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| Names | |
|---|---|
| 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 |
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| ECHA InfoCard | 100.014.988 |
| EC Number |
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| KEGG |
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| MeSH | daminozide |
| RTECS number |
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| UNII | |
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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 theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Daminozide, also known asaminozide,Alar,Kylar,SADH,B-995,B-nine,[2] andDMASA,[3] is anorganiccompound which acts as aplant growth regulator.[2] It was produced in theU.S. by theUniroyal Chemical Company, Inc., (now integrated into theChemtura Corporation[not verified in body]), which registered daminozide for use on fruits intended for human consumption in 1963. It was primarily used onapples until 1989, when the manufacturer voluntarily withdrew it after theU.S. Environmental Protection Agency proposed banning it based on concerns about cancer risks to consumers.[4] In addition to apples and ornamental plants, Uniroyal also registered daminozide for use oncherries,peaches,pears, Concordgrapes,tomato transplants, andpeanut vines.
When used on fruit trees, daminozide affects flower bud initiation, fruit maturity, fruit firmness and coloring, preharvest drop and market quality of fruit at time of harvest and during storage.[4] When consumed bymammals, daminozide iscatabolised intosuccinic acid (a non-toxic general intermediate inprimary metabolism[citation needed]) and1,1-dimethylhydrazine (UDMH, a compound with a history of studies associating it withcarcinogenic activity in animal models relevant to humans). Breakdown into these two compounds also occurs when the sprayed chemical residue remains on stored fruit, especially with higher temperatures and over longer time periods.[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 theExport–Import Bank of the United States.[7]
![[icon]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aWiki_letter_w_cropped.svg) | This sectionneeds expansion with: a source-derived description of the chemical, its properties, and syntheses. You can help byadding to it.(August 2022) |
While described by the FDA as an amino acid derivative,[2] daminozide is more formally and correctly described as adicarboxylic acid monohydrazide.[8][citation needed] It is the product of the condensation ofsuccinic acid with 2,2-dimethylhydrazine,[citation needed] and in its pure form is a high-melting temperature water-soluble white crystalline solid.[2][citation needed]
| This sectionneeds expansion with: 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 byadding to it.(August 2022) |
Daminozide is classified as aplant growth regulator, achemical sprayed onfruit to regulate their growth.[4] When used on fruit trees, it affects flower bud initiation, fruit maturity, fruit firmness and coloring, and preharvest drop,[how?] which together make harvest easier and keep fruit from falling off the trees before they ripen; it also improves quality of fruit at time of harvest and during storage.[4]
When daminozide residue on fruit is consumed bymammalian species, it iscatabolised into two chemical components,succinic acid (a non-toxic general intermediate inprimary metabolism[citation needed]), and1, 1-dimethylhydrazine ("unsymmetrical dimethylhydrazine", UDMH). Degradation into these products also occurs when the sprayed chemical residue remains on stored fruit, increasing with time and elevated temperature.[5] UDMH has had a history of studies associating it with carcinogenic activity in animal models relevant to humans, beginning in 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 theScientific Advisory Panel (SAP), which concluded that the tests were inadequate to determine thecarcinogenicity 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 theNews & Views section of theAAAS 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 theU.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 acceptedafter 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] TheAmerican 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 1989NYT opinion byNatural 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, theCBS television program60 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 ofCBS broadcast were swift and severe; as Percival, Schroeder, Miller, and Leape note in review of legal aspects in theirEnvironmental 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 theChicago 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 theList of Banned and Severely Restricted Pesticides Under the Prior Informed Consent (PIC) Program of theExport-Import Bank of the United States, making its shipments ineligible for export credit insurance.[7]
In November 1990,Washington apple growers filed a lawsuit inYakima County Superior Court against CBS,NRDC andFenton 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 JudgeWilliam Fremming Nielsen ruled in 1993 that the apple growers had not proved their case,[23][better source needed] and it was subsequently dismissed by theUnited States Court of Appeals for the Ninth Circuit.[24][better source needed]
Elizabeth Whelan and her organization, theAmerican Council on Science and Health (ACSH), which had received $25,000 from Alar's manufacturer,[25] stated that Alar and its breakdown productUDMH had not been shown to be carcinogenic.[26] During a 1990 speech atHillsdale 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]
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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 theICH)[29]—supportinginsignificant 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 underCalifornia'sProp 65.[25][needs update]
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.[independent 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.
