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Lindane

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Lindane
Clinical data
Pregnancy
category
  • C
Routes of
administration		Topical
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • Listed in 2009 under the Stockholm Convention on Persistent Organic Pollutants, which bans lindane in ratified countries, with a specific exemption for use of lindane as a human health pharmaceutical for the control of head lice and scabies as second-line treatment [2]
In the U.S., pharmaceutical lindane FDA approved for second-line treatment of scabies and head lice; agricultural uses cancelled by the EPA in 2006 (use of stockpiles allowed through 2009) [3]
Pharmacokinetic data
Protein binding91%
MetabolismHepatic cytochrome P-450 oxygenase system
Elimination half-life18 hours
Identifiers
  • (1r,2R,3S,4r,5R,6S)-1,2,3,4,5,6-hexachlorocyclohexane
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.000.365 Edit this at Wikidata
Chemical and physical data
FormulaC6H6Cl6
Molar mass290.83 g/mol g·mol−1
3D model (JSmol)
  • Cl[C@H]1[C@H](Cl)[C@H](Cl)[C@@H](Cl)[C@H](Cl)[C@@H]1Cl
  (verify)

Lindane, also known as gamma-hexachlorocyclohexane, (?-HCH), gammaxene, Gammallin and erroneously known as benzene hexachloride (BHC), (because it lacks a benzene ring),[4][5] is an organochlorine chemical variant of hexachlorocyclohexane that has primarily been used both as an agricultural insecticide but also as a pharmaceutical treatment for infestations of lice and scabies.[6]

Lindane works as a neurotoxin to kill parasatic insects by interfing with GABA neurotransmitter function, specifically by interacting with the GABAA receptor-chloride channel complex at the picrotoxin binding site. In humans, exposure to toxic amonts of lindane primarily affects the nervous system, liver and kidneys, and may be a carcinogen and/or endocrine disruptor.[7][8] Lindane has been indicated in one death from multiple topical applications for repeating mite infestations [9].

The World Health Organization classifies lindane as "Moderately Hazardous," and its international trade is restricted and regulated under the Rotterdam Convention on Prior Informed Consent.[10] It is presently banned in more than 50 countries, and in 2009 was included in the Stockholm Convention on persistent organic pollutants, which bans its production and use worldwide. [11][12]

Most of the adverse health effects reported in humans have related to occupational exposures and accidental oral ingestions of lindane-based agricultural products and pharmaceutical lotions (see also "Human Health Effects" below). There is some evidence to suggest that lindane may be an endocrine disruptor; however, the US Department of Health and Human Services has noted that "the evidence is limited and further investigation is necessary to ascertain the relevance and impact to public health." [13] Data regarding the carcinogenic effects of lindane have been conflicting[14][15][16], though the most recent assessments indicate that lindane is not likely to pose a major carcinogenic risk to humans (see also Cancer Risk below).

The World Health Organization classifies lindane as "Moderately Hazardous" based on acute animal toxicity studies and its international trade is restricted and regulated under the Rotterdam Convention on Prior Informed Consent. [17] It is presently banned in more than 50 countries, and in 2009 was included in the Stockholm Convention on persistent organic pollutants, which bans its production and use for agricultural purposes in participating (ratified) countries but with a specific exemption for use as a human health pharmaceutical for the control of head lice and scabies as second-line treatment. [18] While the US is not currently a member country to the Stockholm Convention, it similarly called for the voluntary cancellation of registered agricultural products but continues to support FDA-approved medical uses of pharmaceutical lindane.


History

In the United States, lindane pesticide products are regulated by the U.S. Environmental Protection Agency (EPA), while lindane-based medications are regulated by the Food and Drug Administration (FDA). In the 1940s, lindane was registered as an agricultural insecticide, and in 1951 it was approved for medical use in the treatment of scabies and lice. Since this time, the vast majority of lindane use―more than 99%―has been in agriculture and much of the safety and environmental concerns have related to this application.[19][20]

In 2006, the EPA called for the voluntary cancellation of all agricultural uses of lindane, which in recent years had already been limited to pre-planting seed treatments.[3] Lindane medications continue to be available in the US,[21] and Canada and other countries have similarly banned agricultural use while allowing its use in medicine to continue.

