National Toxicology Program

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

Names (NTP)

• Lindane
• (1ALPHA,2ALPHA,3BETA,4ALPHA,5ALPHA,6BETA)-1,2,3,4,5,6-HEXACHLORO-CYCLOHEXANE (9CI)
• GAMA-HCH

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: ... /Investigators/ found that patients tolerated highly purified gamma-isomer (lindane) at rate of 40 mg/man/day for 14 days, although same dosage of technical BHC produced diarrhea, vertigo, and headache. [American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 3]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Chronic exposure to vapors of ... /lindane/ has resulted in fatal aplastic anemia & other hematologic disorders. These adverse effects have not been reported following use of 1% lindane lotion, cream, or shampoo. [American Hospital Formulary Service-Drug Information 85. Bethesda, MD: American Society Hospital Pharmacists, 1985. (Plus supplements A & B, 1985)., p. 1601]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... Therapeutic doses used in treatment of scabies have been found to have neurotoxic and other effects (ie, nausea, convulsions, cyanosis). Ingestion of large (unspecified) doses has led to muscle and kidney necrosis and, in 1 case, to pancreatitis. Digestive tract inflammation, hemorrhage, coma, & death have been reported after lindane poisoning. [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 220 (1979)]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Irritation of eyes, skin, nose, throat; dizziness, headache, nausea, vomiting, diarrhea, tremors, weakness, convulsions, dyspnea, cyanosis; aplastic anemia; muscle spasms. [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. 986]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Aplastic anemia has been reported with prolonged administration of lindane lotion. Inhalation of lindane vapors may produce headache, nausea, vomiting, and irritation of eyes, nose, and throat. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3440]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... Dermatitis has ... been reported among workers in lindane manufacturing operations, but the reported cases were possibly attributable to precursors and by-products not typically found in commercial formulations ... Although the agricultural products may contain as much as 40% lindane, post-treatment dermatitis has also occasionally occurred in patients treated for scabies with 1% formulations ... . [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 316]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... abdominal pain, nausea, vomiting, excitability, seizures, muscle tremors, hyperreflexia, and coma /from acute ingestion/. Rhabdomyolysis, myoglobinuria, and leukocytosis have been observed. [Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1066]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Exposure to lindane ... produces signs of poisoning that resemble those caused by DDT (eg, tremors, ataxia, convulsions, stimulated respiration, and prostration). In severe cases of acute poisoning, violent tonic and clonic convulsions occur and degenerative changes in the liver and renal tubules have been noted. [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 772]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: ... Refreshment stand operators suffered severe headache, nausea, and irritation of eyes, nose, and throat shortly after exposure to vapors from a dispenser in which lindane ... became overheated. Symptoms abated two hours after device was removed. [Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982., p. 223]**PEER REVIEWED**
  
• CASE REPORTS: Accidental ingestion by a 1-year-old boy of 1 teaspoonful of a 1% lindane solution, in addition to local application of this solution for the treatment of scabies, resulted in irritability, hyperactivity, and vomiting, followed by recovery in the hospital. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:671]**PEER REVIEWED**
  
• CASE REPORTS: Dermal application of 1% lotions of lindane ... for treatment of scabies resulted in ... marked mental and motor retardation ... noted 2 days after treatment in a 4-month-old child. Local application of 1% lindane proved particularly dangerous following a hot soapy bath, because this increased percutaneous absorption of the 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. 5:671]**PEER REVIEWED**
  
• CASE REPORTS: A two month old, 4.5 kg, male infant was found dead in his crib after excessive application of 1% lindane lotion. It was identified in brain at concentration of 110 ppb which was three times greater than levels found in blood. [Davies JE et al; Arch Dermatol 119 (2): 142-4 (1983) ]**PEER REVIEWED**
  
• CASE REPORTS: Kwell, a pediculicide for external use, contains a solid organochlorine, 1% lindane (BHC). In six months, ... five cases of accidental ingestions of Kwell /have been treated/. Case #1 occurred in a mental institution, #2 and #3 involved misunderstanding by a Spanish speaking mother and #4 and #5 were a mother and child who mistook Kwell for a bottle of cough syrup. The first case was given ipecac but seized while vomiting and aspirated, seized several more times and arrested. He suffered anoxic brain damage when resuscitated, developed rhabdomyolysis and died in one week. Treated with cholestyramine, his BHC blood level fell from 1.3 mg/L to 0.11 mg/L on the fifth day. BHC tissue levels were measured at autopsy. /Cases/ #2, #3, ingested 30 to 60 mL each, #3 seizing initially was not given ipecac. Their BHC levels were 0.22 and 0.48 mg/L, respectively. Cases #4 and #5 took a teaspoon each and were managed at home with poison center /consultation/. [Kurt TL et al; Vet Human Toxicol 28: 569-71 (1986) ]**PEER REVIEWED**
  
• CASE REPORTS: In the biopsy report of one man who had eaten lindane-contaminated foods and who had experienced grand mal seizures for 2 hr, /observers/ described widespread muscle necrosis that followed acidemia, hypertension, myoglobinuria, anemia, and acute renal failure. [American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 3]**PEER REVIEWED**
  
• CASE REPORTS: In 18 month-old infant fatally poisoned with lindane, about 350 ppm were found in the adipose tissue and 88 ppm in the liver. Unchanged compound was found in feces; and several urinary metabolites ... [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 220 (1979)]**PEER REVIEWED**
  
• CASE REPORTS: ... Intentional ingestion of a concentrated lindane solution in a 25-year-old patient, 16 weeks pregnant, resulted in death of twin fetuses. [Ford MD, Delaney KA, Ling LJ, Erickson T; Clinical Toxicology. W.B. Saunders Company., Philadelphia, PA. 2001, p. 833]**PEER REVIEWED**
  
• CASE REPORTS: Three of 19 elderly patients treated topically with 1% lindane /each/ developed a single seizure of 5-10 minutes duration within 4-5 days of application. Although it was not recommended, all of the patients received a hot bath prior to lindane application, and they may have been given up to twice the recommended dose. This combined with atrophic skin, a generalized dermatitis in one patient, and perhaps and age-related increased sensitivity, may have predisposed these patients to seizures. [Goldfrank, L.R. (ed). Goldfrank's Toxicologic Emergencies. 7th Edition McGraw-Hill New York, New York 2002., p. 1370]**PEER REVIEWED**
  
• CASE REPORTS: Vomiting and diarrhea occurred in a child and a woman who had 1% gamma-HCH applied to the skin to treat a rash and to treat scabies. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.109 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• CASE REPORTS: There have been cases of adverse events reported for Lindane Lotion and Lindane Shampoo in which a serious outcome (hospitalization, disability or death) has occurred. In approximately 20% of the total reported cases, Lindane Lotion and Shampoo were reported to have been used according to the labeled directions. Of these cases, thirteen deaths were reported, many cases which were remote from the time of actual Lindane use. Lindane toxicity, verified by autopsy was the cause of one infant's death, was the cause of death reported for an adult who ingested it orally in a successful suicide. The direct causes of death for the other cases were attributed to reasons other than Lindane. Most of these adverse events occurred with Lindane Lotion. [US FDA; Lindane lotion USP, 1% Available from http://www.fda.gov/cder/foi/label/2003/006309lotionlbl.pdf as of July 20, 2006 ]**PEER REVIEWED**
  
• CASE REPORTS: The blood level /4 hours after/ ... accidental ingestion of the contents of a bottle of Kwell (lindane) lotion /by a toddler/, which resulted in short-term adverse effects ... /was/ 0.32 ug/mL. [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.19 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• CASE REPORTS: ... A central nervous stimulant ... lindane has highest acute toxicity /of BHC isomers/; its lethal dose is perhaps 125 mg/kg. ... Few human fatalities have been ascribed to ... lindane, but many nonfatal poisonings have been reported. In U.S. many of these ... occurred in children who swallowed lindane pellets intended for use in vaporizers. ... Within 30 minutes after ingesting an estimated 1.5 grams lindane, a 2.5 year old girl exhibited irritability and grand mal convulsions. With supportive care she recovered within 24 hours; serum levels of lindane were high initially but fell rapidly. Considerable amounts were recovered in first stool samples. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-239]**PEER REVIEWED**
  
• CASE REPORTS: A woman ... developed urticaria soon after vaporizer was installed in her place of employment. Dermatitis improved during weekends but recurred when she returned to work. ... Complete recovery followed removal of vaporizer. [Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982., p. 223]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Sixty male workers between 24 and 62 years old employed 1 to 30 years in lindane producing factory were examined with regards to functions of nervous system in comparison with 2 external control groups (20 clerks and 20 dairy workers of same age distribution) having no contact with hazardous substances. No signs of neurological impairment of pertubation of "neuromuscular function" could be ascertained. [BAUMANN K ET AL; INT ARCH OCCUP ENVIRON HEALTH 48 (2): 165-72 (1981) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Data from population-based case-control studies of non-Hodgkin's lymphoma among white men from Kansas, Nebraska, Iowa, and Minnesota were pooled to evaluate potential risks from environmental exposures in more detail, while controlling for potential confounding factors. These data provided the opportunity to evaluate the risk of non-Hodgkin's lymphoma from potential exposures to lindane, a pesticide that causes cancer in laboratory animals and has been associated with human cancer in a few epidemiologic investigations. This pooled data set includes 987 individuals with non-Hodgkin's lymphoma and 2,895 population-based controls. Information was obtained by telephone or in person interviews, which included detailed questions on farm practices and agricultural use of chemicals. Logistic regression was used to calculate odds ratios (ORs) adjusted for age, state of residence, and subject or proxy interviews. Reported use of lindane significantly increased the risk of non-Hodgkin's's lymphoma by 50%. Some use characteristics were suggestive of an association. ORs were greater among persons who first used the pesticide 20 years before diagnosis (OR = 1.7) than more recently (OR = 1.3), among those who reported more frequent use (OR = 2.0 for use 5 or more days per year versus 1.6 for fewer than five days per year), and from use on crops (OR = 1.9), rather than from use on animals (OR = 1.3), although these differences were not statistically significant. On the other hand, ORs were lower when based on direct interviews (OR = 1.3) than on data from proxy respondents (OR = 2.1) and adjustment for potential confounding by use of 2,4-D and diazinon reduced the ORs associated with lindane use from 1.5 to 1.2 and 1.3, respectively. Lindane does not appear to be a major etiologic factor in the development of non-Hodgkin's's lymphoma, although a small role cannot be ruled out. [Blair A et al; American Journal of Industrial Medicine 33 (1): 82-7 (1998) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: In the cacao growing region in the southern part of the state of Bahia, gamma benzene hexachloride has been used for about 40 yr on cacao crops and in public health programs for control of the insect vectors of different diseases, especially malaria. The results of tests performed on 127 persons are presented; all males, between the ages of 15 and 52 yr, three groups consisted of persons occupationally exposed to 1.5% benzene hexachloride, that is, technical hexachlorocyclohexane; two groups consisted of individuals who had had occasional contact with the product or worked in areas near those in which they were used; and the last group - the control group - consisted of 50 individuals who had had no history of occupational exposure to insecticides. All the participants underwent testing to determine the parameters of biochemistry, hematology, and organochlorine insecticide residues in the blood. It was found that improper handling of the product and failure to use individual protective equipment, together with longer time of exposure, significantly increased the rates of GOT and GPT in the appliers of technical hexachlorocyclohexane, and the rates of alkaline phosphatase, albumin, and cholesterol were also found to be higher. [Carvalho WA; Bol Of Sanit Panam 111 (6): 512-24 (1991) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: ... Eighty individuals, 40 of whom were employed in a plant in which lindane was processed /were studied/. All were Caucasians; 12 were female. Each of these people was matched with a control having no occupational exposure ... Only blood lindane concentrations were found to differ in the control and occupational groups; they were 0.1 and 11.9 ppb, respectively ... Significant differences were not observed in regard to blood uric acid, alkaline phosphatase, platelet count, hemoglobin and lymphocyte, eosinophil and monocyte counts. There was no evidence of pancytopenia with reticulopenia, the hallmark of hypoplastic or aplastic anemia ... The possibility of an idiosyncratic or a hypersensitive response in a few individuals /was not ruled out/. Although ... conclusions that are based on statistical analysis of relatively small groups of people /were questioned/, /It was concluded/ that “within the limitations of this study, lindane does not appear to produce hematologic disorders on a basis of toxic suppression of hematopoiesis.” [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:672]**PEER REVIEWED**
  
