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Names | |
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Preferred IUPAC name 4-(2,2-Dimethylhydrazin-1-yl)-4-oxobutanoic acid | |
Other names N-(Dimethylamino)succinamic acid; Butanedioic acid mono (2,2-dimethyl hydrazine); Succinic acid 2,2-dimethyl hydrazide | |
Identifiers | |
3D model (JSmol) | |
1863230 | |
ChemSpider | |
ECHA InfoCard | 100.014.988 |
EC Number |
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KEGG | |
MeSH | daminozide |
PubChem CID | |
RTECS number |
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UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C6H12N2O3 | |
Molar mass | 160.173 g·mol−1 |
Appearance | White crystals |
Melting point | 159.24 °C; 318.63 °F; 432.39 K |
Hazards | |
Lethal dose or concentration (LD, LC): | |
LD50 (median dose) |
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Related compounds | |
Related alkanoic acids | Octopine |
Related compounds | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Daminozide, also known as aminozide, Alar, Kylar, SADH, B-995, B-nine, [2] and DMASA, [3] is a plant growth regulator. [2] It was produced in the U.S. by the Uniroyal Chemical Company, Inc, (now integrated into the Chemtura Corporation [ not verified in body ]), which registered daminozide for use on fruits intended for human consumption in 1963. In addition to apples and ornamental plants, they also registered it for use on cherries, peaches, pears, Concord grapes, tomato transplants, and peanut vines. Alar was first approved for use in the U.S. in 1963. It was primarily used on apples until 1989, when the manufacturer voluntarily withdrew it after the U.S. Environmental Protection Agency proposed banning it based on concerns about cancer risks to consumers. [4]
On fruit trees, daminozide affects flow-bud initiation, fruit-set maturity, fruit firmness and coloring, preharvest drop and market quality of fruit at harvest and during storage. [4] When consumed by mammals, daminozide is catabolised into two chemical components, succinic acid (a non-toxic general intermediate in primary metabolism [ citation needed ]), and 1, 1-dimethylhydrazine (a component with a history of studies associating it with carcinogenic activity in animal models relevant to humans). The scission also occurs when the sprayed chemical residue remains on stored fruit, increasingly with higher temperatures and longer times. [5] In 1989, the EPA outlawed daminozide on U.S. food crops, but still allowed it for non-food crops like ornamental plants. [6] As of August 2022, daminozide appeared as severely restricted in its exports on the list of pesticides whose shipments were ineligible for export credit insurance under the Export–Import Bank of the United States. [7]
This section needs expansionwith: a source-derived description of the chemical, its properties, and syntheses. You can help by adding to it. (August 2022) |
While being described in FDA reporting as an amino acid derivative, [2] it is more formally and correctly described as a dicarboxylic acid monohydrazide. [8] [ citation needed ] It is the product of the condensation of succinic acid with 2,2-dimethylhydrazine,[ citation needed ] and is, in pure form, a high-melting white crystalline solid. [2] [ citation needed ] It is soluble in water. [2]
This section needs expansionwith: a source-based description of both the modes of the plant regulatory bioactivity, and of its metabolism, and the involvement of its catabolites in toxicity. You can help by adding to it. (August 2022) |
Daminozide is classified as a plant growth regulator, a chemical sprayed on fruit to regulate growth. [4] On fruit trees, it affects flow-bud initiation, fruit-set maturity, fruit firmness and coloring, and preharvest drop,[ how? ] which together make harvest easier, and keep apples from falling off the trees before they ripen; as well it improves quality of fruit at harvest and during storage (by maintaining them firm, and for red apples, red in color). [4]
When daminozide residue on fruit is consumed by mammalian species, it is catabolised into two chemical components, succinic acid (a non-toxic general intermediate in primary metabolism [ citation needed ]), and 1, 1-dimethylhydrazine ("unsymmetrical dimethylhydrazine", UDMH), the degradative process also occurring when the sprayed chemical residue remains on stored fruit (in "increasing extent with increasing temperature and time"). [5] The UDMH component has had a history of studies associating it with carcinogenic activity in animal models relevant to humans, since the 1960s. [5]
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In 1985, the EPA studied daminozide's effects on mice and hamsters, concluding that it was a "probable human carcinogen" with a dietary risk possibly as high as one cancer for every thousand people exposed, and proposed banning its use on food crops. [9] They submitted the proposal to the Scientific Advisory Panel (SAP), which concluded that the tests were inadequate to determine the carcinogenicity of the tested substances. [10]
