Daminozide

Last updated
Daminozide
Daminozide Structural Formula V1.svg
Daminozide 3D BS.png
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
ECHA InfoCard 100.014.988 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 216-485-9
KEGG
MeSH daminozide
PubChem CID
RTECS number
  • WM9625000
UNII
  • InChI=1S/C6H12N2O3/c1-8(2)7-5(9)3-4-6(10)11/h3-4H2,1-2H3,(H,7,9)(H,10,11) Yes check.svgY
    Key: NOQGZXFMHARMLW-UHFFFAOYSA-N Yes check.svgY
  • CN(C)NC(=O)CCC(O)=O
Properties
C6H12N2O3
Molar mass 160.173 g·mol−1
AppearanceWhite crystals
Melting point 159.24 °C; 318.63 °F; 432.39 K
Hazards
Lethal dose or concentration (LD, LC):
  • >1,600 mg kg−1(dermal, rabbit)
  • 8,400 mg kg−1(oral, rat)
[1] [ needs update ]
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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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]

Contents

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]

Chemistry

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]

Modes of action

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]

U.S. campaign to ban Alar

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.[ citation needed ]

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". [10] 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. [10] 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, [10]

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 ]). [10] 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 ] [11] [ 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]. [10]

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. [11] [ 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, [12] 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.'" [13] [ 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. [14] [15]

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. [14] [16] 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" [14] 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). [16] 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]

Backlash

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) [17] claiming that unfair business practices (product disparagement in particular) cost them $100 million. [18] [19] [20] The suit was moved from state to federal court at the request of CBS. [21] U.S. District Judge William Fremming Nielsen ruled in 1993 that the apple growers had not proved their case, [22] [ better source needed ] and it was subsequently dismissed by the United States Court of Appeals for the Ninth Circuit. [23] [ 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, [24] stated that Alar and its breakdown product UDMH had not been shown to be carcinogenic. [25] 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. [26] [ page needed ]

Current views

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. [15] [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 ] [27] [ 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) [28] —supporting insignificant levels of "carcinogenicity of daminozide, alone or in combination with... 1,1-dimethylhydrazine". [29] [ 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. [24] [ needs update ]

Related Research Articles

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.

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<span class="mw-page-title-main">Glyphosate</span> Systemic herbicide and crop desiccant

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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.

<span class="mw-page-title-main">Malathion</span> Chemical compound

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.

<span class="mw-page-title-main">Chlorpyrifos</span> Chemical compound

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.

<span class="mw-page-title-main">Bruce Ames</span> American biochemist (born 1928)

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<span class="mw-page-title-main">Endosulfan</span> Chemical compound

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<span class="mw-page-title-main">Organic food</span> Food complying with organic farming standards