Lindane medications

Lindane is a prescription topical treatment for head lice and scabies, and it is formulated as a shampoo and a lotion. Since 1995 it has been designated a "second-line" treatment, meaning it should be used only when other "first-line" treatments have failed.[21][22][23] The efficacy of lindane has decreased in recent years because of increasing resistance, and lindane is generally not as effective as other treatments or as safe.[24][25]

In December 2007, the FDA sent a warning letter to Morton Grove Pharmaceuticals, the sole U.S. manufacturer of lindane products,[26] requesting that the company correct misleading advertising information it had distributed. The letter said, in part, that the materials "are misleading in that they omit and/or minimize the most serious and important risk information associated with the use of Lindane Shampoo, particularly in pediatric patients; include a misleading dosing claim; and overstate the efficacy of Lindane Shampoo."[27]

The State of California banned the pharmaceutical use of lindane, effective 2002. The Michigan House of Representatives passed House Bill 4402 in March 2009 to restrict the use of pharmaceutical lindane to doctors' offices. [28] A recent analysis of the California ban concluded that a majority of pediatricians had not experienced problems treating lice or scabies since that ban took effect. The study also documented a marked decrease in lindane wastewater contamination and a dramatic decline in lindane poisoning incidents reported to Poison Control Centers. The authors concluded that, "The California experience suggests elimination of pharmaceutical lindane produced environmental benefits, was associated with a reduction in reported unintentional exposures and did not adversely affect head lice and scabies treatment."[29]

Human health effects

The EPA and WHO both classify lindane as "moderately" acutely toxic. It has an oral LD50 of 88 mg/kg in rats and a dermal LD50 of 1000 mg/kg. Most of the adverse human health effects reported for lindane have been related to agricultural uses and chronic, occupational exposure of seed treatment workers.[30]

Exposure to large amounts of lindane can harm the nervous system, producing a range of symptoms from headache and dizziness to seizures, convulsions and more rarely death.[7][31] The most common side effects associated with the use of lindane medications are burning sensations, itching, dryness and rash.[32] Lindane has not been shown to affect the immune system in humans and, it is not considered to be genotoxic.[7] Prenatal exposure to β-HCH, an isomer of lindane and production byproduct, has been associated with altered thyroid hormone levels and could affect brain development.[33]

Cancer risk

Based primarily on evidence from animal studies, most evaluations of the carcinogenicity of lindane have concluded that lindane may cause cancer. In 1987, the International Agency for Research on Cancer (IARC) classified lindane as a group 2B "possible" human carcinogen,[34] and in 2001 the EPA concluded there was “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.”[35] The U.S. Department of Health and Human Services determined that all isomers of hexachlorocyclohexane, including lindane, "may reasonably be anticipated to cause cancer in humans,"[7] however the World Health Organization concluded in 2004 that “lindane is not likely to pose a carcinogenic risk to humans.”[36]

Adverse reactions to lindane pharmaceuticals

A variety of adverse reactions to lindane pharmaceuticals have been reported, ranging from skin irritation to seizures to, in rare instances, death. While serious effects are rare and have most often resulted from misuse, adverse reactions have occurred when used properly.[21][37][38][39] The FDA therefore requires a so-called black box warning on lindane products, which explains the risks of lindane products and its proper use.[32][40]

The black box warning emphasizes that lindane should not be used on premature infants and individuals with known uncontrolled seizure disorders, and should be used with caution in infants, children, the elderly, and individuals with other skin conditions (e.g., dermatitis, psoriasis) and people who weigh less than 110 lbs (50 kg) as they may be at risk of serious neurotoxicity. [37][38]

Environmental contamination

Lindane is a persistent organic pollutant: it is relatively long-lived in the environment, it is transported long distances by natural processes like global distillation, and it can bioaccumulate in food chains.[30]

The production and agricultural use of lindane are the primary causes of environmental contamination,[41] and levels of lindane in the environment have been decreasing in the U.S., consistent with decreasing agricultural usage patterns.[42] The production of lindane generates large amounts of waste hexachlorocyclohexane isomers, and it is estimated that "every ton of lindane manufactured produces about 9 tons of toxic waste."[43]

When lindane is used in agriculture, an estimated 12-30% of it volatilizes into the atmosphere, where it is subject to long-range transport and can be deposited by rainfall. Lindane in soil can leach to surface and even ground water and can bioaccumulate in the food chain.[3] Most exposure of the general population to lindane results from agricultural uses and the intake of contaminated foods, such as produce, meats and milk. Over time, lindane is broken down in soil, sediment and water into less harmful substances by algae, fungi and bacteria; however, the process is relatively slow and dependent on ambient environmental conditions.[7] The ecological impact of lindane’s environmental persistence continues to be debated.

