Endosulfan

Endosulfan is an organochlorine insecticide and acaricide, which acts by blocking the GABA-gated chloride channel of the insect. It became highly controversial due to its acute toxicity, potential for bioaccumulation, and role as an endocrine disruptor. Because of its threats to human health and the environment, a global ban on the manufacture and use of endosulfan was negotiated under the Stockholm Convention in April 2011. The ban took effect in mid-2012, with certain uses exempted for five additional years. More than 80 countries, including the European Union, Australia, New Zealand, several West African nations, the United States, Brazil, and Canada had already banned it or announced phase-outs by the time the Stockholm Convention ban was agreed upon. It is still used extensively in India and China despite laws against its use. It is also used in a few other countries. It is produced by the Israeli firm Makhteshim Agan and several manufacturers in India and China. On May 13, 2011, the India Supreme Court ordered a ban on the production and sale of endosulfan in India, pending further notice.

Uses

Endosulfan has been used in agriculture around the world to control insect pests including whiteflies, aphids, leafhoppers, Colorado potato beetles and cabbage worms. Due to its unique mode of action, it is useful in resistance management; however, as it is not specific, it can negatively impact populations of beneficial insects. It is, however, considered to be moderately toxic to honey bees, and it is less toxic to bees than organophosphate insecticides.

Production

The World Health Organization estimated worldwide annual production to be about 9,000 tonnes in the early 1980s. From 1980 to 1989, worldwide consumption averaged 10,500 tonnes per year, and for the 1990s use increased to 12,800 tonnes per year.
Endosulfan is a derivative of hexachlorocyclopentadiene, and is chemically similar to aldrin, chlordane, and heptachlor. Specifically, it is produced by the Diels-Alder reaction of hexachlorocyclopentadiene with cis-butene-1,4-diol and subsequent reaction of the adduct with thionyl chloride. Technical endosulfan is a 7:3 mixture of stereoisomers, designated α and β. α- and β-Endosulfan are configurational isomers arising from the pyramidal stereochemistry of the tetravalent sulfur. α-Endosulfan is the more thermodynamically stable of the two, thus β-endosulfan irreversibly converts to the α form, although the conversion is slow.

History of commercialization and regulation

Early 1950s: Endosulfan was developed.
1954: Hoechst AG won USDA approval for the use of endosulfan in the United States.
2000: Home and garden use in the United States was terminated by agreement with the EPA.
2002: The U.S. Fish and Wildlife Service recommended that endosulfan registration should be cancelled, and the EPA determined that endosulfan residues on food and in water pose unacceptable risks. The agency allowed endosulfan to stay on the US market, but imposed restrictions on its agricultural uses.
2007: International steps were taken to restrict the use and trade of endosulfan. It is recommended for inclusion in the Rotterdam Convention on Prior Informed Consent, and the European Union proposed inclusion in the list of chemicals banned under the Stockholm Convention on Persistent Organic Pollutants. Such inclusion would ban all use and manufacture of endosulfan globally. Meanwhile, the Canadian government announced that endosulfan was under consideration for phase-out, and Bayer CropScience voluntarily pulled its endosulfan products from the U.S. market but continues to sell the products elsewhere.
2008: In February, environmental, consumer, and farm labor groups including the Natural Resources Defense Council, Organic Consumers Association, and the United Farm Workers called on the U.S. EPA to ban endosulfan. In May, coalitions of scientists, environmental groups, and arctic tribes asked the EPA to cancel endosulfan, and in July a coalition of environmental and workers groups filed a lawsuit against the EPA challenging its 2002 decision to not ban it. In October, the Review Committee of the Stockholm Convention moved endosulfan along in the procedure for listing under the treaty, while India blocked its addition to the Rotterdam Convention.
2009: The Stockholm Convention's Persistent Organic Pollutants Review Committee agreed that endosulfan is a persistent organic pollutant and that "global action is warranted", setting the stage of a global ban. New Zealand banned endosulfan.
2010: The POPRC nominated endosulfan to be added to the Stockholm Convention at the Conference of Parties in April 2011, which would result in a global ban. The EPA announced that the registration of endosulfan in the U.S. will be cancelled Australia banned the use of the chemical.
2011: The Supreme Court of India banned manufacture, sale, and use of toxic pesticide endosulfan in India. The apex court said the ban would remain effective for eight weeks during which an expert committee headed by DG, ICMR, will give an interim report to the court about the harmful effect of the widely used pesticide.
2011: the Argentinian Service for Sanity and Agroalimentary Quality decided on August 8 that the import of endosulfan into the South American country will be banned from July 1, 2012, and its commercialization and use from July 1, 2013. In the meantime, a reduced quantity can be imported and sold.
Health effects

