Hexachlorocyclopentadiene: Difference between revisions

| Watchedfields = changed

| verifiedrevid = 443007568

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ImageFileL1 = Hexachlorocyclopentadiene-2D-skeletal.png

| ImageSizeL1 =

| = Skeletal formula

| ImageFileR1 = Hexachlorocyclopentadiene.png

| ImageSizeR1 =

| = Ball-and-stick model

| IUPACName = 1,2,3,4,5,5-hexachlorocyclopenta-1,3-diene

| OtherNames = graphlox, perchlorocyclopentadiene

|Section1={{Chembox Identifiers

| InChI = 1/C5Cl6/c6-1-2(7)4(9)5(10,11)3(1)8

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| UNII_Ref = {{fdacite|correct|FDA}}

| =

|

SMILES = ClC1(Cl)C(/Cl)=C(/Cl)\C(\Cl)=C1\Cl

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|Section2={{Chembox Properties

|C=5|Cl=6

| = −10

| = 239

| Density = 1.702 g/cm3

| VaporPressure =

| Appearance = Pale-yellow to amber-colored liquid

| Odor = Pungent, unpleasant<ref name=PGCH />

| Solubility = 0.0002% (Reacts, 25°C)<ref name=PGCH />

|Section7={{Chembox Hazards

| MainHazards = Teratogen

| FlashPtC = 100

| NFPA-H =

| NFPA-F =

| NFPA-R =

| PEL = none<ref name=PGCH>{{PGCH|0315}}</ref>

| REL = TWA 0.01 ppm (0.1 mg/m³)<ref name=PGCH />

| IDLH = N.D.<ref name=PGCH />

}}

'''Hexachlorocyclopentadiene''' is an [[organochlorine compound]] is a precursor to is [[]]. Many of its derivatives proved to be highly controversial, as studies showed them to be [[persistent organic pollutant]]s. An estimated 270,000 tons were produced until 1976,<ref name=Ullmann>Robert L. Metcalf 2002|10.1002/14356007.a14_263}}</ref>

== Synthesis and production ==

Hexachlorocyclopentadiene is prepared by [[Chlorination reaction|chlorination]] of [[cyclopentadiene]] to give 1,1,2,3,4,5-octachlorocyclopentane, which in a second step undergoes [[dehydrochlorination]]:<ref>{{Ullmann|author=Dieter Hönicke, Ringo Födisch, Peter Claus, Michael Olson|title=Cyclopentadiene and Cyclopentene|year=2002|doi=10.1002/14356007.a08_227}}</ref> The first procedure uses [[alkali]]ne hypochlorite and after fractional distillation has a yield of about 75%, the other 25% consists of lower chlorinated cyclopentadienes.<ref>[http://www.pops.int/Home/tabid/2121/Default.aspx Production of hexachlorocyclopentadiene] McBee; Baranauckas Industrial and Engineering Chemistry; '''1949''', 41; p806</ref> The second process uses thermal dechlorination, which occurs at 470-480&nbsp;°C and gives a yield higher than 90%. Therefore, the first process is easier to perform, but the second gives a more pure product.<ref name=":0">{{cite web|url=https://www.atsdr.cdc.gov/ToxProfiles/tp.asp?id=992&tid=208|author=U.S. Department of Health and Human services|title=Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)|year=1999}}</ref>

Besides manufacturers that produce the chemical for scientific synthesis and reference, there are two companies that produce HCCPD for industrial use: Velsicol Chemical LLC in the United States and Jiangsu Anpon Electrochemicals Co. in China. The first produces the chemical on a large scale to be used for producing rubber adherents, [[flame retardant]]s and [[pesticide]]s. Velsicol knows the dangers of handling HCCPD and therefore requires its buyers to go through a strict review and educational program on the storage, use and disposal of the chemical. The company also provides safety data sheets and a handling guide on its website, and delivers the chemical to purchasers all over the world.<ref>{{Cite web|url=https://www.velsicol.com/products/hexachlorocyclopentadiene|title=Hexachlorocyclopentadiene &#124; Velsicol Chemical, LLC|website=Hexachlorocyclopentadiene &#124; Velsicol Chemical, LLC}}</ref> Of the Chinese company less is known. It is said to be a company specialized in chloro-alkali and [[agrochemical]]s and operating as a subsidiary of China National Agrochemical Corporation.<ref>{{Cite web|url=https://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=30492867|title=Company Overview of Jiangsu Anpon Electrochemical Co., Ltd.|publisher=Bloomberg}}</ref>