• SURVEILLANCE: ... 488 reports of adverse events related to the use of lindane /are/ in the Adverse Event Reporting System (AERS) database as of April 1, 2002. ... The AERS database reports included: outcome of death (15), hospitalization (46), life threatening condition (7), and congenital anomaly (6). Only sixteen of these cases occurred with lindane shampoo, and four of the sixteen were oral ingestion. There were fifteen deaths, nine in adults and five in children, and one stillborn infant possibly exposed during pregnancy. Of the cases where the route of administration could be determined, thirteen of the patients were treated topically and one patient ingested lindane to commit suicide. Two adult cases reported serious preexisting conditions, and four were elderly. Three of the elderly patients died within 24 hours of treatment, one from pulmonary edema, one from chronic obstructive pulmonary disease, and the third of /an/ unreported condition. A fourth elderly patient suffered a seizure on the day of death, 41 days after treatment with lindane. Three of the four elderly patients had contraindications to the use of lindane. Three of the pediatric deaths were secondary to the other causes, including respiratory syncytial virus infection, myelocytic leukemia, and lymphoma of the brain. The fourth pediatric case involved a fetus that may have been exposed in utero and was stillborn. The adverse event report form stated that application occurred up to four times over four days. This would suggest that the child received multiple treatments on consecutive days. FDA has concluded that in all age groups, adverse events occurred mainly in patients who appeared to have misapplied or ingested lindane. [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.23 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006 ]**PEER REVIEWED**
  
• SURVEILLANCE: Lindane used in malaria control in India in 1975-77 caused no skin and coordination problems in 464 sprayers, nor did it cause higher SGPT and serum alkaline phosphatase activities or serum whole cell counts relative to 201 controls. ... Serum protein concentration was affected, as was serum glucose. [Que Hee, S. (ed.). Biological Monitoring an Introduction. New York, NY: Van Nostrand Reinhold Co., 1993., p. 501-2]**PEER REVIEWED**
  
• BIOMONITORING: In a document from 1982, WHO has recommended that a whole blood lindane concentration of 0.02 mg/L ( ca 70 nmol/L) be used in biologic monitoring as an individual maximum value. [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 152]**PEER REVIEWED**
  