Later, in May 1989, Democrats Joseph Lieberman (D-CT) and Harry Reid (D-NV) held a press conference[ why? ] in which the pesticide program at the FDA was accused of being "riddled with pro-industry bias", charging that 7 of 8 SAP members had worked as "consultants for the 'chemical industry'" — that the worst of them, after serving on the SAP (see below), had "later broke[n] conflict-of-interest laws", with career university academic toxicologists Wendell Kilgore and Christopher Wilkinson (29 years, UCal-Davis and 22 years, Cornell) being singled out as "possible violators of the [FDA] ethics code", with invitation to the "EP[A] inspector general [IG] to investigate". [11] Marshall Elliot, writing for the News & Views section of the AAAS publication, Science, noted that these Senators' public scolding of SAP members—which was prompted by the FDA's "waffling on Alar"—led to the investigation of just these two academics by that agency's IG, and of forwarding of Kilgore's file to the U.S. Justice Department for review. [11] Marshall further noted that the event was being seen, in the months following, more for its forcing clarification of rules regarding
how much the government [can limit its]... more than 100,000 advisors, including scientists... who deal with issues ranging from biomedicine to arms control... [quotes spliced to clarify advisor roles] involvement with industry without isolating itself from the expertise it seeks, [11]
than for unearthing formal wrongdoing in the Alar case (wherein, after reversal of an earlier, similar conviction on appeal, no charges were ultimately brought[ verification needed ]). [11] In particular, the Senators alleged that Kilgore had a financial connection to Uniroyal, with Wilkinson and the other five being accused of having more general financial ties to the chemical industry;[ verification needed ] [12] [ better source needed ] notably, the key formal contention was of possible violation of FDA ethics rules regarding limits to the "kind of consulting jobs that can be accepted after leaving an advisory panel" [emphasis in original source]. [11]
The next year, the EPA retracted its proposed ban on Alar and required farmers to reduce its use by 50%.[ citation needed ] The American Academy of Pediatrics urged EPA to ban daminozide,[ citation needed ] and some manufacturers and supermarket chains announced they would not accept Alar-treated apples. [12] [ better source needed ]
In a 1989 NYT opinion by Natural Resources Defense Council (NRDC) trustee John B. Oakes, regarding a two-year NRDC study peer-reviewed by an independent panel, [13] Oakes presented the report's argument that children ingesting daminozide in legally permissible quantities were at "intolerable risk" (from it and a wide variety of other potentially harmful chemicals); by their estimate, Oakes said, the "average pre-schooler's exposure to this carcinogen... result[s] in a cancer risk '240 times greater than the cancer risk considered acceptable by E.P.A. following a full lifetime of exposure.'" [14] [ better source needed ] In February, 1989, the CBS television program 60 Minutes broadcast a story about Alar that featured the NRDC report highlighting problems with the chemical. [15] [16]
Later in 1989, the U.S. Environmental Protection Agency (EPA) decided to ban Alar on the grounds that "long-term exposure" posed "unacceptable risks to public health."[ This quote needs a citation ] However, in June 1989—before the EPA's preliminary decision to ban all food uses of Alar went into effect—Uniroyal, Alar's sole manufacturer, agreed to halt voluntarily all domestic sales of Alar for food uses. [15] [17] Hence, the consequences of CBS broadcast were swift and severe; as Percival, Schroeder, Miller, and Leape note in review of legal aspects in their Environmental Regulation text,
"[t]he denouement... came quickly. Alar was removed from the apple market by its manufacturer, not because of regulatory requirements imposed by the EPA, but because of consumer pressure"
in particular, the "rapid decline in apple consumption that followed the "60 Minutes" report" [15] As the Chicago Tribune noted at that time, Alar's export was not prohibited, such that Uniroyal could continue its sales in about 70 countries, which led critics to note that Americans still faced exposure (via imported fruit and juice). [17] However, as of August 2022, daminozide/alar was appearing as a "severely restricted" entry on the List of Banned and Severely Restricted Pesticides Under the Prior Informed Consent (PIC) Program of the Export-Import Bank of the United States, making its shipments ineligible for export credit insurance. [7]
In November 1990, Washington apple growers filed a lawsuit in Yakima County Superior Court against CBS, NRDC and Fenton Communications (hired by NRDC to publicize their report on Alar) [18] claiming that unfair business practices (product disparagement in particular) cost them $100 million. [19] [20] [21] The suit was moved from state to federal court at the request of CBS. [22] U.S. District Judge William Fremming Nielsen ruled in 1993 that the apple growers had not proved their case, [23] [ better source needed ] and it was subsequently dismissed by the United States Court of Appeals for the Ninth Circuit. [24] [ better source needed ]