In addition, Hexachlorocyclopentadiene readily undergoes the [[Diels-Alder reaction]] to give a variety of [[adduct]]s that were commercialized as pesticides. The main derivatives are:

* [[aldrin]] from [[norbornadiene]] (the related [[dieldrin]] is a metabolite of aldrin)

*[[]] from [[]], followed by

*[[]] from cyclopentadiene, followed by

*[[]] from , followed by

*[[]] from [[,-]] followed by

* [[endosulfan]] from [[cis-butene-1,4-diol]], followed by esterification with [[Thionyl chloride|SOCl₂]]

* [[dienochlor]]

== Reactions ==

HCCP is electrophilic. It degrades in base. Alcoholysis affords ketals C₅Cl₄(OR)₂.<ref>{{cite journal|title=7,7-Dimethoxybicyclo[2.2.1]heptene|first1=P. G.|last1=Gassman|first2=J. L. |last2=Marshall|journal=Org. Synth.|year=1968|volume=48|page=68|doi=10.15227/orgsyn.048.0068}}</ref>

HCCP readily undergoes [[Diels–Alder reaction|Diels-Alder]] reactions with [[alkene]]s. This reaction is used to produce pesticides such as Aldrin (named after the reaction) and Isodrin. Most of these pesticides are no longer commercially available and banned by the Stockholm convention on persistent organic pollutants due to their toxicity to humans and animals.<ref>{{Cite web|url=http://www.pops.int/Home/tabid/2121/Default.aspx|title=Stockholm Convention - Home page|website=www.pops.int}}</ref>

===Biodegradation===

In surface water, [[photolysis]] is the most common reaction route, with a degradation half-life of 2 to 4 minutes.<ref name=":0" /> Deeper under water where less light penetrates [[hydrolysis]] and [[biodegradation]] are prominent pathways.<ref>EPA. 1984. Health effects assessment for hexachlorocyclopentadiene. Cincinnati, OH: U.S. Environmental Protection Agency, Office of Research and Development, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. EPA/540/1-86/001</ref> The figure below gives an indication of possible degradation pathways when HCCPD is released into the environment. Light, water and oxygen can cause a double bond to [[oxidize]] to give a [[ketone]] structure, which can then undergo a [[Ring-opening reaction|ring-opening]] and form pentachlorodienoic acid, which forms two [[butadiene]] species with the release of [[carbon dioxide]]. However, this is only a minor pathway.

== Toxicokinetics ==

HCCPD absorption in the body occurs mostly through the lungs, [[gastrointestinal tract]] and skin. Overall the levels of HCCPD in blood were lower when administered through food compared to when inhalation was used. This may indicate a poor absorption in the gastrointestinal tract due to binding to the gastrointestinal contents. When HCCPD is absorbed, it is distributed to the liver, kidney and lungs. The organ with the highest concentration differs when comparing rats and mice. The highest concentration in rats is found in the kidney versus in the liver of mice.<ref name=":0" />

=== Absorption ===

The relevant absorption studies are done using [[radiolabeled]] HCCPD. In rats, the route of absorption appeared to have a significant effect on the degree of absorption. The low levels in blood might indicate poor gastrointestinal absorption.<ref name=":0" /> Generally, the site of uptake shows the highest concentration in animals. In inhalation studies, the lungs showed the highest concentration of HCCPD. The concentration at that time found in kidneys was 8 times higher compared to the liver. When given oral doses, the concentration in blood peaked at 4 hours after ingestion. The general distribution pattern stayed the same as the concentration found in the liver was 30–40% of what was found in the liver. Opposite results are found for mice. In mice the concentration in the liver is found to be higher than in the kidney after oral ingestion. The amount of HCCPD in the kidneys was between 33–50% of that in the liver.