The US EPA has determined that lindane does not contaminate drinking water in excess of the Agency's level of concern.[7] U.S. Geologic Survey teams in 1999 and 2000.[44] With regard to lindane medications, the EPA conducted “down-the-drain” estimates of the amount of lindane reaching public water supplies and concluded that lindane levels from pharmaceutical sources were “extremely low” and not of concern.[20]

Isomers

Lindane is the gamma isomer of hexachlorocyclohexane ("γ-HCH"). In addition to the issue of lindane pollution are concerns related to the other isomers of HCH, namely alpha-HCH and beta-HCH, which are notably more toxic than lindane, lack its insecticidal properties, and are byproducts of lindane production.[7] In the 1940s and 1950s lindane producers stockpiled these isomers in open heaps, which led to ground and water contamination. The International HCH and Pesticide Forum has since been established to bring together experts to address the clean-up and containment of these sites.[45][dead link] Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic industrial chemicals, a process known as “cracking.”[42][45] Today, only a few production plants remain active worldwide to accommodate public health uses of lindane and declining agricultural needs.[19] Lindane has not been manufactured in the U.S. since the mid-1970s but continues to be imported.

  • α-hexachlorocyclohexane
    α-hexachlorocyclohexane
  • β-hexachlorocyclohexane
    β-hexachlorocyclohexane

Regulatory status

As of November 2006, Lindane was banned in 52 countries, restricted in 33 countries, not registered in 10 countries, and registered in 17 countries.[19][41] The latter includes the U.S. and Canada, which support public health uses of pharmaceutical lindane but no longer allow agricultural applications.[19][3] It is banned by the Stockholm Convention On Persistent Organic Pollutants.[12][46][47] but is still used in agriculture in India,[48] Nigeria,[49] and elsewhere.

Lindane is banned in California, and there are currently bills pending in the New York and Michigan state legislatures that would further restrict its medical uses on children in the those states.[50][51] Michigan passed the lindane bill through the House on May 2008, and again in March, 2009. [52]

In May 2009 the Fourth Conference of signers of the Stockholm Convention on Persistent Organic Pollutants added lindane and its alpha and beta isomers to the list of globally banned chemicals.[53]

Morton Grove lawsuit

In the face of negative publicity concerning its lindane products, in 2006 Morton Grove Pharmaceuticals filed a lawsuit against the National Pediculosis Association, the Michigan Ecology Center, and two physicians, alleging that statements they disseminated to healthcare providers and consumers constituted defamation, tortious interference, trade disparagement, and deceptive trade practices. Morton Grove alleged more than $9.3 million in damages. The case pled that “[d]efendants swap agricultural and pharmaceutical research selectively quoting and/or misstating findings from studies relating to the agricultural use of lindane, and widely disseminate false, misleading, and defamatory statements about the safety profile and effectiveness of lindane.”[54] The defendants considered the legal action to be SLAPP suit.

Morton Grove and the Ecology Center settled in 2008. The settlement did not require the defendants to admit liability or make any payments to Morton Grove, but the Ecology Center did agree to clarify 7 of the statements it had published in its lindane factsheet.[51][55][56] Morton Grove re-filed its complaint against the National Pediculosis Association, seeking a permanent injunction and corrective advertising under the Lanham Act and companion Illinois' statutes. This case remains ongoing.[57] [verification needed]

Morton Grove Pharmaceuticals and the National Pediculosis Association have agreed to dismiss their respective lawsuits with no admission of wrongdoing and no payment of any damages.