• IMMUNOTOXICITY: In vitro exposure of human peripheral blood mononuclear cells (PBMC) to 0.1-0.3 mM lindane inhibited the mitogenic response to a T-cell mitogen. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 771]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The rapidity with which symptoms develop after the ingestion of BHC varies with the isomer: the gamma isomer is fastest (within 1 hr) and the alpha isomer /is the slowest/ (within 24 hours), and the technical or commercial mixture is intermediate (usually within 2 hours but sometimes as late as 12 hours). Death from the pure gamma isomer is usually prompt (24 hr), whereas from the others it may be several days. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-240]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Statistically significant increases in the levels of serum luteinizing hormone were reported in a group of 54 men occupationally exposed to unspecified concentrations of gamma-HCH for approximately 8 years in a gamma-HCH producing factory. Although the mean serum concentration of follicle stimulating hormone was increased and testosterone was decreased, these differences were not statistically significant compared to mean values determined in a control group. These hormonal changes may have resulted in diminished reproductive capability. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.37 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The effect of lindane that is observed at lowest exposure levels is thought to be the induction of hepatic monooxygenase enzyme system. Induction (shortened half-time of model drugs) has been observed when the plasma lindane concentration exceeds about 30 nmol/L ... [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 152]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The chronic toxicity for isomers of BHC decreases in the order beta > alpha > gamma > delta and is directly related to their tissue retention, and inversely to rates of metabolism. This contrasts with the order of acute toxicities, which are in the decreasing order of gamma > alpha > delta > beta. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:668]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: alpha-, gamma- and delta-Hexachlorocyclohexane, but not the beta-isomer, are shown to be potent stimuli for the production of superoxide anion (O2-) and the release of calcium in human polymorphonuclear leukocytes. [Kuhns DB et al; Blood 68 (2): 535-40 (1986) ]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: Mild eye irritation was seen in rabbits exposed to 40 mg/kg gamma-HCH in the conjunctival sac for up to 72 hours, giving a primary irritation score of 0.6 out of a maximum possible cumulative score of 16. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.111 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: It is not an eye or dermal irritant /in rabbits or a dermal sensitizer in guinea pigs/. [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.27 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Daily oral exposure /of New Zealand rabbits (Oryctolagus cuniculus)/ to lindane (4.21 mg/kg bw, 90% a.i.) for 28 days did not cause acute poisonings..., but did result in decreased feed intake and weight loss compared to controls. Hematological changes in rabbits exposed to lindane were minimal. Rabbits orally dosed with either endosulfan or lindane had increased alanine aminotransferase (ALT) activities immediately after initiation of dosing, suggesting liver toxicity with hepatocyte damage, bile duct alterations, and generalized damage to liver, kidney, and heart. [Shore R.F., Rattner BA. Ecotoxicology of Wild Mammals. Ecological & Environmental Toxicology Series 2001. John Wiley & Sons, New York, N.Y. 2001, p. 220]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Increased kidney weights of females and bone marrow effects occurred at 1.3 mg/kg/day (LOAEL) in a 90-day inhalation study in rats. /from table/ [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.26 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Dietary administration of ... gamma-hexachlorocyclohexane (HCH) to albino rats caused an abnormal excessive excretion of glucose in the urine, blood glucose level being nearly normal. Occurrence of glucosuria was also accompanied by increased excretions of the two low threshold compounds, creatinine and urea, their levels in blood being normal. The interference of HCH isomers with renal function as evidenced by biochemical data was also indicated by histopathological lesions observed in the kidney sections, including, hypertrophy and degeneration of the renal tubular epithelia. [Srinivasan K et al; J Environ Sci Health 19 (4-5): 453-66 (1984) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Differences in activities of enzymes involved in lindane metabolism may account for different carcinogenic activity observed among Osborne-Mendel rats, CF1, and B6C3F1 mice. Animals were treated 3 days or 3 months at various dosage levels. B6C3F1 mice showed no increase in absolute or relative liver weight. In susceptible CF1 strain it led to large increase in both sexes, while a smaller increase was observed in Osborne-Mendel rats. At highest dose a 5 to 6-fold induction of glutathione-S-transferase activity was observed in female CF1 mice, which then together with male CF1 mice had higher activity than untreated and treated B6C3F1 mice and rats. Rat liver microsomes showed higher UDP-glucuronosyl transferase activity than mouse liver microsomes. Untreated and treated CF1 mice showed higher monooxygenase activity and, after treatment, lower epoxide hydrolase activity than rats. [OESCH F ET AL; CHEM-BIOL INTERACT 40 (1): 1-14 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Canaries were exposed to vapors of lindane (liberated as a cloud when a solid formulation was heated) in air concentration of 0.34 mg/L; the birds died after 6-16 days of exposure ... [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:669]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In series of experiments in 8-week-old DD mice ... lindane (99% pure by gas chromatography) was added to diet at concentrations of 100, 250, and 500 mg/kg diet. Each group included 20 mice ... treatment lasted ... 24 weeks at which time all survivors were killed. /No signs of carcinogenic effects were observed/. (The IARC working group noted the short duration of the experiment). [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 211 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In an experiment lasting 110 weeks ... a group of 29 male and 29 female /CF1 mice/ received 400 mg/kg diet lindane (purity, 99.5%). A group of controls comprising 45 male and 44 female mice were fed a standard diet. Benign and malignant liver tumors were found in ... animals receiving 0 ... or 400 mg/kg lindane: In males, 11 (24%) ... and 27(93%), respectively; and in females, 10 (23%) ... and 20 (69%), respectively. Lung metastases were found in ... 3 (10%) males ... and 9 (3%) females ... . [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 212 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Groups of 50 NMRI mice of each sex received diets containing 12.5, 25, or 50 mg/kg diet lindane (purity not specified), starting at 34 days of age. Untreated controls included 100 mice of each sex. Treatment lasted 80 weeks, at which time all survivors were killed; a total of 79 control and treated mice died during the experiment, with no effects related to treatment. Liver tumors were found in 4 control males and 1 control female, in 2 males and 1 female fed 12.5 mg/kg diet and in 2 males fed 50 mg/kg diet; all were liver-cell adenomas except 1 malignant hemangioendothelioma in a male fed 12.5 mg/kg ... a total of 35 animals developed lymphocytic leukemia or lymphosarcoma (17 controls and 7, 4, and 7 mice fed 12.5, 25, and 50 mg/kg diet, respectively); and 50 mice developed lung tumors (21 controls and 11, 8, and 10 mice fed 12.5, 25, and 50 mg/kg diet, respectively). Other tumors included 8 reticulum-cell neoplasms (1 in controls), and 3 cutaneous or subcutaneous sarcomas. (The IARC working group noted the relatively low dose administered, in comparison with other experiments with lindane 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. V20 213 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: /In a study reported by the NCI in 1977/ Groups of 50 male and 50 female B6C3F1 hybrid mice, 5 weeks of age, were fed diets containing 80 or 160 mg/kg lindane (100% pure) for 80 weeks, and then observed for additional 10-11 weeks. Groups of 50 mice of each sex were used as controls; of these only 10 were fully contemporary to the treated animals, whereas the other 40 overlapped the study with lindane by at least a year. Survival rates were similar for treated and control groups; at least 88% of the males and 89% of the females lived to the end of the study. In males, hepatocellular carcinomas were found in 5/49 pooled controls (2/10 matched controls), in 19/49 mice fed 80 mg/kg diet and in 9/46 mice fed 160 mg/kg diet. The corresponding proportions in females were 2/47 (0/10), 2/47, and 3/46. In addition, 1 mouse of each sex in matched controls, 3 males and 1 female pooled controls, 2 females fed low dose and 1 male fed high dose had neoplastic nodules of liver in absence of hepatocellular carcinoma. Four hepatocellular carcinomas in males given low dose produced metastases. ... In males, first liver tumor was observed at 60 weeks in those given the low dose, at 77 weeks in controls and at 79 weeks in high-dose group. (The IARC working group noted the relatively low dose used and the small number of controls contemporary to the experimental groups). [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 213 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: /In a study reported in 1950/ Groups of 10 male and female weanling Wistar rats were fed for lifespan on diets containing 5, 10, 50, 100, 400, 800, or 1,600 mg/kg diet lindane as solution in corn oil; or 10, 100, or 800 mg/kg diet powdered lindane /> 98% pure/. Average lifespan was significantly reduced in all groups given the 800 mg/lg diet levels, except for those given powdered lindane; mean age at death was 58 weeks in group of 40 controls ... and 33-70 weeks in experimental groups ... No increase in tumor incidence was reported in treated animals; however, organs were examined microscopically in only /some/animals ... (The IARC working group noted the early mortality and the relatively small proportions of rats submitted to pathological study). [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 214 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: /In a study reported by NCI in 1977/ Groups of 50 male and female 5-week-old Osborne-Mendel rats were fed diets containing lindane (100% pure) at 2 dose levels for 80 weeks and kept under observation for further 29-30 weeks.Preliminary experiments had indicated that a dietary concentration of 640 mg/kg diet caused a reversible early decrease in wight gain but no deaths; therefore, initial dietary concentrations of lindane were set at 640 and 320 mg/kg diet. Because of intercurrent deaths, however, these concentrations were reduced to 1/2 after 2 and 38 weeks of treatment in females and males, respectively; in females, a further reduction to 1/4 of the original dietary concentration was introduced 49 weeks after beginning of treatment. Time-weighted average dietary concentrations were 236 and 472 mg/kg diet for males and 135 and 270 mg/kg mg/kg diet for females. Groups of 55 rats of each sex were used as controls; of these only 10 were fully contemporary to treated animals, whereas the other 45 overlapped the study with lindane by at least a year. Over 80% of rats lived for longer than 52 weeks. ...Proportions of rats that developed neoplastic liver nodules were males and females: 0/10 and 0/10 (matched controls), 0/49 and 1/49; thyroid follicular-cell adenomas or carcinomas: 1/6 and 0/8 (matched controls), 3/42 and 0/48 (pooled controls), 6/37 and 2/44 (low-dose) and 4/37 and 1/42 (high-dose); and thyroid c-cell adenomas: 1/6 and 0/8 (matched controls), 3/42 and 0/48 (pooled controls), 3/37 and 4/44 (p < 0.05) (low-dose) and 1/37 and 3/42 (high-dose), respectively. (The IARC working group noted the small number of contemporary controls and poor survival rates in all groups. In addition, there was no adequate evidence that the dose given to male rats corresponded to the max tolerated dose). [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 215 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: As with most other chlorinated insecticides, lindane has been shown to exhibit tumor promotional activity, possibly via inhibition of intercellular communication. Lindane exposures do inhibit formation of liver tumors following exposures to aflatoxin B1, suggesting an activity other than tumor promotion for lindane. Enhancement of enzymatic deactivation of aflatoxin via induction of microsomal enzymes may play a role in this phenomenon. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:670]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... Rats can tolerate long-term feeding of diets containing 800 ppm of lindane, but showed some liver enlargement at this level ... [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:668]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: /It was/ indicated that the highest tolerated daily dose of lindane in rats over a 2-year period without effect was 5 mg/kg or a dietary feeding level of 50 ppm. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:668]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Lindane technical, 99.5%-99.7% purity, was fed /to Wistar rats/ in the diet at 0, 1, 10, 100, and 400 ppm. Estimated achieved dosages were 0.05, 0.45, 4.5, and 18.7 mg/kg/day for males, and 0.06, 0.57, 5.6, and 23.1 mg/kg/day for females. In the toxicity phase, 15 Wistar rats/sex/group received treated diet for 30 days, 26 weeks, or 52 weeks. A fourth series (same group sizes) was treated for 52 weeks and then maintained on control diet for 26 weeks prior to sacrifice. The oncogenicity study used 55 animals/sex/group treated for 104 weeks. In all toxicity and oncogenicity phase groups, 5 rats/sex/group were allocated for lindane tissue level assays. NOEL = 1 ppm in males (hyaline droplets in proximal tubules, and periacinar hepatocytic hypertrophy at 10 ppm upwards). ... Kidney findings due to lindane have been shown to be associated with an alpha 2u-globulin mechanism, not considered relevant to humans. Common kidney findings in males at 100 and 400 ppm also included cortical tubule necrosis and regeneration, interstitial chronic nephritis, and papillary mineralization. Kidneys were not a target tissue in females. Periacinar hepatocytic hypertrophy incidence was markedly increased at 100 and 400 ppm in both sexes. Liver changes were largely reversible, particularly in males. Thus the NOEL of 10 ppm in females is an appropriate "working NOEL" for relevant chronic effects in males also. Pheochromocytomas were marginally elevated in 400 ppm males. This was considered a possible adverse effect in the initial Department of Pesticide Regulation review ... /but/ the lack of any compelling pattern of tumor incidence in the primary report as amended, coupled with the body of historical data showing this to be a common tumor type, indicate that the small numerical increase in pheochromocytoma incidence among 400 ppm males was incidental. Other findings included increased mortality in 400 ppm females and possibly also in 100 and 400 ppm males; body weight decrements after about 1 yr in both sexes at 400 ppm; increased incidence of convulsions in 400 ppm females; small reductions in RBC parameters (Hb, HCT, and RBC count) in 400 ppm males and females (with indications of a reciprocal increase in platelet counts in 100 and 400 ppm males); blood chemistry changes, generally limited to 400 ppm groups, which appeared to be treatment-related in males [increased calcium (minimum extent), and increased total protein], females (increased cholesterol and increased urea), or both (increased inorganic phosphorus and decreased albumin/globulin ratio); elevated organ weights (kidneys in 100 to 400 ppm males, and livers in 400 ppm males and females). [California Environmental Protection Agency Department of Pesticide Regulation; Lindane Summary of Toxicological Data (1998) Available from http://www.cdpr.ca.gov/docs/toxsums/pdfs/359.pdf as of July 21, 2006 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... /An attempt was made/ to determine quantitatively the ability of HCH isomers to promote tumor development. Rats received a single dose of N-nitrosomorpholine. Then five different doses of each HCH isomer or phenobarbital (as a positive control) were administered continuously via the diet for 4, 15, and 20 weeks. Both number and size of altered foci were enhanced by doses of 2 to 3 mg/kg or more of the three isomers; in addition, foci phenotypes showed a pronounced shift towards strong expression of gamma-glutamyltransferase and sharp demarcation from the surrounding liver. Based on daily doses the three HCH isomers were approx equipotent; based on concentrationn in liver or adipose tissues, gamma-HCH was several fold more effective than alpha- and beta-HCH. ... [Schroter C et al; Cancer Res 47 (1): 80-8 (1987) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Lindane was administered by intragastric intubation to New Zealand white rabbits (13 animals per group) from days 6 to 18 of gestation at doses of 0, 5, 10, and 20 mg/kg body weight. All treated animals showed slight tachypnea and lethargy during the dosing period. Body weight gain was reduced and food intake reportedly lower. Post-implantation loss and incidence of resorptions were higher at 5 and 20 mg/kg. The number of offspring with extra (13th) ribs was lower at 5 mg/kg and higher at 20 mg/kg, both statistically significant with Wilcoxon test. No differences were seen with a non-parametric analysis of variance as Kruskall Wallis test. Fetal and litter-weights were unafffected and the incidence of other anomalies was similar to the control. [European Chemicals Bureau; IUCLID Dataset, Lindane (58-89-9) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of April 21, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In /rat/ ... studies, fertility was not reduced but most of the F1 pups died shortly after birth ... The reproductive NOEL was 20 ppm, based on reduced neonatal pup survival (largely due to total litter losses), slightly reduced pup growth rate, and slightly slower pup development such as delays in hair growth and tooth eruption ... Regional changes in brain noradrenaline and serotonin levels have also been reported as developmental effects. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 397]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... The interaction of gamma-hexachlorocyclohexane (gamma-HCH) with the estrogen receptor of female Sprague-Dawley rats /was explored/. In the immature (21-day-old) female, administration of 40 mg/kg gamma-HCH for 7 days significantly attenuated the estrogen-dependent increase in uterine weight period. Dose-dependent delays in vaginal opening and onset of ovarian cyclicity were also observed. However, it did not alter the concentration of the estrogen receptor in the nuclei of uterine cells 30 hr after administration of gamma-HCH alone, or in combination with estradiol, compared to the relevant controls. In addition, combination with estradiol did not alter the induction of progesterone receptors in the uterus of the immature female, nor did it modify estradiol levels in the serum of estradiol-treated ovariectomized adult females. Thus, gamma-HCH does not appear to exert an estrogenic effect in the intact rat. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 734]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In male rats fed 75 mg/kg/day of lindane for 90 days, testicular atrophy, degeneration of semeniferous tubules, and disruption of spermatogenesis were reported. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 397]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The effects of premating, pregnancy, and lactational exposure to gamma-HCH (1 mg/kg/day) on reproduction in the ewe was evaluated ... Although pregnancy rate was significantly decreased by lindane, there were no effects on serum leuteinizing hormone, follicle stimulating hormone, thyroxin, or cortisol either under basal conditions or following administration of gonadtropin-releasing hormone, thyroid-stimulating hormone (TSH), and adrenocorticotropin. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 734]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a fertility study in rats, there was a reduction in the number of spermatids in the testes of rats 2 weeks after oral administration of a single lindane dose of 30 mg/kg. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3440]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a study designed to examine the effect of lindane on sexual receptivity, groups of five to nine female Fischer CD 344 rats were given lindane (purity unspecified) by ip injection at a dose of 0, 25, 33, 50 or 70 mg/kg bw in the morning of proestrus ... . The sexual receptivity of females was tested by housing them with experienced studs on the evening of proestrus for about 10 min or greater than 10 mounts. A successful mount was defined as a male accomplishing pelvic contact and a pelvic thrust. The lordosis:mount ratio was used to calculate female sexual receptivity. Females showing typical signs of mating behavior (i.e. hopping and darting) were considered proceptive. Statistically significant decreases in the lordosis:mount ratio coupled with decreased proceptive behaviour were reported at doses greater than 33 mg/kg bw. These decreases could not be attributed to decreases in overall activity, as the lindane-treated females kicked and avoided the males. They also showed normal levels of rearing and vocalization. Lordosis occurred within three mounts in controls and females at 25 mg/kg bw but only after seven mounts at 33 mg/kg bw, eight mounts at 50 mg/kg bw and six mounts at 75 mg/kg bw. ... The NOAEL was 25 mg/kg bw on the basis of decreased sexual receptivity and proceptive behavior. [FAO/WHO; JMPR Pesticide residues in food, Part II Toxicology- Lindane (2002). Available from: http://www.inchem.org/documents/jmpr/jmpmono/2002pr08.htm as of May 15, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: When mink were exposed to 1 mg/kg/day lindane from the time they were weaned for 3 generations, no overt signs of toxicity were noted. However, lindane treatment reduced the production of mated mink that subsequently whelped, and the litter size of mink that did whelp. Testes size was reduced in third-generation males. No effects were noted on serum concentrations of cortisol, testosterone, or estradiol during the study. