Daminozide: Difference between revisions

{{redirect|Alar}}

{{multiple issues |

{{update | date = August 2022}}

{{globalize | date = August 2022}}

{{cite check | reason = in random checks, some end of sentence/paragraph citations failed to support all information preceding | date = August 2022}}

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| Watchedfields = changed

| verifiedrevid = 444260008

| ImageFile = Daminozide Structural Formula V1.svg

| ImageSize = 200

| ImageName = Skeletal formula of daminozide

| ImageFile2 = Daminozide 3D BS.png

| ImageSize2 = 200

| ImageName2 = Ball and skill formula of daminozide

| PIN = 4-(2,2-Dimethylhydrazin-1-yl)-4-oxobutanoic acid

| OtherNames = ''N''-(Dimethylamino)succinamic acid; Butanedioic acid mono (2,2-dimethyl hydrazine); Succinic acid 2,2-dimethyl hydrazide

|Section1={{Chembox Identifiers

| CASNo = 1596-84-5

| CASNo_Ref = {{cascite|correct|CAS}}

| PubChem = 15331

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

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

| EINECS = 216-485-9

| KEGG = C10996

| KEGG_Ref = {{keggcite|correct|kegg}}

| MeSHName = daminozide

| RTECS = WM9625000

| Beilstein = 1863230

| SMILES = CN(C)NC(=O)CCC(O)=O

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

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

}}

|Section2={{Chembox Properties

| C=6 | H=12 | N=2 | O=3

| Appearance = White crystals

| MeltingPtK = 432.39

}}

|Section3={{Chembox Hazards

| LD50 = {{unbulleted list|>1,600 mg kg⁻¹ <small>(dermal, rabbit)</small>|8,400 mg kg⁻¹ <small>(oral, rat)</small>}}<ref>{{Cite web |last=EXTOXNET Staff |date=September 1993 |title=Pestocide Information Profile: Daminozide |url=http://pmep.cce.cornell.edu/profiles/extoxnet/carbaryl-dicrotophos/daminozide-ext.html |archive-url=https://web.archive.org/web/20130606215140/http://pmep.cce.cornell.edu/profiles/extoxnet/carbaryl-dicrotophos/daminozide-ext.html |archive-date=June 6, 2013 |access-date=10 September 2013 |publisher=Extension Toxicology Network [EXTOXNET] [CCE |location=Ithaca, NY |quote=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 |date=August 2022}}</ref>{{update after|2022|8|11}}

}}

|Section4={{Chembox Related

| OtherFunction_label = alkanoic acids

| OtherFunction = [[Octopine]]

| OtherCompounds = {{unbulleted list|[[1,2-Dimethylhydrazine]]|[[Biurea]]|[[Bis-tris propane]]}}

}}

'''Daminozide,''' also known as '''aminozide''', '''Alar''', '''Kylar''', '''SADH''', '''B-995''', '''B-nine''',<ref name=AlarEPA_PFS_840630/> and '''DMASA''',<ref>{{Cite web |title=daminozide {{!}} Ligand page {{!}} IUPHAR/BPS Guide to PHARMACOLOGY |url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7025 |access-date=2023-09-24 |website=www.guidetopharmacology.org}}</ref> is an [[Organic chemistry|organic]] [[Chemical compound|compound]] which acts as a [[plant growth regulator]].<ref name=AlarEPA_PFS_840630/> It was produced in the [[United States|U.S.]] by the [[Uniroyal Chemical Company|Uniroyal Chemical Company, Inc.]], (now integrated into the [[Chemtura Corporation]]{{not verified in body|date = August 2022}}),<!--PER WP:VERIFY, placing a Wikilink does not satisfy the requirement to state the source of information presented.--> which registered daminozide for use on fruits intended for human consumption in 1963. It was primarily used on [[apple]]s 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.<ref name="EPA1" /> In addition to apples and ornamental plants, Uniroyal also registered daminozide for use on [[cherry|cherries]], [[peach]]es, [[pear]]s, Concord [[grape]]s, [[tomato]] transplants, and [[peanut]] 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.<ref name="EPA1">{{Cite press release |title=Daminozide (Alar) Pesticide Canceled for Food Uses |date=7 November 1989 |publisher=U.S. Environmental Protection Agency |url=http://www.epa.gov/aboutepa/history/topics/food/02.html |archive-url=https://web.archive.org/web/20121003173526/http://www.epa.gov/aboutepa/history/topics/food/02.html |archive-date=October 3, 2012}}</ref> When consumed by [[mammal]]s, daminozide is [[catabolism|catabolised]] into [[succinic acid]] (a non-toxic general intermediate in [[primary metabolism]]{{citation needed|date = August 2022}}) and [[1,1-dimethylhydrazine]] (a compound with a history of studies associating it with [[Carcinogen|carcinogenic]] 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.<ref name="ZeiseJackson1991">{{Cite book |chapter-url=https://doi.org/10.1007/978-1-4899-2370-7_27 |chapter=Alar in Fruit: Limited Regulatory Action in the Face of Uncertain Risks |vauthors=Zeise L, Painter P, Berteau PE, Fan AM, Jackson RJ |title=The Analysis, Communication, and Perception of Risk |date=1991 |publisher=Springer |veditors=Garrick BJ, Gekler WC |series=Advances in Risk Analysis |volume=9 |location=Boston, MA |pages=275–284 |doi=10.1007/978-1-4899-2370-7_27 |isbn=978-1-4899-2372-1 |access-date=10 August 2022}}</ref>