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References

  1. ↑ EXTOXNET Staff (September 1993). "Pestocide Information Profile: Daminozide". Ithaca, NY: Extension Toxicology Network [EXTOXNET] [CCE. Archived from the original on June 6, 2013. Retrieved 10 September 2013. 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 ]
  2. 1 2 3 4 5 EPA Office of Prevention, Pesticides and Toxic Substances (June 30, 1984). Daminozide (Alar) (Report). Pesticide Fact Sheets. Washington, DC: U.S. Environmental Protection Agency. PFS no. 26.
  3. ↑ "daminozide | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org. Retrieved 2023-09-24.
  4. 1 2 3 4 "Daminozide (Alar) Pesticide Canceled for Food Uses" (Press release). U.S. Environmental Protection Agency. 7 November 1989. Archived from the original on October 3, 2012.
  5. 1 2 3 4 5 6 Zeise L, Painter P, Berteau PE, Fan AM, Jackson RJ (1991). "Alar in Fruit: Limited Regulatory Action in the Face of Uncertain Risks". In Garrick BJ, Gekler WC (eds.). The Analysis, Communication, and Perception of Risk. Advances in Risk Analysis. Vol. 9. Boston, MA: Springer. pp. 275–284. doi:10.1007/978-1-4899-2370-7_27. ISBN   978-1-4899-2372-1 . Retrieved 10 August 2022.
  6. ↑ Office of Prevention, Pesticides and Toxic Substances (September 1993). Daminozide (PDF) (Report). R.E.D.[Reregistration Eligibility Decision] Facts. Washington, DC: U.S. Environmental Protection Agency. EPA-738-F-93-007. Archived from the original (PDF) on 2006-10-06.
  7. 1 2 EXIM Staff (11 August 2022). "Lists of Pesticides, Chemicals and Substances Ineligible for Export Credit Insurance: ANNEX C—List of Banned and Severely Restricted Pesticides Under the Prior Informed Consent (PIC) Program". EXIM.gov. Washington, DC: Export-Import Bank of the United States . Retrieved 11 August 2022.
  8. ↑ The agent is neither synthesized from, not does it contain as component, any amino acid.[ citation needed ]
  9. ↑ Hathaway, Janet S. (1993), Pimentel, David; Lehman, Hugh (eds.), "Alar: The EPA's Mismanagement of an Agricultural Chemical", The Pesticide Question: Environment, Economics, and Ethics, Boston, MA: Springer US, pp. 337–343, doi:10.1007/978-0-585-36973-0_13, ISBN   978-0-585-36973-0 , retrieved 2024-03-02
  10. 1 2 3 4 5 Marshall, Eliot (7 July 1989). "Science Advisers Need Advice [News & Comment: Ethics in Science]". Science. 245 (4913). American Association for the Advancement of Science: 20–22. doi:10.1126/science.2740907. PMID   2740907 . Retrieved 13 August 2022. Charges that two scientists who served on an EPA advisory panel later broke conflict-of-interest laws raise some vexing questions.
  11. 1 2 Montague, Peter (January 29, 1997). "How They Lie – Part 4: The True Story of Alar – Part 2" (PDF). Rachel's Environment & Health News. Brunswick, NJ: Environmental Research Foundation. Archived from the original (PDF) on August 30, 2017. Retrieved October 18, 2015.[ better source needed ]
  12. ↑ Sewell, Bradford H.; Whyatt, Robin M.; Hathaway, Janet; Mott, Lawrie (February 27, 1989). Intolerable Risk: Pesticides in Our Children's Food (PDF) (Report). Project Coordinator: Jane Bloom. New York: Natural Resources Defense Council. pp. 2–3, 10–11, etc. [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.
  13. ↑ Oakes, John B. (1989-03-30). "Opinion: A Silent Spring, for Kids". The New York Times . Retrieved August 11, 2022. John B. Oakes, a Natural Resources Defense Council trustee, was Editorial Page Editor of The New York Times.
  14. 1 2 3 Percival, Robert V.; Schroeder, Christopher H.; Miller, Alan S.; Leape, James P. (2003). Environmental Regulation: Law, Science, and Policy (4th ed.). Frederick, MD: Aspen Publishing. pp. 388–392, esp. p. 391. ISBN   9780735536562 . Retrieved 11 August 2022. 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...
  15. 1 2 Shaw, David (September 12, 1994). "Alar Panic Shows Power of Media to Trigger Fear". Los Angeles Times . Retrieved August 11, 2022.
  16. 1 2 Gunset, George (3 June 1989). "Apple Chemical Alar Off Market". Chicago Tribune . Retrieved 30 April 2017. 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.
  17. ↑ Carlson, Peter (11 February 1990). "The Image Makers". The Washington Post . Retrieved 30 April 2017. Fenton engineered a PR campaign that was the worst thing to happen to the apple since Eve.
  18. ↑ "Apple Growers Sue Over CBS Alar Report". Chicago Tribune . Associated Press. 29 November 1990. Retrieved 30 April 2017.
  19. ↑ Puzo, Daniel P. (20 November 1990). "Apple Growers to File Lawsuit in Alar Dispute". Los Angeles Times . Retrieved 30 April 2017. Agriculture: Eleven farmers will seek $250 million from '60 Minutes' and an environmental group. They charge 'product disparagement.'
  20. ↑ Egan, Timothy (July 9, 1991). "Apple Growers Bruised and Bitter After Alar Scare". The New York Times.
  21. ↑ "CBS Seeks to Move Alar Suit". Lewiston Morning Tribune . Associated Press. 4 January 1991. Retrieved 30 April 2017. Lawyers for the network and its affiliates said the issue involved freedom of speech and should be heard in federal court.
  22. ↑ "Apple Growers' Lawsuit Against CBS Thrown Out". Orlando Sentinel . 14 September 1993. Archived from the original on March 9, 2020. Retrieved 30 April 2017. First Amendment law requires plaintiffs bringing such lawsuits to prove media reports were false.[ better source needed ]
  23. ↑ Bernard, Mitchell S. (2 June 2013). "The Natural Resources Defense Council was right on Alar in 1989 and it still is". The Washington Examiner . Retrieved 30 April 2017. Mitchell S. Bernard is litigation director for the Natural Resources Defense Council.[ third-party source needed ]
  24. 1 2 Neff RA, Goldman LR (2005). "Regulatory parallels to Daubert: stakeholder influence, "sound science," and the delayed adoption of health-protective standards". Am J Public Health. 95 (Suppl 1): S81–91. doi:10.2105/AJPH.2004.044818. hdl: 10.2105/AJPH.2004.044818 . PMID   16030344. S2CID   10175577.
  25. ↑ Kroll, Andy; Schulman, Jeremy (28 October 2013). "Leaked Documents Reveal the Secret Finances of a Pro-Industry Science Group". Mother Jones . Foundation for National Progress. Retrieved 30 April 2017. 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.
  26. ↑ Whelen, Elizabeth (June 1991). "Cancer Scares and Our Inverted Health Priorities". Imprimis . 20 (6).
  27. ↑ Sadowitz, March; Graham, John D. (January 1995). "A Survey of Residual Cancer Risks Permitted by Health, Safety and Environmental Policy". RISK: Health, Safety & Environment. 6 (1). article no. 4. Retrieved 11 August 2022.
  28. ↑ Ito N, Tamano S, Shirai T (January 2003). "A Medium-Term Rat Liver Bioassay for Rapid in vivo Detection of Carcinogenic Potential of Chemicals". Cancer Sci. 94 (1): 3–8. doi: 10.1111/j.1349-7006.2003.tb01343.x . PMID   12708466. S2CID   337527. 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.
  29. ↑ Cabral R, Hakoi K, Hoshiya T, Hasegawa R, Ito N (1995). "Lack of Carcinogenicity of Daminozide, Alone or in Combination with its Contaminant 1,1-Dimethylhydrazine, in a Medium-Term Bioassay". Teratog. Carcinog. Mutagen. 15 (6): 307–312. doi:10.1002/tcm.1770150607. PMID   8732881. 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.

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