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 734]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In the developmental neurotoxicity study, Han Wistar rats were exposed to 0, 10, 50, or 120 ppm gamma-HCH in the diet from gestation day 6 through lactation day 10. Reported daily maternal dose levels were 0, 0.8-0.9, 4.2-4.6, or 8.0-10.5 mg/kg/day during gestation, and 0, 1.2-1.7, 5.6-8.3, or 13.7-19.1 mg/kg/day during lactation. The F1 offspring were evaluated for functional observational battery (FOB), motor activity, auditory startle response, learning and memory, developmental landmarks (e.g., vaginal perforation and balanopreputial separation), and brain end points (weight, histology, and morphometrics) on postpartum days 11 and 65. Maternal toxicity occurred at 13.7 mg/kg/day as shown by effects that included decreased body weight gain (64-79% less than controls on gestation days 6-20), decreased food consumption, and increased reactivity to handling. The offspring showed effects at the two highest dose levels, including increased motor activity (both sexes), decreased habituation of motor activity (females), decreased body weights (12-20% less than controls), and decreased body weight gains (60-84% less than controls) during lactation days 1-11 (both sexes) at > or =5.6 mg/kg/day. Effects observed at 13.7 mg/kg/day included reduced auditory startle response habitation in both sexes, increased stillbirths (live birth index of 77% compared to 99% in controls), and increased neonatal mortality (postnatal day 4 viability index of 71% compared to 89% in controls). [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.90 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Lindane, an organochlorine insecticide, is suspected of preimplantation embryonic toxicity based on in vitro experiments with bovine and murine embryos. To verify this hypothesis in vivo /the authors/ tested lindane for developmental alterations during early embryonic cleavage in the mouse. Two treatment schedules were tested: three daily doses of 15 or 25 mg/kg bw lindane were orally administered to female mice either before mating or immediately after mating. Morphologic alterations (lysis or fragmentation of blastomeres, developmental arrest) of two-cell embryos and morulae were evaluated by inverted microscopy. In addition, cytologic abnormalities and cell proliferation delay, possibly induced during the first four cleavage cycles, were evaluated by fluorescent microscope analysis of the number and morphology of blastomere nuclei. A statistically significant increase of degenerating two-cell embryos was induced by exposure of preovulatory oocytes to the highest tested lindane dose. Early cleavage embryos exposed to the same dose showed a lower average number of blastomeres per morula, as well as a 40% reduction of the mitotic index with respect to matched controls. However, mean values in individual litters were variable and litter analysis did not show a lindane-related effect. One possible mechanism for the observed effects could be the recently demonstrated inhibitory action of lindane on gap junction-mediated cell communication between oocyte and cumulus cells. [Scascitelli M, Pacchierotti F; Reprod Toxicol 17 (3): 299-303 (2003) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Long-lasting effects on mouse spermatogenesis induced by prenatal exposure to the insecticide lindane have been investigated by conventional reproductive endpoints complemented by the flow cytometric (FCM) DNA content analysis of testis cells and by the Sperm Chromatin Structure Assay (SCSA). Two lindane dose levels, 15 and 25 mg/kg bw, and diethylstilbestrol (DES, 10 ug/kg bw) as positive control, were administered daily by gavage to pregnant CD1 mice on gestation days (GD) 9-16. Reproductive endpoints were evaluated on F1 male mice on postnatal day (PND) 60; additionally, animals treated with lindane 25 mg/kg per day and DES were examined on PND 100 to evaluate the possible reversibility of the effects. On PND 60, lindane and DES caused a reduction in the sperm head count and concentration, with recovery in older lindane 25 mg/kg per day animals (PND 100). By contrast, the DES group exhibited a greater reduction in the sperm head count on PND 100 than on PND 60. Changes in biochemical parameters in the testes, lactate dehydrogenase-C(4) (LDH-C(4)), and sorbitol dehydrogenase (SDH) activities, were also observed in adult treated F1 mice. Furthermore on PND 60, the FCM analysis revealed changes in the pattern of testicular germ cell distribution, especially in the haploid subcompartment, in the lindane 25 mg/kg per day group. A dose-dependent increase in chromatin abnormalities of the epididymal sperm was also shown by SCSA. These changes recovered on PND 100. Preliminary qualitative examination did not reveal any significant difference in the structure of testicular tissue; however, there were suggestions of a moderate increase in number and size of Leydig cells in both DES- and lindane-treated animals. The partial reversibility of these effects and the lack of structural modification of the testicular tissue as evidenced by histopathologic assessment suggest a functional impairment of sperm production and maturation, possibly associated with changes induced by lindane on factors affecting intratesticular steroidogenesis. [Traina ME et al; Reprod Toxicol 17 (1): 25-35 (2003) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases in T3 and/or T4 in both sexes and generations at 300 ppm were presumed to be secondary changes associated with the induction of hepatic drug-metabolizing enzymes. Blood hormone analysis revealed no changes in sex hormones attributable to lindane in males or females. Hepatic drug-metabolizing enzyme activities were increased dose-dependently from 10 ppm in both sexes and generations, with the rise in BROD activity being the most prominent. There were also increases in MROD, EROD, T-6beta-OH, and T4-UDP-GT activities (BROD >> EROD > MROD, T-6beta-OH, T4-UDP-GT). This suggests that while lindane most strongly induces CYP2B, it also upregulates a number of other drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT. As for effects on reproductive function, lack of maternal behavior, including lactation and retrieval behavior, and consequent total litter loss were observed in F1 dams at 300 ppm. There were no effects of lindane on the estrous cycle, spermatogenesis, mating, fertility, pregnancy, or parturition. Neonatal toxicity was observed in both sexes and generations, including suppressed body weight gain at 60 and 300 ppm, and decreased thymus and spleen weights without histological change at 300 ppm. The postnatal survival rate in F2 offspring was decreased due to lack of maternal behavior in dams at 300 ppm. [Matsuura I et al; J Toxicol Sci 30: 125-61 (2005) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The chlorinated insecticide Lindane can be considered as an endocrine disrupter, according to its pattern of effects and possible mechanisms of action. Two groups of pregnant CD1 (12 dams each) mice were treated /orally/ on gestational days 9-16 with daily doses of 15 mg/kg bw of Lindane in corn oil and vehicle only (C). F1 mice were observed for general and sexual development up to sexual maturity and were sacrificed on postnatal day 60, whereas dams were killed on postnatal day 23. The uterus, ovary and mammary glands of both dams and F1 female were ... stained with hematoxylin and eosin for histological and histomorphometric examinations. Using an image analysis system (Arkon by Nikon) and an optical microscope ... , / the authors/ calculated the endometrium area/myometrium area ratio and the rate of the area occupied by glands inside the endometrium to the total endometrium area. Lindane did not induce maternal toxicity or prenatal and postnatal toxicity. Earlier vaginal opening was observed in treated females (2 days) in comparison to controls. No effects on maternal absolute or relative uterus weight were present. In F1 generation, the relative uterus weight was slightly increased (4.3%) in treated females. Preliminary histological analysis of ovary and mammary glands of both dams and F1 females did not reveal major alterations. The uteri of treated group showed slightly increased branching of villi and oedema in the endometrial stroma. Preliminary histomorphometric analysis of uteri showed a slightly reduced endometrium/myometrium area ratio in treated females in comparison to controls, although the difference was not statistically significant. No differences were observed regarding the rate of the areas occupied by glands to the total endometrium area. ... /The authors/ reported in a previous paper that Lindane (15 or 25 mg/kg bw) elicited a moderate and reversible impairment of spermatogenesis in male F1 mice exposed in utero and examined at the onset of sexual maturity. The present preliminary findings suggest that prenatal exposure to Lindane might exert slight endocrine modulation also during female sexual development ... [Maranghi F et al; Reprod Toxicol 17 (4): 499-500 (2003) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Lindane technical ... purity 99.5 to 99.7%. Two generation study, 1 litter/generation, with test article administered in the diet at 0, 1, 20, and 150 ppm to 30 CD rats (Charles River, Margate, England) per sex per group. Treatment began 10 weeks prior to mating. Estimated dose levels for low, medium, and high doses, respectively during week 1 of the F0 pre-mating period were 0.14, 2.77, and 19.7 mg/kg/day for males and 0.13, 2.75, and 19.5 mg/kg/day for females. Corresponding values at week 10 of premating were 0.05, 0.99, and 7.42 mg/kg/day for males and 0.06, 1.20, and 8.74 mg/kg/day for females. F1 pre-mating doses were comparable. Parental NOEL = 1 ppm [increased incidence of periacinar hepatocytic hypertrophy in males (slight degree); typical alpha 2u-globulin-related kidney effects in males, such as hyaline droplets in proximal tubules, tubular necrosis, regeneration, tubular casts, and chronic interstitial nephritis]. Neither of the above findings appears important to human safety, since the liver effect was shown to be reversible after much higher exposures in the combined study, and the kidney effects are species- and sex-specific. Parental NOAEL = 20 ppm (slight body weight decrements in females during gestation, and in F1 males during the growth period; periacinar hepatocytic hypertrophy in both sexes; apparent hydronephrosis effect in males). Reproductive NOEL = 20 ppm [reduced neonatal pup survival (largely due to total litter losses); slightly reduced pup growth rate; slightly slower pup development (delays in hair growth and tooth eruption)]. Acceptable, with a possible adverse effect (decreased pup survival). [California Environmental Protection Agency Department of Pesticide Regulation; Lindane Summary of Toxicological Data (1998) Available from http://www.cdpr.ca.gov/docs/toxsums/pdfs/359.pdf as of July 21, 2006 ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Daily doses of 0.5 mg/kg bw lindane given orally for 4 months to female rats produced disturbances of estrus cycle, inhibited animals' capacity for conception and fertility, lowered viability of embryos and delayed ... physical development. Treatment of rats with 0.05 mg/kg bw did not produce such effects. No significant teratogenic effect of stillborn pups was produced by administration of oral doses of 5, 10 or 20 mg.kg bw lindane on days 6-18 of gestation to rabbits or on days 6-15 of gestation to rats. An increased incidence of stillborn pups was observed in litters of beagle bitches given 7.5 or 15 mg/kg bw/day from day 5 throughout gestation. [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 217 (1979)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Dietary lindane (5, 10, or 15 mg/kg) lengthened average duration of pregnancy in rats from 21-22 days in control animals to 21-24 days. Fertility index decreased from 100 births per control parental population to 60 births per parental population in the lindane-fed (15 mg/kg) animals. A dose-dependent delayed initiation of first estrus in offspring was observed in lindane-treated rats. Progressive increase /occurred/ in proportion of stillbirths with each successive generation. [Petrescu ST et al; Rev Med Chir Soc Med Nat Iasi 78 (4): 831-842 (1974) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: ... Repeated, relative low-level exposures /of rats/ to lindane (10 mg/kg/day for 7 days) during postnatal week 1 or 2 induced transient changes in reflex behaviors (eg, surface righting, cliff avoidance) and locomotor hyperactivity, in the absence of overt signs of toxicity ... Early postnatal lindane exposure reduced the level of myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase activity, an enzyme in high concentrations in myelin and myelin-forming cells, in a dose-dependent manner. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 879]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: The effects of three isomers (alpha, beta, gamma) of hexachlorocyclohexane (HCH) on the acquisition and expression of kindled amygdaloid seizures were compared. Treatment with corn oil (vehicle) was compared with daily 5 mg/kg doses of the isomers for 15 days during kindling procedures. The results confirmed the proconvulsant action previously described for the gamma-HCH isomer (lindane). alpha-HCH did not produce significant effects. Rats treated with beta-HCH exhibited delayed rates of kindling acquisition and less severe seizures. [Stark LE et al; Neurobehav Toxicol Teratol 8 (5): 487-91 (1986) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: As with other chlorinated pesticides, lindane exhibits substantial neurotoxic effects following acute or chronic exposures. The symptoms may include violent epileptiform convulsions, rapid in onset and quickly leading to either death or recovery ... There is evidence that chronic lindane exposure may lead to decreases in muscarinic receptors in the brain, increases in calcium uptake in rat brain synaptosomes, and possible inhibition of Na,K-ATPase-linked calcium extrusion in neural tissue. There is also an indication that lindane interferes with transmission of gamma-aminobutyric and (GABA) transmission at neuronal junctions. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:668]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Lindane exposure (either acute (20 mg/kg) or repeated (10 mg/kg/day for 7 days)) in rats 15 days of age caused complex behavioral changes (improvement in passive avoidance behavior, alterations in locomotor activity) and apparent enhanced turnover of brain monoaminergic neurotransmitters. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 879]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: The neurotoxicity of gamma-HCH has also been assessed in acute, subchronic, and developmental exposure screening batteries in rats. In the acute study, a single 0, 6, 20, or 60 mg/kg dose of gamma-HCH was administered to Crl:CDBR rats. End points included functional observational battery (FOB) and motor activity (MA) tests performed prior to treatment, within 3 hours of dosing (time of peak effect), and on post-exposure days 7 and 14, as well as histopathology of nervous system tissues at study termination. No clinical signs or other effects were observed at 6 mg/kg. Exposure to 20 mg/kg caused decreased motor activity 3 hours post-treatment in females at > or = to 20 mg/kg and in males at 60 mg/kg. Females also had increased forelimb grip strength and decreased grooming behavior at 20 mg/kg, and an absence of grooming behavior at 60 mg/kg. Other effects at 60 mg/kg, included clinical signs (e.g., piloerection, urine-stained fur, tremors, and/or convulsions) in both sexes and increased hindlimb foot splay in males. Gavage administration of 2.5, 5, 10, or 15 mg gamma-HCH/kg/day for 5 days produced a dose-dependent increase in the activities of EROD, PROD, and NDMA-d in the brain of Wistar rats. Compared with the liver, the magnitude of the induction of the P-450 enzymes in the brain was much smaller. In the same study, /the authors/ examined the effect of metabolism on the convulsive effect of gamma-HCH in rats. A single dose of 35 mg/kg of gamma-HCH induced convulsions in 4 out of 10 animals. Pretreatment of the rats with 3-methylcholanthrene (MC), an inducer of P-4501A1/1A2, had no significant effect in the incidence of convulsions induced by gamma-HCH. However, pretreatment with phenobarbitol (PB), an inducer of P-4502B1/2B2, or ethanol, an inducer of P-4502E1, or blocking P-450-mediated metabolism with cobalt chloride, significantly increased the incidence of convulsions caused by gamma-HCH. Taken together, the results suggest that the convulsive activity is due to gamma-HCH per se and/or to metabolites formed by PB- or ethanol-inducible P-450 isoenzymes. [DHHS/ATSDR; Toxicological Profile for alpha-, beta-, gamma-, and delta-Hexachlorocyclohexane p.89 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: In the subchronic neurotoxicity screening battery, Crl:CDBR rats were exposed to 0, 20, 100, or 500 ppm gamma-HCH in the diet for 13 weeks. Due to severe toxicity, the high concentration was reduced to 400 ppm on day 11. Reported average daily intake levels of gamma-HCH for the entire study were 0, 1.4, 7.1, and 28.1 mg/kg/day for the males and 0, 1.6, 7.9, and 30.2 mg/kg/day for the females. End points included functional observational battery (FOB) and motor activity (MA) tests performed prior to administration and after 4, 8, and 13 weeks of treatment, and histopathology of nervous system tissues at study termination. No clinical signs or other changes were observed in females at 1.6 mg/kg/day or males at < or = to 7.1 mg/kg/day. Effects in females at 7.9 mg/kg/day included decreased body weight gain and food consumption (40 and 16% lower than controls, respectively, during the first week). Both systemic and neurotoxic effects occurred in both sexes at the high dose, including clinical signs (e.g., staining of urogenital region, piloerection, abnormal grooming behavior), increased rearing, walking on tiptoes, hypersensitivity to touch, hunched posture, weight loss, and several deaths. In the developmental neurotoxicity study, Han Wistar rats were exposed to 0, 10, 50 or 120 ppm gamma-HCH in the diet from gestation day 6 through lactation day 10 (Myers 1999). Reported daily maternal dose levels were 0, 0.8 to 0.9, 4.2 to 4.6, or 8.0 to 10.5 mg/kg/day during gestation, and 0, 1.2 to 1.7, 5.6 to 8.3, or 13.7 to 19.1 mg/kg/day during lactation. The F(1) offspring were evaluated for FOB, motor activity, auditory startle response, learning and memory, developmental landmarks (e.g., vaginal perforation and balanopreputial separation), and brain end points (weight, histology, and morphometrics) on postpartum days 11 and 65. Maternal toxicity occurred at 13.7 mg/kg/day as shown by effects that included decreased body weight gain (64 to 79% less than controls on gestation days 6 to 20), decreased food consumption, and increased reactivity to handling. The offspring showed effects at the two highest dose levels, including increased motor activity (both sexes), decreased habituation of motor activity (females), decreased body weights (12 to 20% less than controls), and decreased body weight gains (60 to 84% less than controls) during lactation days 1 to 11 (both sexes) at > or = to 5.6 mg/kg/day. Effects observed at 13.7 mg/kg/day included reduced auditory startle response habitation in both sexes, increased stillbirths (live birth index of 77% compared to 99% in controls), and increased neonatal mortality (postnatal day 4 viability index of 71% compared to 89% in controls). This study was classified as an unacceptable developmental neurotoxicity study by EPA in 2000 because there was no laboratory validation of the neurobehavioral tests and the number of animals (six per dose level) was insufficient. [DHHS/ATSDR; Toxicological Profile for alpha-, beta-, gamma-, and delta-Hexachlorocyclohexane p.89 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Patch clamp experiments using rat dorsal root ganglia (DRG) neurons showed differential actions of the 4 HCH isomers. Gamma-HCH had a weak potentiating action and a strong inhibitory action on gamma-aminobutyric acid (GABA)-induced currents. Delta-HCH had a strong potentiating action and an inhibitory action. Alpha-HCH and Beta-HCH had little or no effect on GABA-induced currents. The differential modulation of GABA response by HCH isomers accounts for variable symptoms of poisoning in insects and mammals. However, somewhat different results were obtained for the effects of HCH isomers on the alpha 1-beta 3-gamma 2S (short splice variants of the gamma 2 subunit) and alpha 6-beta 3-gamma 2S subunit combinations of GABA-A receptors expressed in Xenopus oocytes. GABA responses were inhibited by gamma-HCH, potentiated by alpha- and delta-HCH, and not affected by beta-HCH. Furthermore, the alpha subunit composition had no influence on these effects of HCH isomers. These differences in the responses to chemicals represent an example of the dissimilarity between native receptors and receptors expressed in xenopus oocytes which is often encountered. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 343]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Two opposite effects of lindane on the threshold from pentylenetetrazol-induced convulsions have been reported ... The convulsive properties of lindane on the convulsive threshold of pentylenetetrazol and brain content of GABA (gamma-aminobutyric acid) in the mouse /was studied/. /It was found/ that following the administration of a single dose of lindane, the threshold first decreases and then, after 2 days, increases above the normal level. None of the tested metabolites of lindane altered the convulsive threshold. When lindane elevated the convulsive threshold, it also elevated the GABA content of the brain. Lindane elevated both convulsive threshold and the GABA content. The smallest single oral dose of lindane lowering the convulsive threshold for pentylenetetrazol in the mouse, 3 hr after administration, corresponded to a lindane concentration of 56 ppb in whole blood. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:668]**PEER REVIEWED**
  