For multiple oral exposures in rats, [[steady state concentrations]] ranged were achieved in 10 to 30 days. The liver reached the steady state concentration in 30 days. At this time the concentration of HCCPD was roughly half of what was found in the kidneys. In mice, steady state in reproductive and fat tissue was reached in 20 days. At this time, the amount of HCCPD in the kidney was approximately half of the concentration found in the liver. In an [[Intravenous therapy|intravenous]] study in rats, the approximate distribution of HCCPD in the tissues remained the same.

=== Toxicodynamics ===

Complete [[oxidation]] of the compound to [[carbon dioxide]] is limited as apparently less than 1% of the [[radiolabel]] is found in [[carbon dioxide]].<ref name=":0" />

The exact pathway for the complete [[metabolism]] of HCCPD is not known. There are contradicting results from different studies regarding the composition of excreted material. The metabolites were found to be [[Chemical polarity|polar]] in one study and [[Chemical polarity|nonpolar]] in the other. In addition, some of the potential metabolites such as hexachloro-2-cyclopentanone, hexachloro-3-cyclopentanone, hexachloroindone, or octachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene-1,8-dione were not yet identified by extraction of excreted material.<ref name=":0" />

As the compound readily undergoes [[Diels–Alder reaction]]s synthetically, it is possible that the HCCPD could react directly with cellular alkenes in a [[cycloaddition]] reaction. This might then explain why HCCPD causes effects at the point of contact for all the possible routes of exposure, in addition to the tissue-binding properties.<ref name=":0" />

=== Excretion ===

There is a slight difference in ratios of the amount excreted in urine and the amount excreted in feces between rats and mice. Though generally, the highest portion of [[radiolabeled]] metabolites is recovered in [[urine]] if HCCPD is inhaled. Furthermore, the highest portion of radiolabeled molecules is recovered in [[feces]] if HCCPD is orally ingested.<ref name=":0" />

== Indications (biomarkers) ==

=== Effects ===

Humans exposed to HCCPD do not show adverse health effects exclusive to that chemical. A small percentage of wastewater treatment workers who were exposed to water containing HCCPD in 1977 reported irritation of skin and eyes, chest discomfort, headaches, nausea and fatigue. In the long term, they showed irregularities in their liver function using tests that monitor [[enzyme]] levels. However, these irregularities could be due to many other compounds and variations in health.<ref name=":1">Kominsky JR, Wisseman CL, Morse DL. 1980. Hexachlorocyclopentadiene contamination of a municipal wastewater treatment plant. Am Ind Hyg Assoc J 415.52-556</ref> Other proposed parameters for characterizing effects in humans, like urinary [[porphyrin]] excretion, were also tested for their potential use as a [[biomarker]], but none were deemed significant enough. Experiments performed on laboratory animals like rats and mice show that a yellow-brown pigment forms in the epithelium of the nose after long-term inhalation exposure, even at low doses, which is considered a useful biomarker for long-term exposure.<ref name=":0" />

=== Unusual susceptibility ===

When there is pre-existing damage to organs involved in uptake or [[metabolism]] such as lungs and the liver, people can be more susceptible to HCCPD exposure because of their already compromised organ function. Because respiratory exposure seems to be the most prevalent route of exposure, people suffering from [[asthma]] are probably more susceptible to adverse effects than the general population.<ref name=":1" /> Another group that is particularly vulnerable to hazardous chemicals is children. In their development there are critical periods where distinct structures and functions can be more susceptible towards disruption, and the damage done might only become apparent in a later stage of life. Absorption may differ for children because of their incompletely developed organs and larger surface to body weight ratio. Fortunately, it is very unlikely that small children are immediately exposed to HCCPD because it is only found as an impurity in pesticides and is not used in homes.<ref name=":0" />

== Effects on animals ==

No studies were done on the [[lethality]] of humans in relation to HCCPD. It was however tested on animals and is postulated to have effects on brain and [[adrenal gland]]s. In the brain, HCCPD or a metabolite thereof can react with [[lipid]]s. In order to see degenerative brain effects in for example rats, the animals are exposed to a high dose of  HCCPD concentration by inhalation. When dealing with low exposure levels, HCCPD reactivity makes the chance of reactive species in the blood at high concentrations very low. However, at higher doses the probability of transporting reactive material across the [[Blood–brain barrier|blood-brain barrier]] is higher.<ref name=":0" />

