEER REVIEWED**
  
• (14)C-labeled trans-chlordane in acetone was applied to leaves of young cabbage plants. ... Three metabolittes were observed. One of the metabolites was ... Dihydroxy-beta-dihydroheptachlor. [Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974., p. 87]**PEER REVIEWED**
  
• ... An actinomycete (Nocardiopsis sp.) isolated from soil was capable of extensively degrading chlordane in pure culture. Growing broth cultures of Nocardiopsis metabolized pure cis- or trans-chlordane to at least 8 solvent soluble substances including dichlorochlordane, oxychlordane, heptachlor, heptachlor endo-epoxide, chlordane chlorohydrin, and 3-hydroxy-trans-chlordane. Identifications were based on GC or MS analysis. Oxychlordane was metabolically inert, and accumulated in the mycelium as a terminal residue. patterns of metabolic activity in microorganisms were compared to the residue patterns in chlordane treated soil. [Beeman RW, Matsumura F; J Agric Food Chem 29 (1): 84-9 (1981) ]**PEER REVIEWED**
  

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Footnotes

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