Endosulfan is alleged to be responsible for many fatal pesticide poisoning incidents around the world by NGOs opposing pesticide usage. Endosulfan is also a xenoestrogen—a synthetic substance that imitates or enhances the effect of estrogens—and it can act as an endocrine disruptor, causing reproductive and developmental damage in both animals and humans. It has also been found to act as an aromatase inhibitor. Whether endosulfan can cause cancer is debated. With regard to consumers' intake of endosulfan from residues on food, the Food and Agriculture Organization of United Nations has concluded that long-term exposure from food is unlikely to present a public health concern, but short-term exposure can exceed acute reference doses.

Toxicity

Endosulfan is acutely neurotoxic to both insects and mammals, including humans. The US EPA classifies it as Category I: "Highly Acutely Toxic" based on a LD₅₀ value of 30 mg/kg for female rats, while the World Health Organization classifies it as Class II "Moderately Hazardous" based on a rat LD₅₀ of 80 mg/kg. It is a GABA-gated chloride channel antagonist, and a Ca²⁺, Mg²⁺ ATPase inhibitor. Both of these enzymes are involved in the transfer of nerve impulses. Symptoms of acute poisoning include hyperactivity, tremors, convulsions, lack of coordination, staggering, difficulty breathing, nausea and vomiting, diarrhea, and in severe cases, unconsciousness. Doses as low as 35 mg/kg have been documented to cause death in humans, and many cases of sublethal poisoning have resulted in permanent brain damage. Farm workers with chronic endosulfan exposure are at risk of rashes and skin irritation.
EPA's acute reference dose for dietary exposure to endosulfan is 0.015 mg/kg for adults and 0.0015 mg/kg for children. For chronic dietary expsoure, the EPA references doses are 0.006 mg/ and 0.0006 mg/ for adults and children, respectively.

Endocrine disruption

, an expert on endocrine disruption, lists endosulfan as a known endocrine disruptor, and both the EPA and the Agency for Toxic Substances and Disease Registry consider endosulfan to be a potential endocrine disruptor. Numerous in vitro studies have documented its potential to disrupt hormones and animal studies have demonstrated its reproductive and developmental toxicity, especially among males. A number of studies have documented that it acts as an antiandrogen in animals. Endosulfan has shown to affect crustacean molt cycles, which are important biological and endocrine-controlled physiological processes essential for the crustacean growth and reproduction. Environmentally relevant doses of endosulfan equal to the EPA's safe dose of 0.006 mg/kg/day have been found to affect gene expression in female rats similarly to the effects of estrogen. It is not known whether endosulfan is a human teratogen, though it has significant teratogenic effects in laboratory rats. A 2009 assessment concluded the endocrine disruption in rats occurs only at endosulfan doses that cause neurotoxicity.

Reproductive and developmental effects

Some studies have documented that endosulfan can also affect human development. Researchers studying children from many villages in Kasargod District, Kerala, India, have linked endosulfan exposure to delays in sexual maturity among boys. Endosulfan was the only pesticide applied to cashew plantations in the villages for 20 years, and had contaminated the village environment. The researchers compared the villagers to a control group of boys from a demographically similar village that lacked a history of endosulfan pollution. Relative to the control group, the exposed boys had high levels of endosulfan in their bodies, lower levels of testosterone, and delays in reaching sexual maturity. Birth defects of the male reproductive system, including cryptorchidism, were also more prevalent in the study group. The researchers concluded, "our study results suggest that endosulfan exposure in male children may delay sexual maturity and interfere with sex hormone synthesis." Increased incidences of cryptorchidism have been observed in other studies of endosulfan exposed populations.
A 2007 study by the California Department of Public Health found that women who lived near farm fields sprayed with endosulfan and the related organochloride pesticide dicofol during the first eight weeks of pregnancy are several times more likely to give birth to children with autism. However a 2009 assessment concluded that epidemiology and rodent studies that suggest male reproductive and autism effects are open to other interpretations, and that developmental or reproductive toxicity in rats occurs only at endosulfan doses that cause neurotoxicity.