• GENOTOXICITY: Lindane was not mutagenic in host-mediated assay when Salmonella typhimurium (strain G46) and Serratia marcescens (strain A21) were used for reversion studies. ... Exposure to lindane was not accompanied by increase in respiration-deficient yeast mutants. ... No sex-linked recessive mutants were found in Drosophila melanogaster injected with 0.001% soln ... although it does not induce mutations, lindane is potent in inducing complete c-mitosis (colchicine-like effect; mitotic arrest at metaphase) in Allium cepa roots. ... Induction of mitotic arrest, as well as polyploidy, by lindane have also been recorded in root tips of 8 varieties of common plants, including Pisum sativum /pea/. Commercially avail powder &and liquid insecticide preparations containing lindane (10 or 20%) and lindane crystals (100% pure) induced chromosome aberrations in Allium cepa roots. ... Lindane caused slight increase in frequencies of chromatid gaps and breaks in Chinese hamster fibroblasts in vitro. [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 219 (1979)]**PEER REVIEWED**
  
• GENOTOXICITY: Lindane technical ... 99.7% by weight, was tested with Fischer 344 adult male primary rat hepatocytes. Cells were incubated for 18.8 hours with 0 (DMSO), 0.25, 0.50, 2.5, 5.0, 10 or 15 ug/mL with 2-AAF as positive control. Triplicate cover slips for UDS by autoradiography and duplicates for viability by dye exclusion were scored. No evidence of induction of unscheduled DNA synthesis. [California Environmental Protection Agency Department of Pesticide Regulation; Lindane Summary of Toxicological Data (1998) Available from http://www.cdpr.ca.gov/docs/toxsums/pdfs/359.pdf as of July 21, 2006 ]**PEER REVIEWED**
  