In 1989, the EPA outlawed daminozide on U.S. food crops, but still allowed it for non-food crops like ornamental plants.<ref>{{Cite report |url=http://www.epa.gov/oppsrrd1/REDs/factsheets/0032fact.pdf |title=Daminozide |last=((Office of Prevention, Pesticides and Toxic Substances)) |date=September 1993 |publisher=U.S. Environmental Protection Agency |location=Washington, DC |id=EPA-738-F-93-007 |archive-url=https://web.archive.org/web/20061006081728/http://www.epa.gov/oppsrrd1/REDs/factsheets/0032fact.pdf |archive-date=2006-10-06 |url-status=dead |series=R.E.D.[Reregistration Eligibility Decision] Facts}}</ref> 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]].<ref name="EXIM_221108" />

==Chemistry==

{{expand section | with = a source-derived description of the chemical, its properties, and syntheses | small = no | date = August 2022}}

While described by the FDA as an amino acid derivative,<ref name="AlarEPA_PFS_840630">{{Cite report |url=https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=91024KMX.TXT |title=Daminozide (Alar) |last=EPA Office of Prevention, Pesticides and Toxic Substances |date=June 30, 1984 |publisher=U.S. Environmental Protection Agency |location=Washington, DC |id=PFS no. 26 |series=Pesticide Fact Sheets}}</ref> daminozide is more formally and correctly described as a [[dicarboxylic acid]] mono[[hydrazide]].<ref>The agent is neither synthesized from, not does it contain as component, any [[amino acid]].{{citation needed|date = August 2022}}</ref>{{citation needed|date = August 2022}} It is the product of the condensation of [[succinic acid]] with 2,2-dimethyl[[hydrazine]],{{citation needed|date = August 2022}} and in its pure form is a high-melting temperature water-soluble white crystalline solid.<ref name=AlarEPA_PFS_840630/>{{citation needed|date = August 2022}}<!--The "white... solid" is from the EPA source, the "high-melting... crystalline" is from the ChemBox, and the source for that information must be identified and added here.-->

==Modes of action==

{{expand section | 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 | small = no | date = August 2022}}

Daminozide is classified as a [[plant growth regulator]], a [[chemical]] sprayed on [[fruit]] to regulate their growth.<ref name=EPA1/> When used on fruit trees, it affects flower bud initiation, fruit maturity, fruit firmness and coloring, and preharvest drop,{{how|date = August 2022}} 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.<ref name=EPA1/>

=== Carcinogenicity of daminozide degradation products ===

When daminozide residue on fruit is consumed by [[mammal]]ian species, it is [[catabolism|catabolised]] into two chemical components, [[succinic acid]] (a non-toxic general intermediate in [[primary metabolism]]{{citation needed|date = August 2022}}), and [[unsymmetrical dimethylhydrazine|1, 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.<ref name="ZeiseJackson1991" /> UDMH has had a history of studies associating it with carcinogenic activity in animal models relevant to humans, beginning in the 1960s.<ref name="ZeiseJackson1991" />

==U.S. campaign to ban Alar==

{{multiple issues| section = yes |

{{more citations needed section| date=August 2022}}

{{POV section | date = August 2022}}

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<!--Tag posted regarding content surrounding "Rachel's" source, and in general. Note, the Elliott Marshall source and content were added as the beginning of a corrective to the earlier non-neutrality.-->