Short-term inhalation of HCCPD is  [[Lethality|lethal]] to mice, rats, rabbits and guinea pigs. The [[lethality]] of the animals can be affected by the concentration and duration of HCCPD exposure. From all the animals tested, guinea pigs showed to be the most resistant to the compound toxicity. Almost all biological systems are shown to be vulnerable to the toxicity of HCCPD, except the [[hematological]] and [[musculoskeletal]] systems.<ref name=":0" />

=== Oral effects ===

Single doses of HCCPD were found to be moderately toxic to animals if ingested orally. However, as the compound was not entirely pure (93.3%) while performing studies, some of the toxic effects could be attributed to the impurities, especially at high doses.

Data of oral effects on other species that mice and rats are limited. Single high doses of HCCPD resulted in increased effort to breathe in rats and rabbits alike. The lung tissues of these animals were [[Hyperaemia|hyperemic]] and [[edematous]] after a given dose. Extensive lung [[hemorrhage]] appeared after a single non lethal dose after 21 days. Lower doses in rats caused no observable tissue changes in the lungs. High doses created degenerative changes to the heart as well. Again, low doses resulted in no observable change in heart tissue. Also, these rats and rabbits experienced [[diarrhea]] after single oral dosages of HCCPD, and showed acute necrotic [[lesion]]s in the [[forestomach]]. In repeated exposure experiments on rats and mice [[inflammation]] and [[epithelial hyperplasia]] of the [[forestomach]] were observed. The dose had a direct relationship to the severity of these effects. This and the location suggests that these effects result from direct contact of the tissue with HCCPD. Body weight was heavily affected after oral ingestion of HCCPD by rats, more severely for males than females.<ref name=":0" />

=== Dermal effects ===

Increasing dermal doses showed a shorter survival time for the animals. Lung effects of rabbits were examined in dermal animal studies, showing [[Congested lungs|congested]] blood and fluid by exposure of HCCPD (93,3% pure, so again a possibility of contaminant interference). Other effects regarding organs with dermal dose were degenerative changes in the heart, [[necrosis]] of the liver and [[kidney tubules]] and degenerative changes of the adrenal glands.<ref name=":0" />

The form in which HCCPD appears in the environment, so in its pure form or in solution, showed a striking effect on the [[epidermis]] of rabbits, guinea pigs and monkeys. Damage to the skin could be seen, namely discolored and inflamed skin. When the animals did not die by these lesions, they healed over time by itself.<ref name=":0" />

=== Inhalation effects ===

HCCPD is highly toxic to animals when inhaling its vapours. No human studies regarding lethality were done, but there has been an incident involving a waste water treatment centre where humans were exposed, from which most relevant human information is taken.

==== Human inhalation effects ====

There is data for human exposure to HCCPD for numerous organ systems. Waste water treatment plant and water cleanup crew workers were exposed after industrial release of the compound into the environment. The initial concentration of the compound in air was unknown but was later determined to be ranging between 0.27 and 0.97 [[Parts per million|ppm]]. Workers noticed a strange odor on the plant and even a blue haze after a heavy rain. When some of them sought medical attention, it was determined the plant was contaminated with HCCPD, and numerous tests were performed to document these circumstances. Approximately one fifth of waste water treatment workers reported having nausea and abdominal cramps after exposure for a period between 3 and 15 days. They also reported respiratory complaints like sore throats, coughing and breathing difficulty. However, tests on lung function and chest [[X-ray]]s did not show any abnormalities.<ref name=":1" /> Workers exposed to HCCPD for a longer time reported respiratory irritation, [[Nose|nasal]] irritation and [[Paranasal sinuses|sinus]] congestion, most likely because of direct contact of these tissues with HCCPD from the air, and not as a [[systemic effect]] through the lungs.