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ Report of the Conference of the Parties of the Stockholm Convention on Persistent Organic Pollutants on the work of its fourth meeting. Convention on Persistent Organic Pollutants. Fourth meeting, Geneva, 4–8 May 2009. http://chm.pops.int/Portals/0/Repository/COP4/UNEP-POPS-COP.4-38.English.pdf
  3. ^ a b c d U.S. EPA. Addendum to the 2002 Lindane Reregistration Eligibility Decision (RED). July 2006. http://www.epa.gov/oppsrrd1/REDs/lindane_red_addendum.pdf
  4. ^ Brandenberger, Hans; Maes, Robert A. A. (1997). Analytical toxicology: for clinical, forensic, and pharmaceutical chemists. Berlin: Walter de Gruyter. p. 243. ISBN 9783110107319. Retrieved 2009-05-10.
  5. ^ Persistent Organic Pollutant Review Committee (POPRC). Draft risk management evaluation for lindane. May, 2007.
  6. ^ Drugs.com Professional Drug Information: Lindane. Retrieved 2009-05-10
  7. ^ a b c d e f g Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Toxicologic profile for alpha-, beta, gamma- and delta-hexachlorocyclohenxane. August 2005. http://www.atsdr.cdc.gov/toxprofiles/tp43.pdf
  8. ^ Lindane Voluntary Cancellation and RED Addendum Fact Sheet, US EPA, July 2006.
  9. ^ http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm052201.htm
  10. ^ World Health Organization, The WHO Recommended Classification of Pesticides by Hazard, 2005.
  11. ^ Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Toxicologic profile for alpha-, beta, gamma- and delta-hexachlorocyclohenxane. August 2005. http://www.atsdr.cdc.gov/toxprofiles/tp43.pdf
  12. ^ a b Eliane Engeler, "UN: Treaty expanded by 9 more dangerous chemicals", Associated Press 2009-05-09
  13. ^ Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Toxicologic profile for alpha-, beta, gamma- and delta-hexachlorocyclohenxane. August 2005. http://www.atsdr.cdc.gov/toxprofiles/tp43.pdf
  14. ^ International Agency for Research on Cancer (IARC). Summaries & Evaluations: HEXACHLOROCYCLOHEXANES (Group 2B). Updated March 2, 1998.
  15. ^ U.S. EPA. Evaluation of the Carcinogenic Potential of Lindane, PC. Code: 009001. 2001. http://www.lindane.com/pdf/EPA_Cancer_Assessment_of_Lindane2001.pdf
  16. ^ World Health Organization (WHO). Lindane in Drinking Water: Background Document for Development of WHO Guidelines for Drinking-Water Quality. 2004.
  17. ^ World Health Organization, The WHO Recommended Classification of Pesticides by Hazard, 2005.
  18. ^ Eliane Engeler, "UN: Treaty expanded by 9 more dangerous chemicals", Associated Press 2009-05-09
  19. ^ a b c d Commission for Environmental Cooperation. North American Regional Action Plan (NARAP) on lindane and other hexachlorocyclohexane (HCH) isomers. November 30, 2006. http://www.cec.org/files/PDF/POLLUTANTS/LindaneNARAP-Nov06_en.pdf
  20. ^ a b U.S. Environmental Protection Agency (EPA). Lindane Reregistration Eligibility Decision (RED). 2002. http://www.epa.gov/espp/effects/lindane/attach-1.pdf
  21. ^ a b c Food and Drug Administration. Lindane Assessment Memorandum. Posted 2003. http://www.fda.gov/cder/drug/infopage/lindane/lindanememoassessment.pdf.
  22. ^ McCarthy JS, Kemp DJ, Walton SF, Currie BJ (2004). "Scabies: more than just an irritation". Postgrad Med J. 80 (945): 382–7. doi:10.1136/pgmj.2003.014563. PMID 15254301.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Thomas DR, McCarroll L, Roberts R; et al. (2006). "Surveillance of insecticide resistance in head lice using biochemical and molecular methods". Arch. Dis. Child. 91 (9): 777–8. doi:10.1136/adc.2005.091280. PMID 16774979. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ West DP (2004). "Head lice treatment costs and the impact on managed care". Am J Manag Care. 10 (9 Suppl): S277–82. PMID 15515633.
  25. ^ Zargari O, Golchai J, Sobhani A; et al. (2006). "Comparison of the efficacy of topical 1% lindane vs 5% permethrin in scabies: a randomized, double-blind study". Indian J Dermatol Venereol Leprol. 72 (1): 33–6. PMID 16481707. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  26. ^ Sciele Pharma Completes Acquisition of Alliant Pharmaceuticals. Press Release; June 12, 2007. http://phx.corporate-ir.net/phoenix.zhtml?c=120763&p=irol-newsArticle&ID=1014610&highlight
  27. ^ Warning Letter from the U.S. Food and Drug Administration to Morton Grove. (undated.)
  28. ^ http://www.legislature.mi.gov/(S(qmov3e45chfz0w55ymrrcl45))/mileg.aspx?page=getObject&objectName=2009-HB-4402