Elizabeth Whelan and her organization, the American Council on Science and Health (ACSH), which had received $25,000 from Alar's manufacturer, [25] stated that Alar and its breakdown product UDMH had not been shown to be carcinogenic. [26] During a 1990 speech at Hillsdale College, Whelan said that groups like the NRDC were ignoring a basic principle of toxicology: the dose makes the poison. "It is an egregious departure from science and logic when a substance is labeled 'cancer-causing' based on a response in a single animal study using high doses of a test material", she said. [27] [ page needed ]
Taken together, the complexity of the problem of assigning risk to this agent—the debate over assumptions concerning risks from early-in-life exposure, the principal role of a decomposition product rather than the agent itself in determining its long-term toxicity, the generation of that product both abiotically and through metabolism after consumption, as well as challenges in determining appropriate "subpopulations for study, representative parameters of the potency distribution, and corrections for bioassay length" [5] —have had as a consequence that disagreement and controversy remain about the safety of daminozide and the appropriateness of responses to it in its history. [16] [5] [ needs update ][ citation needed ]
Consumers Union did its own analyses and estimated that the human lifetime cancer risk was 5 cases per million, as compared to the previously reported figure of 50 per million.[ citation needed ] (The EPA had argued for a level of lifetime cancer risk of 1 per million to be the highest acceptable, in this type of case.[ clarification needed ] [28] [ verification needed ]) On the other hand, representatives of the California Department of Health Services are on record as of 1991 stating that "the plausible estimates of risk, derived from conservative, reasonable assumptions, exceed those developed by EPA and NRDC". [5] As late as 1995, results continued to appear (e.g., from a medium-term carcinogenicity assay approved for use by the ICH) [29] —supporting insignificant levels of "carcinogenicity of daminozide, alone or in combination with... 1,1-dimethylhydrazine". [30] [ needs update ]
As of 2005, daminozide remained classified as a probable human carcinogen by the EPA, and listed as a known carcinogen under California's Prop 65. [25] [ needs update ]
Unsymmetrical dimethylhydrazine (UDMH; 1,1-dimethylhydrazine, heptyl or codenamed Geptil) is a chemical compound with the formula H2NN(CH3)2 that is used as a rocket propellant. It is a colorless liquid, with a sharp, fishy, ammonia-like smell typical for organic amines. Samples turn yellowish on exposure to air and absorb oxygen and carbon dioxide. It is miscible with water, ethanol, and kerosene. In concentration between 2.5% and 95% in air, its vapors are flammable. It is not sensitive to shock. Symmetrical dimethylhydrazine (1,2-dimethylhydrazine) is also known but is not as useful. UDMH can be oxidized in air to form many different substances, including toxic ones.
Bromomethane, commonly known as methyl bromide, is an organobromine compound with formula CH3Br. This colorless, odorless, nonflammable gas is produced both industrially and biologically. It is a recognized ozone-depleting chemical. It was used extensively as a pesticide until being phased out by most countries in the early 2000s. From the chemistry perspective, it is one of the halomethanes.
Glyphosate is a broad-spectrum systemic herbicide and crop desiccant. It is an organophosphorus compound, specifically a phosphonate, which acts by inhibiting the plant enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSP). It is used to kill weeds, especially annual broadleaf weeds and grasses that compete with crops. Its herbicidal effectiveness was discovered by Monsanto chemist John E. Franz in 1970. Monsanto brought it to market for agricultural use in 1974 under the trade name Roundup. Monsanto's last commercially relevant United States patent expired in 2000.
Food libel laws, also known as food disparagement laws and informally as veggie libel laws, are laws passed in thirteen U.S. states that make it easier for food producers to sue their critics for libel. These thirteen states are the following: Alabama, Arizona, Colorado, Florida, Georgia, Idaho, Louisiana, Mississippi, North Dakota, Ohio, Oklahoma, South Dakota, and Texas. Many of the food-disparagement laws establish a lower standard for civil liability and allow for punitive damages and attorney's fees for plaintiffs alone, regardless of the case's outcome.
Lindane, also known as gamma-hexachlorocyclohexane (γ-HCH), gammaxene, Gammallin and benzene hexachloride (BHC), is an organochlorine chemical and an isomer of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for lice and scabies.
Malathion is an organophosphate insecticide which acts as an acetylcholinesterase inhibitor. In the USSR, it was known as carbophos, in New Zealand and Australia as maldison and in South Africa as mercaptothion.
In organic chemistry, chlorpyrifos (CPS), also known as chlorpyrifos ethyl, is an organophosphate pesticide that has been used on crops, animals, and buildings, and in other settings, to kill several pests, including insects and worms. It acts on the nervous systems of insects by inhibiting the acetylcholinesterase enzyme. Chlorpyrifos was patented in 1966 by Dow Chemical Company.