• GENOTOXICITY: Lindane (purity unspecified) tested at 0, 15.8, 50, 158, 500, 1580, and 5000 ug/plate with and without S9 in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2 uvrA; duplicate plates; S9 mixes prepared + or - Aroclor induction from NMRI and CF-1 mice; additional assays with TA98 with and without activation and with and without the drug norharman. NO ADVERSE EFFECT: no mutagenicity with lindane under any conditions. [California Environmental Protection Agency Department of Pesticide Regulation; Lindane Summary of Toxicological Data (1998) Available from http://www.cdpr.ca.gov/docs/toxsums/pdfs/359.pdf as of July 21, 2006 ]**PEER REVIEWED**
  
• GENOTOXICITY: Lindane technical ... 99.7% by weight, was tested for induction of chromosomal aberrations with CHO-WBL cells. Concentrations for non-activated cultures were 0 (negative and DMSO), 38.1, 50.8, 76.1, 102 and 152 (toxic) ug/ml with a 20 hour harvest. For activation with Aroclor 1254-induced male rat liver S9, three harvest times were used: 10, 20 and 30 hours following a 2-hour treatment. Concentrations scored were: 10 hours - 25, 49.9, 74.9 and 99.8 ug/mL; 20 hours - 25.4, 50.8, 76.1, 102 and 152 (toxic) ug/mL; 30 hours - 99.8 and 150 (toxic) ug/mL. No induction of chromosomal aberrations was reported. [California Environmental Protection Agency Department of Pesticide Regulation; Lindane Summary of Toxicological Data (1998) Available from http://www.cdpr.ca.gov/docs/toxsums/pdfs/359.pdf as of July 21, 2006 ]**PEER REVIEWED**
  
• GENOTOXICITY: Negative in V79 cells for mutation to HGPRT deficiency up to levels of toxicity and/or solubility, with or without activation. [California Environmental Protection Agency Department of Pesticide Regulation; Lindane Summary of Toxicological Data (1998) Available from http://www.cdpr.ca.gov/docs/toxsums/pdfs/359.pdf as of July 21, 2006 ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: gamma-Hexachlorocyclohexane-induced hepatotoxicity is associated with oxidative stress. ... The hypothesis that gamma-hexachlorocyclohexane triggers the redox activation of nuclear factor-kappaB (NF-kappaB), leading to proinflammatory cytokine expression /was tested/. Liver NF-kappaB activation (electrophoretic mobility shift assay), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1alpha (IL-1alpha) mRNA expression (reverse transcription-polymerase chain reaction), and their serum levels (enzyme-linked immunosorbent assay) were measured at different times after gamma-hexachlorocyclohexane treatment (50 mg/kg). The relationship between these and hepatic O(2) uptake, glutathione and protein carbonyl levels, and sinusoidal lactate dehydrogenase (LDH) efflux in liver perfusion studies was determined. gamma-Hexachlorocyclohexane increased liver NF-kappaB DNA binding at 14-22 hr after treatment, concomitantly with significant glutathione depletion and an increase in the rate of O(2) consumption, the content of protein carbonyls, and the sinusoidal LDH efflux. In these conditions, the expression of TNF-alpha and IL-1alpha is enhanced, with maximal increases in their respective mRNA content and serum levels of the cytokines being elicited at 18 hr after gamma-hexachlorocyclohexane treatment. All these changes are suppressed by the administration of alpha-tocopherol (100 mg/kg) or the Kupffer cell inactivator gadolinium chloride (10 mg/kg) prior to gamma-hexachlorocyclohexane. gamma-Hexachlorocyclohexane-induced TNF-alpha levels in serum are suppressed by pretreatment with an antisense oligonucleotide (ASO TJU-2755; daily doses of 10 mg/kg for 2 days) targeting the primary transcript for the cytokine, whereas those of IL-1alpha are not modified. It is concluded that gamma-hexachlorocyclohexane-induced liver oxidative stress triggers the DNA binding activity of NF-kappaB, with the consequent increase in the expression of NF-kappaB-dependent genes for TNF-alpha and for IL-1alpha, factors that may mediate the hepatotoxicity of the insecticide. [Videla LA et al; Antioxid Redox Signal 6 (2): 471-80 (2004) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: The insecticide lindane (gamma-hexachlorocyclohexane) inhibits gap junction intercellular communication in rat myometrial cells by a mechanism involving oxidative stress. /The authors/ hypothesized that oxidation of reduced glutathione (GSH) to glutathione disulfide (GSSG) and subsequent S-glutathionylation provide a mechanistic link between lindane-induced oxidative stress and lindane's inhibition of myometrial gap junction communication. Gap junction communication between cultured rat myometrial myocytes was assessed by Lucifer yellow dye transfer after microinjection. A biphasic pattern was confirmed, with dye transfer nearly abolished after 1 h of exposure to 100 microM lindane followed initially by recovery after lindane removal, and then the development 4 h after termination of lindane exposure of a delayed-onset, sustained inhibition that continued for 96 h. As measured by HPLC, cellular GSH varied over a 24-h period in a biphasic fashion that paralleled lindane-induced inhibition of dye transfer, whereas GSSG levels increased in a manner inversely related to GSH. In accordance, GSH/GSSG ratios were depressed at times when GSH and dye transfer were low. Lindane substantially increased S-glutathionylation in a concentration-dependent manner, measured biochemically by GSSG reductase-stimulated release of GSH from precipitated proteins. Furthermore, treatments that promoted accumulation of GSSG (50 microM diamide and 25 microM 1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU]) inhibited Lucifer yellow dye transfer between myometrial cells. Findings that lindane induced GSH oxidation to GSSG with increased S-glutathionylation, together with the diamide and BCNU results, suggest that oxidation of GSH to GSSG is a component of the mechanism by which lindane inhibits myometrial gap junctions. [Caruso RL et al; Toxicol Sci 86 (2): 417-26 (2005) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: The in vitro effect of the gamma-isomer of hexachlorocyclohexane, lindane, on rat Leydig cell steroidogenesis was studied. Leydig cells from mature male rats were incubated with human chorionic gonadotropin (hCG, 1 IU) for 3 hr at 34 deg C in the presence of different doses of lindane (2-200 ug/mL; 2-200 ppm). Results demonstrate that lindane produces a dose-dependent inhibition of testosterone production in hCG-stimulated Leydig cells. The decreased testosterone synthesis was accompanied with a half-reduced LH/hCG receptor number without any modification in the K(d) value. In addition, lindane also decreased cAMP production. These effects were not due to a detrimental action of lindane on cell viability. Results of this study demonstrate a direct inhibitory action of lindane on testicular steroidogenesis, at least in part, through a reduction in the classical second messenger production involved in this pathway. [Ronco AM et al; Toxicology 159 (1-2): 99-106 (2001) ]**PEER REVIEWED**
  
• GENOTOXICITY: /Human cell line/ Concentration of 5-10 ug/mL lindane inhibited cell division in human peripheral blood lymphocytes in vitro and caused concentration-related increase in frequency of chromatid breaks. In SV40-transformed human fibroblasts (VA-4), 1 or 1,000 umol lindane failed to induce unscheduled DNA synthesis ... in presence or absence of rat liver microsomal activation system. [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 220 (1979)]**PEER REVIEWED**
  
• IMMUNOTOXICITY: Immunosuppression, as measured by decreased agglutinin titers against typhoid vaccine and Salmonella vaccine, was reported in rats /treated/ by gavage to 6.25 and 25 mg gamma-HCH/kg/day for 5 weeks and in rabbits /treated with/ capsules 5 times each week to 1.5, 6, and 12 mg/kg/day for 5-6 weeks. Humoral immune response, as indicated by serum antibody response to injected sheep red blood cells (SRBC), was suppressed in rats that were exposed to gamma-HCH in estimated dietary doses of 3.6 or 7 mg/kg/day for 8 weeks. The primary antibody response to SRBC was also suppressed in albino mice after /treatment with/ 9 mg/kg/day gamma-HCH in the diet for 12 weeks. Suppression of secondary antibody response was also observed after 3 weeks of /treatment with/ 9 mg/kg/day gamma-HCH and after 12 weeks of 5.4 mg/kg/day gamma-HCH /treatment/. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.86 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• IMMUNOTOXICITY: A biphasic dose-dependent immunological effect of gamma-HCH on components of cell- and humoral-mediated immunity, characterized by initial stimulation followed by immunosuppression, was reported in mice fed 0.012, 0.12, or 1.2 mg gamma-HCH/kg/day for 24 weeks. In addition, histological examinations revealed decreased lymphocyte populations in the thymus and lymph nodes and a reduction in overall cellularity in the spleen and necrosis of the thymus at 1.2 mg/kg/day. Cell-mediated immune response, as measured by delayed type hypersensitivity reaction to dinitrofluorobenzene antigen, was suppressed in sheep that were exposed to 1.25 ppm gamma-HCH in the diet for 6 months. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.86 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• IMMUNOTOXICITY: Administration of 150 ppm lindane per day orally for 1 month to mice did not alter the levels of IgA, IgG1, IgG2a, and IgM in the serum or the ability to generate a humoral immune response to sheep red blood cells. However, the serum levels of IgG2b were elevated ... [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 771]**PEER REVIEWED**
  
• IMMUNOTOXICITY: In the rabbit, administration of 3 mg/kg/day or more lindane for 5 weeks decreased the humoral immune response to bacterial antigen ... [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 771]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Rapidity with which symptoms develop after ingesting BHC varies with the isomer: gamma is fastest (within 1 hr ... ), alpha slowest (within 24 hr), and technical or commercial mixt is intermediate (usually within 2 hr, but sometimes as late as 12 hr). Death from ... gamma isomer is usually prompt ... from others it may be delayed several days. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-240]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... Lindane causes alpha-2u-globulin nephropathy or hyaline droplet nephropathy. This nephropathy occurs in male rats, is characterized by the accumulation of protein droplets in the S2 segment of the proximal tubule, and results in single-cell necrosis, the formation of granular casts at the junction of the proximal tubule and the thin loop of Henle, and cellular regeneration. Chronic exposure to /lindane/ results in progression of these lesions and ultimately in chronic nephropathy ... Alpha-2u-globulin nephropathy appears to be sex- and species-specific. That is, it occurs in male rats but not female rats /nor/ in male or female mice, rabbits, or guinea pigs because they do not produce alpha-2u-globulin ... Current data suggest that humans are not at risk ... [Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 507]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: ... lindane exposure (50 mg/kg, ip) caused only minimal lipid peroxidation in liver of 30-day-old chickens but more extensive oxidative changes in 7-day-old animals ... Superoxide dismutase was inhibited and glutathione levels were elevated by lindane in 7-day-old but not 30-day-old chickens. Thus, lindane can cause diverse age-related changes that generally target younger animals. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 879]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Some studies of gamma-HCH in rodents suggest that oxidative stress and depletion of GSH may be developmentally significant. Mouse fetal and placental tissues exhibited increased superoxide production, lipid peroxidation, and DNA-single strand breaks at 48 hours after administration of single dose of 30 mg/kg gamma-HCH to pregnant dams on day 12 of gestation. In vitro exposures of rat conceptuses to gamma-HCH solutions of > or =50 uM on gestational day 10 resulted in significantly lower intracellular levels of GSH compared to controls. Data were not available, however, to determine whether a relationship exists in the prenatal rat between oxidative stress and GSH depletion. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.137 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The effect of oral administration of lindane (gamma-HCH) has been studied on the intestine in 10-day, 20-day and 100-day old rats. In 10 day-old suckling pups exposed to lindane, there was a significant decrease in the activities of sucrase (29%), lactase (20%) and that of alkaline phosphatase (24%) compared to control. Sialic acid content of the brush borders was significantly decreased (29%) in 10-day old as well as in 20- and 100-day old rats (20 and 25% respectively), while fucose content of the membranes was significantly enhanced in all the age groups upon pesticide treatment. Among the brush border lipids, cholesterol content was significantly increased in all the age groups studied, the maximum increase of 35% being observed in 10-day-old rats. Membrane phospholipids were also increased in 20- and 100-day old animals (22% each) on lindane exposure. The present studies indicated that brush border membranes of suckling rat intestine were more susceptible to pesticide induced changes compared to older animals. [Labana S et al; Indian J Biochem Biophys 38 (4): 249-52 (2001) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: A low-protein diet potentiated the effects of gamma-HCH on reducing the weights of various organs in male rats. Serum and liver lipid contents and cholesterol levels were increased in animals fed low-protein diets. The low-protein diet increased the levels of gamma-HCH found in the various organ tissues. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.150 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Guinea pigs maintained on diets deficient in vitamin C and protein showed altered gamma-HCH metabolism and excretion. Vitamin C deficiency decreased the amount of gamma-HCH and its metabolites excreted in the urine and increased the amount stored in the kidney. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.149 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 76 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Rat (male) oral 88 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:667]**PEER REVIEWED**
  