  29. ^ Humphreys EH, Janssen S, Heil A, Hiatt P, Solomon G, Miller MD (2008). "Outcomes of the California ban on pharmaceutical lindane: clinical and ecologic impacts" (PDF). Environ. Health Perspect. 116 (3): 297–302. doi:10.1289/ehp.10668. PMC 2265033. PMID 18335094. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ a b Persistent Organic Pollutant Review Committee (POPRC). Draft risk management evaluation for lindane. May, 2007. http://www.pops.int/documents/meetings/poprc/drprofile/drme/DraftRME_Lindane.pdf
  31. ^ "Unintentional topical lindane ingestions--United States, 1998-2003". MMWR Morb. Mortal. Wkly. Rep. 54 (21): 533–5. 2005. PMID 15931156..
  32. ^ a b U.S. FDA Centers for Drug Evaluation and Research. Lindane lotion and lindane shampoo questions and answers. Updated April 15, 2003. http://www.fda.gov/cder/drug/infopage/lindane/lindaneQA.htm
  33. ^ Alvarez-Pedrerol M, Ribas-Fitó N, Torrent M; et al. (2008). "Thyroid disruption at birth due to prenatal exposure to beta-hexachlorocyclohexane". Environ Int. 34: 737. doi:10.1016/j.envint.2007.12.001. PMID 18207242. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  34. ^ International Agency for Research on Cancer (IARC). Summaries & Evaluations: HEXACHLOROCYCLOHEXANES (Group 2B). Updated March 2, 1998. http://www.inchem.org/documents/iarc/suppl7/hexachlorocyclohexanes.html
  35. ^ U.S. EPA. Evaluation of the Carcinogenic Potential of Lindane, PC. Code: 009001. 2001. http://www.lindane.com/pdf/EPA_Cancer_Assessment_of_Lindane2001.pdf
  36. ^ World Health Organization (WHO). Lindane in Drinking Water: Background Document for Development of WHO Guidelines for Drinking-Water Quality. 2004. http://www.who.int/water_sanitation_health/dwq/chemicals/lindane/en/print.html
  37. ^ a b Lindane lotion, USP, 1% prescribing information. Updated March 28, 2003. http://www.fda.gov/cder/foi/label/2003/006309lotionlbl.pdf
  38. ^ a b Lindane shampoo, USP, 1% prescribing information. Updated March 28, 2003. http://www.fda.gov/cder/foi/label/2003/006309shampoolbl.pdf.
  39. ^ U.S. FDA. Lindane Post Marketing Safety Review. Posted 2003. http://www.fda.gov/cder/drug/infopage/lindane/lindaneaeredacted.pdf
  40. ^ http://www.fda.gov/cder/drug/infopage/lindane/default.htm
  41. ^ a b U.S. EPA. Assessment of lindane and other hexachlorocyclohexane isomers. February 8, 2006
  42. ^ a b United Nations Environment Programme. POPRC of the Stockholm Convention. Draft risk profile: Lindane. July 2006.
  43. ^ Life after Lindane in California: Water Concentrations, Poison Control Calls Drop Following Ban, Environmental Health Perspectives, Volume 116, Number 3, March 2008.
  44. ^ Kolpin DW, Furlong ET, Meyer MT, et al. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000: A national reconnaissance. Environ Sci Technol. 2002;36(6):1202–1211.
  45. ^ a b International HCH & Pesticides Association. The legacy of lindane HCH isomer production. 2006. http://www.ihpa.info/docs/library/Lindane%20Main%20Report%20DEF20JAN06.pdf
  46. ^ Persistent Organic Pollutants Review Committee http://www.pops.int/documents/meetings/poprc/chemreview.htm
  47. ^ Pesticide Action Network map of Lindane bans and restrictions http://www.panna.org/campaigns/docsLindane/lindaneBannedMap.pdf
  48. ^ "Pollu beetle menace in pepper". The Hindu. Retrieved 2008-05-29. {{cite web}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  49. ^ Shaibu, Inalegwu (14 May 2008). "Nigeria: NAFDAC Bans 30 Agrochemical Products". Retrieved 2008-05-29.
  50. ^ Bill Summary - A06802
  51. ^ a b Critics of drugs in for bad medicine, Laura Berman, The Detroit News, March 2, 2008.
  52. ^ HB-4569, As Passed House, May 15, 2008 Michigan Legislature website.
  53. ^ Governments unite to step-up reduction on global DDT reliance and add nine new chemicals under international treaty, Geneva: Stockholm Convention Secretariat, 8 May 2008.
  54. ^ Morton Grove Pharmaceuticals, Inc. v. The National Pediculosis Association, et al., No. 06 C 3815 (N.D. Ill. June 18, 2007) (Bucklo, J.)
  55. ^ The Ecology Center's Clarification of Statements Regarding Lindane, Michigan Ecology Center, accessed March 3, 2008.
  56. ^ Ecology Center's lindane suit settled, Art Aisner, Ann Arbor News, March 15, 2008.
  57. ^ Morton Grove Pharmaceuticals, Inc. v. The National Pediculosis Association, No. 08-C-1384 (N.D. Ill.)

Government and organizations

News stories and opinion articles

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