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.<ref>{{Citation |last=Hathaway |first=Janet S. |title=Alar: The EPA's Mismanagement of an Agricultural Chemical |date=1993 |work=The Pesticide Question: Environment, Economics, and Ethics |pages=337–343 |editor-last=Pimentel |editor-first=David |url=https://doi.org/10.1007/978-0-585-36973-0_13 |access-date=2024-03-02 |place=Boston, MA |publisher=Springer US |language=en |doi=10.1007/978-0-585-36973-0_13 |isbn=978-0-585-36973-0 |editor2-last=Lehman |editor2-first=Hugh}}</ref> They submitted the proposal to the [[Scientific Advisory Panel]] (SAP), which concluded that the tests were inadequate to determine the [[carcinogen]]icity of the tested substances.<ref name="x034">{{cite news | last=Mitchell | first=Patricia Picone | title=Daminozide: A Chemical Controversy in the Orchards | newspaper=Washington Post | date=October 2, 1985 | url=https://www.washingtonpost.com/archive/lifestyle/food/1985/10/02/daminozide-a-chemical-controversy-in-the-orchards/ad84c541-8888-4708-ae88-484cac0a8536/ | access-date=May 24, 2024}}</ref>

Later, in May 1989, Democrats Joseph Lieberman (D-CT) and Harry Reid (D-NV) held a press conference{{why|date = August 2022}}<!--Needed here is news analysis regarding what prompted the Senate hearing.--> 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, [[University of California-Davis|UCal-Davis]] and 22 years, [[Cornell University|Cornell]]) being singled out as "possible violators of the [FDA] ethics code", with invitation to the "EP[A] inspector general [IG] to investigate".<ref name="MarshallScience890707">{{Cite journal |last=Marshall, Eliot |date=7 July 1989 |title=Science Advisers Need Advice [News & Comment: Ethics in Science] |url=https://www.science.org/doi/abs/10.1126/science.2740907?sid=09e6ec10-e614-43a0-8c1b-08d14f09a953 |journal=Science |publisher=[[American Association for the Advancement of Science]] |volume=245 |issue=4913 |pages=20–22 |doi=10.1126/science.2740907 |pmid=2740907 |access-date=13 August 2022 |quote=Charges that two scientists who served on an EPA advisory panel later broke conflict-of-interest laws raise some vexing questions.}}</ref> Marshall Elliot, writing for the ''News & Views'' section of the [[American Association for the Advancement of Science|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.<ref name = MarshallScience890707/> Marshall further noted that the event was being seen, in the months following, more for its forcing clarification of rules regarding<blockquote>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,<ref name = MarshallScience890707/></blockquote> than for unearthing formal wrongdoing in the Alar case (wherein, after reversal of an earlier, similar conviction on appeal, no charges were ultimately brought{{verify source|date = August 2022}}).<ref name = MarshallScience890707/> 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;{{verify source|date = August 2022}}<ref name="Rachel's">{{Cite journal |last=Montague |first=Peter |date=January 29, 1997 |title=How They Lie – Part 4: The True Story of Alar – Part 2 |url=http://www.rachel.org/files/rachel/Rachels_Environment_Health_News_592.pdf |journal=Rachel's Environment & Health News |location=Brunswick, NJ |publisher=[[Environmental Research Foundation]] |access-date=October 18, 2015 |archive-date=August 30, 2017 |archive-url=https://web.archive.org/web/20170830060514/http://www.rachel.org/files/rachel/Rachels_Environment_Health_News_592.pdf |url-status=dead }}{{better source needed| date=August 2022}}</ref>{{better source needed | date=August 2022}} 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].<ref name = MarshallScience890707/>

The next year, the EPA retracted its proposed ban on Alar and required farmers to reduce its use by 50%.{{citation needed| date=August 2022}} The [[American Academy of Pediatrics]] urged EPA to ban daminozide,{{citation needed| date=August 2022}} and some manufacturers and supermarket chains announced they would not accept Alar-treated apples.<ref name="Rachel's" />{{better source needed | date = August 2022}}