Bruce Nathan Ames is a prominent American biochemist. He is a professor of biochemistry and Molecular Biology Emeritus at the University of California, Berkeley, and was a senior scientist at Children's Hospital Oakland Research Institute (CHORI). Throughout his career, Dr. Ames has made significant contributions to understanding the mechanisms of mutagenesis and DNA repair. One of his most notable achievements is the invention of the Ames test, a widely used assay for easily and cheaply evaluating the mutagenicity of compounds. The test revolutionized the field of toxicology and has played a crucial role in identifying numerous environmental and industrial carcinogens.
Benomyl is a fungicide introduced in 1968 by DuPont. It is a systemic benzimidazole fungicide that is selectively toxic to microorganisms and invertebrates, but relatively nontoxic toward mammals.
Toxaphene was an insecticide used primarily for cotton in the southern United States during the late 1960s and the 1970s. Toxaphene is a mixture of over 670 different chemicals and is produced by reacting chlorine gas with camphene. It can be most commonly found as a yellow to amber waxy solid.
Captan is a general use pesticide (GUP) that belongs to the phthalimide class of fungicides. It is a white solid, although commercial samples appear yellow or brownish.
Endosulfan is an off-patent organochlorine insecticide and acaricide that is being phased out globally. It became a highly controversial agrichemical 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.
1,3-Dichloropropene, sold under diverse trade names, is an organochlorine compound with the formula C3H4Cl2. It is a colorless liquid with a sweet smell. It is feebly soluble in water and evaporates easily. It is used mainly in farming as a pesticide, specifically as a preplant fumigant and nematicide. It is widely used in the US and other countries, but is banned in 34 countries.
Triclocarban is an antibacterial chemical once common in, but now phased out of, personal care products like soaps and lotions. It was originally developed for the medical field. Although the mode of action is unknown, TCC can be effective in fighting infections by targeting the growth of bacteria such as Staphylococcus aureus. Additional research seeks to understand its potential for causing antibacterial resistance and its effects on organismal and environmental health.
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A Pesticide Information Project of Cooperative Extension Offices of Cornell University, Michigan State University, Oregon State University, and University of California at Davis. Major support and funding was provided by the USDA/Extension Service/National Agricultural Pesticide Impact Assessment Program.[ better source needed ]
Charges that two scientists who served on an EPA advisory panel later broke conflict-of-interest laws raise some vexing questions.
[p. 2] The potent carcinogen, unsymmetrical dimethylhydrazine (UDMH), a break-down product of the pesticide daminozide, is the greatest source of the cancer risk identified by NRDC. The average preschooler's UDMH exposure during the first six years of life alone is estimated to result in a cancer risk of approximately one case for every 4,200 preschoolers exposed. This is 240 times greater than the cancer risk considered acceptable by EPA following a full lifetime of exposure. For children who are heavy consumers of the foods that may contain UDMH residues, NRDC predicts one additional case of cancer for approximately every 1,100 children, 910 times EPA's acceptable risk level.
John B. Oakes, a Natural Resources Defense Council trustee, was Editorial Page Editor of The New York Times.
The denouement of the Alar controversy came quickly. Alar was removed from the apple market by its manufacturer, not because of regulatory requirements imposed by the EPA, but because of consumer pressure. The rapid decline in apple consumption that followed the "60 Minutes" report on February 26, 1989...
However, Uniroyal will continue to export Alar to about 70 countries, which means, critics said, that Americans still will face exposure from imported apple juice.
Fenton engineered a PR campaign that was the worst thing to happen to the apple since Eve.
Agriculture: Eleven farmers will seek $250 million from '60 Minutes' and an environmental group. They charge 'product disparagement.'
Lawyers for the network and its affiliates said the issue involved freedom of speech and should be heard in federal court.
First Amendment law requires plaintiffs bringing such lawsuits to prove media reports were false.[ better source needed ]
Mitchell S. Bernard is litigation director for the Natural Resources Defense Council.[ third-party source needed ]
Initially, ACSH disclosed its donors, and it was obvious that the group embraced numerous causes connected to its funders. ACSH defended the chemical Alar, used to regulate the growth of apples – and accepted donations from Uniroyal, which manufactured and sold Alar.
At the Fourth International Conference on Harmonization, our medium-term liver bioassay based on an initiation and promotion protocol was recommended in the guidelines as an acceptable alternative to the long-term rodent carcinogenicity test.
Hepatocarcinogenic potential was assessed by comparing the number and area of preneoplastic foci positive for the glutathione S-transferase placental form... in the liver of treated rats, with those in controls given [diethylnitrosamine] alone. Daminozide, UDMH, and the combination were not carcinogenic in this model.