• LD50 Rat (female) oral 91 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:667]**PEER REVIEWED**
  
• LD50 Rat skin 500 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LC50 Rat inhalation 1.56 mg/L [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.27 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• LD50 Mouse oral 44 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Mouse ip 125 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Dog oral 40 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Rabbit oral 50 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:667]**PEER REVIEWED**
  
• LD50 Rabbit skin 50 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Rabbit (male) skin 1000 mg/kg [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.27 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• LD50 Rabbit (female) skin 900 mg/kg [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.27 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• LD50 Guinea pig oral 127 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Hamster oral 360 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  
• LD50 Hamster ip 640 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 365]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• A 1% lindane cream (Kwell) was applied to skin of 9 voluteers, left on for 12 hours and washed off with soap and water. Plasma concentratioin increased to 10.3 ng/mL (range 2-24 ng/mL). [HOSLER J ET AL; J INVEST DERMATOL 74 (1): 51-3 (1980) ]**PEER REVIEWED**
  
• ... Serum concentrations of lindane were determined in infants and children with and without scabies infection following application of 1% lindane lotion to the body surface area /for 24 hours instead of the maximum of 12 hours/ prescribed by the label. Studies were performed on 20 infected and noninfected patients who averaged 33 to 64 months of age ... Specimens of blood for determination of lindane concentrations were obtained at 0, 2, 4, 6, 8, 12, 24, and 48 hours after topical application of 1% lotion. The highest measured blood concentration from the clinical study was 0.064 ug/mL /at 6 hours/. [USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Lindane. p.19 September 25, 2002. Available from the Database Query page at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg as of July 21, 2006. ]**PEER REVIEWED**
  
• ... Transplacental passage ... has been established ... [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 220 (1979)]**PEER REVIEWED**
  
• Lindane is slowly and incompletely absorbed through intact skin when applied topically, from the GI tract when ingested, and through the mucous membranes when inhaled. Following topical application of 4 ug of radiolabeled lindane (in acetone) per sq cm of intact forearm surface area in adults in one study, 5.6-13% (mean 9.3%) of the dose was absorbed systemically. Percutaneous absorption usually is greater when the drug is applied to the face, scalp, axillae, neck, scrotum, or damaged or occluded skin. Total body application of lindane lotion in infants and children with scabies has resulted in mean peak blood concentrations of 28 ng/mL 6 hours after application. Lindane is stored in body fat ... and excreted in urine and feces. Lindane is distributed into human milk. ... Data suggest that the drug has a rapid distribution phase followed by a longer elimination phase. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 3441]**PEER REVIEWED**
  
• Lindane is lipophilic and is present in human breast milk, but exact quantities are not known. [US FDA; Lindane lotion USP, 1% Available from http://www.fda.gov/cder/foi/label/2003/006309lotionlbl.pdf as of July 20, 2006 ]**PEER REVIEWED**
  
• Concentrations of lindane in human breast milk are stated to be approximately 5-7 times higher than concentrations in the maternal blood or in umbilical cord blood. Older women tend to have higher lindane concentrations of HCH and lindane in placental and umbilical cord blood than younger women. It has also been noted that lindane concentrations increased in maternal blood during delivery and that during pregnancy higher concentrations have been found in fetal blood and fetal tissue as well as placenta and amniotic fluid compared to maternal fat tissue. [Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1065]**PEER REVIEWED**
  
• Delayed absorption of such organochlorine pesticides as lindane... has been demonstrated by the prolonged urinary excretion of these compounds up to 120 hr post dermal application. [Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1066]**PEER REVIEWED**
  
• The distribution of lindane ... was highest in the fatty tissue, followed by brain, kidney, muscle, lungs, heart, spleen, liver, and blood. Lindane has a propensity to accumulate in the brain more than the beta-HCH. Lindane also induces hepatic mixed function oxidase systems, increasing its own metabolism. This process may minimize or reduce the accumulation of lindane in tissues. [Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1065]**PEER REVIEWED**
  
• Absorption: Systemic, up to 13% may occur; significantly absorbed through the skin. Distribution: Stored in body fat. ...Time to peak serum concentration: Children: Topical: Within 6 hours after application. [Lelkin, J.B., Paloucek, F.P., Poisoning & Toxicology Compendium. LEXI-COMP Inc. & American Pharmaceutical Association, Hudson, OH 1998., p. 353]**PEER REVIEWED**
  
• ...The distribution, metabolism, and excretion of carbon-14 lindane in rats after they had become adapted to lindane administered orally /was studied/ ... Body fat, kidneys, and the musculature were the primary sites of accumulation. Marked differences in radioactivity levels were found between the cortex, brainstem, and cerebellum. The metabolite gamma-2,3,4,5,6-pentachlorocyclohexane amounted to 1-3% of the hexane extract after 24 hr, and 5-8% after 72 hr, in certain organs. Feces, urine, and organs contained large amounts of conjugates and highly polar, hexane-soluble metabolites.The level of extractable (ie, unbound) (14)C activity in the urine was 8%, and in the feces, 43%. The level of extractable activity was 35% in both urine and feces after 72 hr. An additional 3 and 8% after 24 hr, and 18 and 14%, respectively, after 72 hr, were present as glucuronides, and the remainder as unidentified water-soluble conjugates. In the urine, 1-3% of lindane was present in free form; 3-6% of the total lindane was extracted unmetabolized. Half of the lindane administered was excreted within 3-4 days. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:669]**PEER REVIEWED**
  
• Lindane in sheep blood is almost totally bound to serum proteins; at overall concentration of 0.850-1.040 ppm, proportion that was free varied from 1.29-1.49%. ... It may be partially displaced from blood proteins by ... other compounds ... stored in fat ... in rats ... it reaches storage equilibrium within 2-3 weeks at dietary levels of 1 or 10 ppm and in 3-7 days at ... levels of 100 ppm. ... Equilibrium and ... storage ... are consistent with dosage-related induction of microsomal enzymes. ... Residues of lindane disappear ... rapidly after dosing is discontinued. ... In rats preadapted by feeding ... dietary level of 10 ppm for 10 days and then given single oral dose ... /excreted/ 48.5 to 52.0% in urine and 20.8 to 22.2% in feces. [Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982., p. 214]**PEER REVIEWED**
  
• ... Lindane crosses the placenta and is excreted in human breast milk ... [Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 155]**PEER REVIEWED**
  
• Umbilical cord and venous blood samples were collected at the time of delivery from 52 mothers living in urban and rural areas of the Atoya River basin, Nicaragua ... /and/ analyzed for 13 organochlorine pesticides: 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (pp'-DDT); 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (pp'-DDE); pp'-dichlorophenyldichlorodiene (pp'-DDD); alpha-hexachlorocyclohexane (alpha-HCH); beta-hexachlorocyclohexane (beta-HCH); gamma-hexachlorocyclohexane (gamma-HCH); delta-hexachlorocyclohexane (delta-HCH); toxaphene; dieldrin; endrin; aldrin; heptachlor; and heptachlor epoxide. In venous blood only pp'-DDE (100% of samples), pp'-DDT (1.92%), dieldrin (15.38%), heptachlor (15.38%), gamma-HCH (7.69%), beta-HCH (11.53%), and delta-HCH (1.92%) were found, whereas in cord blood only pp'-DDE (100%), pp'-DDT (3.84%), dieldrin (19.23%), and heptachlor (9.16%), were found. [Dorea JG et al; Environ Res 86 (3): 229-37 (2001) ]**PEER REVIEWED**
  
• ... The body fat of stillborns and fetuses in Dade County, Florida (where pesticides are used more vigorously than in most parts of the United States), /was/ analyzed (by gas-liquid chromatography) /and/ recorded concentrations of alpha-BHC of 0.14 ppm, beta-BHC of 0.26 ppm, and gamma-BHC of 0.11 ppm. Little or no lindane or BHC was detected in the blood of individuals not occupationally exposed to lindane. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:672]**PEER REVIEWED**
  
• Because gamma-HCH is rapidly metabolized, the beta-HCH isomer is consistently found in higher concentrations in human fat, blood, and breast milk. [Willett KL et al; Environmental Science & Technology 32 (15): 2197-2207 (1998) ]**PEER REVIEWED**
  
• This paper describes, for the first time, how topical application in rats of a commercial preparation of lindane widely used in public health, at similar doses and routes of administration as in humans, leads to rapid absorption and accumulation of lindane in the testes. An early peak of absorption was detected in plasma 6 hr after topical treatment of male Wistar rats with a commercial preparation of 1% lindane (Plomurol). Higher plasma levels were observed after repetitive doses of 60 mg/kg bw, the amount recommended for the treatment of scabies and pediculosis in humans in several countries. A residue level of 7.4 +/ - 0.67 ug/g was found in testicular tissue 6 hr after a single daily topical application for 4 consecutive days. The ultrastructural study of testicular interstitial cells exposed to dermal application of lindane (Plomurol) revealed widespread damage of a great number of Leydig cells, some of which were completely disintegrated. [Suwalsky M et al; Hum Exp Toxicol 19 (9): 529-33 (2000) ]**PEER REVIEWED**
  