In addition, elevated levels of [[Lactate dehydrogenase|lactic dehydrogenase]] was found in 11 out of 41 workers from the wastewater treatment. These levels was not nearly as high for workers from the water cleanup crew, but the [[Aspartate transaminase|aspartate aminotransferase]] levels were elevated for 12 out of 97 of these workers. These [[enzyme]]s might indicate damage to heart, as well as to the liver. No evidence of heart function impairment was found in both worker groups though. The elevated levels in patients diminished after a period of 3 weeks.<ref name=":0" />

==== Animal inhalation effects ====

For prolonged exposure, significant differences occur between lab animal species. Where all mice died in the first week in a 13-week study, being exposed to 2 ppm HCCPD for 5 days a week, 6 hours a day, rats however survived until the third week. For a very low exposure of 0.04 ppm, 3 out of 20 mice died and none of the rats died. Chronic exposure of HCCPD at very low concentrations produced a yellow-brown pigment in the lung, tracheal and nasal epithelium in rats and mice. The pigmentation did not disappear after the exposure stopped.

For acute high exposures (1 hour, 42 ppm) all animals died, after showing difficulty breathing and gasping for air. Their lung tissues showed hemorrhagic [[lesion]]s, [[inflammation]], [[edema]] and [[necrosis]] in the [[Bronchus|bronchi]]. However recovery of the animals that survived was apparent 2 weeks after the treatment.

[[Heart|Cardiac]] and [[Gastrointestinal tract|gastrointestinal]] function seemed not be impaired after exposure of HCCPD in rats, mice and monkeys. Moderate [[Liver|hepatic]] tissue degeneration was observed for acute inhalation. The same tissue degeneration was observed for longer experiments with lower concentrations.<ref name=":0" />

====

HCCPD is a highly toxic<ref>{{cite web|title=Hexachlorocyclopentadiene Safety Data Sheet, Version 5.|date=January 2019|publisher=Velsicol Chemical Corporation|access-date=2021-10-01|url=https://www.velsicol.com/images/pdf/hexachlorocyclopentadiene/hexachlorocyclopentadiene-sds.pdf}}</ref> organochlorine compound that was first mentioned as a [[diene]] in certain [[Diels–Alder reaction|Diels-Alder]] reactions in 1930. The HCCPD chemical family quickly attracted increased attention with the discovery of its [[insecticide|insecticidal properties]] in 1955 and extensive commercialization. However, due to extensive use, the HCCPD family of insecticides (chlordane, aldrin, dieldrin, endrin, heptachlor) became less effective as a result of [[Mutation|genetic mutations]] of the targeted insects. The number of insects resistant to cyclodienes and [[lindane]] approached 300 by 1989.<ref name="Ullmann" />

Later, in 1957, another use of the compound was found, namely as a [[flame retardant]] for polyesters. In addition, HCCPD was used to make a [[Dimer (chemistry)|dimer]]. This dimer was also known as “[[Mirex]]” or “Box dimer” and was offered commercially as a flame retardant to be used in [[polymer]]s such as [[polypropylene]]. In the 1970s, it was shown that the Mirex dimer degrades in the environment into [[kepone]], a well established [[carcinogen]]. This development raised concern and the use of Mirex was completely discontinued. Before this, [[Diels–Alder reaction|Diels-Alder]] adducts of HCCPD were developed with a number of cyclic dienes. Some of these compounds gained commercial attention such as the adduct of HCCPD with [[1,5-Cyclooctadiene|1,5-cyclooctadiene]], which was sold under the name [[Dechlorane plus|Dechlorane® plus]]. This flame retardant was used in [[polyolefin]]s and [[Nylon]] and also in wires and cables, due to its good moisture resistance. In the meantime, scientific research has also demonstrated its impact on the environment<ref>2: Seymour, R.B; Deanin, R.D; History of Polymeric Composites;'''1987'''; VSP;</ref>

Today, almost all HCCPD derivatives have been banned or are under consideration for banning, according to the deliberations of the [[Stockholm Convention on Persistent Organic Pollutants]]. However, given that HCCPD is a versatile raw material for the synthesis of a wide range of end products, as of October 2021 it is still available commercially.<ref>{{cite web|title=Hexachlorocyclopentadiene: Versatile Intermediate for Multiple End-Uses.|date=October 2021|publisher=Velsicol Chemical Corporation|access-date=2021-10-01|url=https://www.velsicol.com/products/hexachlorocyclopentadiene}}</ref>

== References ==

{{reflist}}

[[Category:Perchlorocarbons]]

[[Category:Cyclopentadienes]]