• There is evidence that gamma-HCH exposure causes functional impairment of the developing blood brain barrier (BBB) in young rats. The integrity (permeability) of the BBB was studied by assessing uptake of sodium fluorescein (a micromolecular tracer dye) into the brain of neonatal rats following single or repeated acute gavage doses of gamma-HCH. The brain uptake index of fluorescein was significantly increased in 10-day old pups treated with a single 2 mg/kg dose (72 and 23% higher than controls after 2 hours and 3 days, respectively), as well as in those treated with 2 mg/kg/day for 8 days (50% higher than controls 7 days after the first exposure, with recovery 20 days after the first exposure). The effect appeared to be age-related because the brain uptake index was lower when rats were administered a single 2 mg/kg/ dose at 15 days of age (20% higher than controls after 2 hours) or a higher dose of 4 mg/kg/day for 3 days as adults (no effect on brain permeability). [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.86 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• Gastrointestinal lindane bioavailability depends upon the vehicle; in rats, some 80% was absorbed when lindane was given in oil, but only 6% was absorbed when lindane was suspended in water. Lindane is distributed principally to adipose tissue, with peak concentrations achieved 2 to 5 days after a single experimental dose. Following a single parenteral injection in rats, 34% of the lindane was excreted unchanged in feces and 5% appeared in urine. Lindane tends to accumulate in adipose tissue, but it is eliminated within 1 week following discontinuation of exposure. Only very small amounts of lindane itself appear in urine, where it is eliminated as sulfate, glucuronide, and glutathione conjugates. [American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 2]**PEER REVIEWED**
  
• Absorption of lindane is highly dependent on the carrier vehicle; it is readily absorbed from solutions of alcohol or other organic solvents, even through the skin. Lindane is lipophilic and accumulates in adipose tissue, albeit to a much smaller extent than organochlorine pesticides in general. In repeated exposures, blood lindane concentrations reach a steady-state level within about a month or two ... metabolic clearance and elimination are rather efficient; half-time of lindane in blood is approximately 1 wk. [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 152]**PEER REVIEWED**
  
• ... Simultaneous application of lotions, ointments, or oils may enhance percutaneous absorption, especially in infants and children. [Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 1187]**PEER REVIEWED**
  
• Absorption of technical-grade HCH following oral exposure has been quantified in rats. The extent of absorption of technical-grade HCH has been estimated to be 95.8% in rats within 4 days following the oral administration of single doses of the substance. Variation of the dosages from 30 to 125 mg/kg had no effect on the percentage of absorption. The overall degree of absorption of technical-grade HCH administered in the feed for 14 days was similar (94.9%), but the average absorption values of alpha-, beta-, gamma-, and delta-HCH were 97.4, 90.7, 99.4, and 91.9%, respectively. [DHHS/ATSDR; Toxicological Profile for Hexachlorocyclohexane p.119 PB2006-100003 (August 2005) ]**PEER REVIEWED**
  
• Experiments with alpha-, beta-, and gamma-hexachlorocyclohexane showed that the absorption rates of the isomers were approximately equal. In 30-day feeding studies with rats, adipose tissue took up the alpha-HCH faster than beta-HCH, and much faster than gamma-HCH. Accumulation of beta-HCH in mammals is related to its low rate of metabolism and transport. [MACHOLZ R; NAHRUNG 26 (9): 747-57 (1982) ]**PEER REVIEWED**
  

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Metabolism/Metabolites

• Metabolism of gamma-BHC was studied in 21 workers producing this insecticide. Using GC with ECD and mass spectrometry 14 mono-, di-, tri-, and tetrachlorophenols were identified in urine. Seven dihydroxychlorobenzenes of unknown configuration were detected. 2,4,6-, 2,3,5-, and 2,4,5-trichlorophenol were main metabolites and were excreted in nearly equal quantities. [ANGERER J ET AL; INT ARCH OCCUP ENVIRON HEALTH 52 (1): 59-68 (1983) ]**PEER REVIEWED**
  
• The primary metabolites of lindane are chlorophenols and chlorobenzenes. Chlorinated metabolites in the urine have been found in lindane production workers. The major metabolite is trichlorophenol, which accounted for approximately 58% of lindane metabolites identified in the urine. Other metabolites are dichlorophenols, tetrachlorophenols, hexachlorobenzene, tetrachlorocyclohexanol, and pentachlorocyclohexene. Pentachlorophenol has also been identified as a urinary metabolite in humans after occupational exposure. [Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1065]**PEER REVIEWED**
  
• Human liver microsomes metabolized lindane to 4 primary metabolites, gamma-1,2,3,4,5,6-hexachlorocyclohex-1-ene; gamma-1,3,4,5,6-pentachlorocyclohex-1-ene; beta-1,3,4,5,6-pentachlorocyclohex-1-ene; and 2,4,6-trichlorophenol. The secondary metabolites, 2,3,4,6-tetrachlorophenol and pentachlorobenzene were also formed. [FITZLOFF JF ET AL; XENOBIOTICA 12 (3): 197-202 (1982) ]**PEER REVIEWED**
  
• In mice, urinary metabolites of single ip injection ... accounted for 57% of dose ... and consisted mostly of glucuronide and sulfate conjugates of 2,4,6-trichlorophenol and 2,4-dichlorophenol. No mercapturic acid conjugates were detected. When ... administered ip to rats, 2,3,5- and 2,4,5-trichlorophenol were identified in urine ... free or as conjugates with glucuronic and/or sulfuric acid. When weanling Sprague-Dawley rats were fed 400 mg/kg diet lindane, 3,4-dichlorophenol, 2,4,6-trichlorophenol, 2,3,4,5- and 2,3,4,6-tetrachlorophenol and 2,3,4,5,6-pentachloro-2-cyclohexene-1-ol were identified in urine. Pentachlorobenzene, 2,3,4,6- and 2,3,5,6-tetrachlorophenol and 2,4,6-trichlorophenol were excreted in urine of rats given oral doses ... pretreatment of rats with other organochlorine pesticides modified lindane metabolism. [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 218 (1979)]**PEER REVIEWED**
  
• ... /In vitro studies using rat liver homogenates to determine/ mechanism involved in formation of phenols ... indicated three pathways of formation ... from lindane: 1) Direct hydroxylation of lindane/derivatives & formation of gem-chlorohydrins. Subsequent decomposition to pentachlorocyclohexanones & dehydrochlorinations of tautomers give rise to 2,4,6-TCP. 2) Formation of HCCH (hexachlorocyclohexene) & PCCH (pentachlorocyclohexene) which give rise to gem-chlorohydrins through an ene-like reaction with activated oxygen. These products spontaneously form enones, tautomerize, & yield 2,4,5-TCP & 2,3,4,6-TeCP from PCCH & HCCH, respectively. 3) Direct hydroxylation of benzene analogs which form. [Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980., p. 72]**PEER REVIEWED**
  
• The metabolic pathway of the gamma isomer of BHC (lindane) in rats is highly complex. Metabolic routes include ring hydroxylation, dechlorination and/or reduction with double-bond formation, and others that lead to chlorinated phenols, chlorinated mercaptobenzenes, and various cyclohexenes and cyclohexadienes. Phenolic and hydroxy metabolites typically form excretable glucuronide and sulfate conjugates. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:669]**PEER REVIEWED**
  
• ...The distribution, metabolism, and excretion of carbon-14-lindane in rats after they had become adapted to lindane administered orally /was studied/ ... The metabolite gamma-2,3,4,5,6-pentachlorocyclohexane amounted to 1-3% of the hexane extract after 24 hr, and 5-8% after 72 hr, in certain organs. Feces, urine, and organs contained large amounts of conjugates and highly polar, hexane-soluble metabolites.The level of extractable (ie, unbound) (14)C activity in the urine was 8%, and in the feces, 43%. The level of extractable activity was 35% in both urine and feces after 72 hr. An additional 3 and 8% after 24 hr, and 18 and 14%, respectively, after 72 hr, were present as glucuronides, and the remainder as unidentified water-soluble conjugates. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 5:669]**PEER REVIEWED**
  
• The effect of chronic treatment with 160 ppm dietary lindane on the comparative metabolism and disposition of /lindane/ in obese yellow Avy/a, lean pseudoagouti Avy/a, and lean black a/a phenotypes of (YS X VY) F1 hybrid female mice at 17, 30, 56, and 86 wk of age. At 24 hr prior to necropsy, all mice were dosed po with 18 mg lindane (containing 55 uCi (U-14C)lindane)/kg. Urine, feces, and expired air were sampled for analysis. Data indicated that metabolism of lindane and excretion of its metabolites by these mice differ significantly from those of rats that are resistant to lindane-induced hepatomas. Treatment of the mice with 160 ppm lindane in the diet appeared to saturate the elimination pathways and resulted in an increased tissue burden of the insecticide and its metabolites in the older animals. [Chadwick RW et al; Journal of Toxicology and Environmental Health 20: 411-34 (1987) ]**PEER REVIEWED**
  
• Laying hen pheasants were admin carbon-14 lindane in gelatin capsules & with seed treated with labeled lindane. Residues were determined in eggs & in tissues of hatched chicks. Residues in eggs from birds given treated seed showed greater variation in total carbon-14 than from capsule-fed birds. Egg yolks were analyzed by ECGC on 3 columns & by use of Coulson conductivity detector on 2 columns. Confirmation was by GC/MS. Chick tissue contained: 1,2-DCB; 1,2,4-TCB; 1,2,3,4-TeCB; 1,2,3,5-/or 1,2,4,5,-TeCB; Gamma-PCCH; PCB. Yolks contained these metabolites plus 1,3,5-TCB & 1,2,3-TCB. [Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980., p. 75]**PEER REVIEWED**
  
• Bacterial metabolites of lindane include the following: gamma-2,3,4,5,6-pentachloro-1-cyclohexene, gamma-3,4,5,6-tetrachloro-1-cyclohexene, beta-3,4,5,6-tetrachloro-1-cyclohexene, pentachlorobenzene, 1,2,4,5-tetrachlorobenzene, and 1,2,3,5-tetrachlorobenzene. [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. 32-7]**PEER REVIEWED**
  
• Lindane was applied to beans (Phaseolus vulgaris) & maize (Zea mays). Analyses of bean plants indicated presence of gamma-PCCH & 1,2,4-TCB. In addn to these ... cmpd, 1,2,3-TCB was observed in maize extracts. When maize plants were exposed to gamma-PCCH in aqueous soln, metabolites observed with GC & MS were m-DCB; 1,2,4-TCB; 1,2,4,5-TeCB; 1,2,3,4-TeCB; 2,4,5-TCP; & 2,3,5-TCP. When plants were used, in addn to m-DCB, 1,2,4,5-TeCB, & 2,4,5-TCB, compounds identified as 1,2,3-TCB & 2,4,6-TCP were observed. [Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980., p. 77]**PEER REVIEWED**
  
• Of 354 microorganisms isolated from the environment, 71 were capable of metabolizing gamma-HCH. Using Pseudomonas putida, it was shown that there were 2 patterns of metabolism of gamma-HCH & that in measure they were related to the nutritional properties of the medium. ... Studies also indicated that the 1st step of gamma-HCH metabolism was oxidative & required NAD; & that the 2nd step was stimulated by FAD. The NAD requiring route produced gamma-BTC & alpha-HCH whereas the other route was one of non-specific metabolism of gamma-HCH to gamma-PCCH. [Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980., p. 79]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

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