In a 1989 [[The New York Times|NYT]] opinion by [[Natural Resources Defense Council]] (NRDC) trustee John B. Oakes, regarding a two-year NRDC study peer-reviewed by an independent panel,<ref>{{Cite report |url=https://www.nrdc.org/sites/default/files/hea_11052401a.pdf |title=Intolerable Risk: Pesticides in Our Children's Food |last1=Sewell, Bradford H. |last2=Whyatt, Robin M. |date=February 27, 1989 |publisher=Natural Resources Defense Council |location=New York |pages=2–3, 10–11, etc. |quote=[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. |last3=Hathaway, Janet |last4=Mott, Lawrie |others=Project Coordinator: Jane Bloom}}</ref> 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.'"<ref>{{Cite news |last=Oakes |first=John B. |date=1989-03-30 |title=Opinion: A Silent Spring, for Kids |work=[[The New York Times]] |url=https://www.nytimes.com/1989/03/30/opinion/a-silent-spring-for-kids.html |access-date=August 11, 2022 |quote=John B. Oakes, a Natural Resources Defense Council trustee, was Editorial Page Editor of The New York Times.}}</ref>{{better source needed| date=August 2022}}<!--An opinion piece by one of the parties in the historic debate should not be used to establish the facts of the case. EPA and other documents should be used to do this. NRDC sources, direct and indirect, should be used to support their perspective on the matter, and when indirect, it should be clear that they are involved in the perspective presented. Hence Oakes identification as a trustee of NRDC.--> In February, 1989, the [[CBS]] television program ''[[60 Minutes]]'' broadcast a story about Alar that featured the NRDC report highlighting problems with the chemical.<ref name="Percival_etal_4th">{{Cite book |last1=Percival, Robert V. |url=https://books.google.com/books?id=jeVCAQAAIAAJ&q=Alar |title=Environmental Regulation: Law, Science, and Policy |last2=Schroeder, Christopher H. |last3=Miller, Alan S. |last4=Leape, James P. |date=2003 |publisher=Aspen Publishing |isbn=9780735536562 |edition=4th |location=Frederick, MD |pages=388–392, esp. p. 391 |quote=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... |access-date=11 August 2022}}</ref><ref name="ShawLATimes940912">{{Cite news |last=Shaw, David |date=September 12, 1994 |title=Alar Panic Shows Power of Media to Trigger Fear |work=[[Los Angeles Times]] |url=https://www.latimes.com/archives/la-xpm-1994-09-12-mn-37733-story.html |access-date=August 11, 2022}}</ref>

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."{{quote without source|date = August 2022}} 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.<ref name = Percival_etal_4th/><ref name="Gunset">{{Cite news |last=Gunset |first=George |date=3 June 1989 |title=Apple Chemical Alar Off Market |work=[[Chicago Tribune]] |url=https://www.chicagotribune.com/1989/06/03/apple-chemical-alar-off-market/ |access-date=30 April 2017 |quote=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.}}</ref> 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,<blockquote>"[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"</blockquote>in particular, the "rapid decline in apple consumption that followed the "60 Minutes" report"<ref name = Percival_etal_4th/> 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).<ref name="Gunset" /> 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.<ref name="EXIM_221108">{{Cite web |last=EXIM Staff |date=11 August 2022 |title=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 |url=https://www.exim.gov/policies/exim-bank-and-environment/list-of-pesticides-chemicals-and-substances-ineligible-for-export-credit-insurance |access-date=11 August 2022 |website=EXIM.gov |publisher=[[Export-Import Bank of the United States]] |location=Washington, DC}}</ref>

===Backlash===

In November 1990, [[Washington (state)|Washington]] apple growers filed a lawsuit in [[Yakima County, Washington|Yakima County Superior Court]] against CBS, [[Natural Resources Defense Council|NRDC]] and [[Fenton Communications]] (hired by NRDC to publicize their report on Alar)<ref name="Carlson">{{Cite news |last=Carlson |first=Peter |date=11 February 1990 |title=The Image Makers |newspaper=[[The Washington Post]] |url=https://www.washingtonpost.com/archive/lifestyle/magazine/1990/02/11/the-image-makers/ccf6936e-4f50-4292-8224-fee6db3b582d/ |access-date=30 April 2017 |quote=Fenton engineered a PR campaign that was the worst thing to happen to the apple since Eve.}}</ref> claiming that unfair business practices ([[defamation|product disparagement]] in particular) cost them $100 million.<ref name="Trib">{{Cite news |date=29 November 1990 |title=Apple Growers Sue Over CBS Alar Report |work=[[Chicago Tribune]] |agency=[[Associated Press]] |url=http://archives.chicagotribune.com/1990/11/29/page/51/article/apple-growers-sue-over-cbs-alar-report |access-date=30 April 2017}}</ref><ref>{{Cite news |last=Puzo |first=Daniel P. |date=20 November 1990 |title=Apple Growers to File Lawsuit in Alar Dispute |work=[[Los Angeles Times]] |url=https://www.latimes.com/archives/la-xpm-1990-11-20-mn-5090-story.html |access-date=30 April 2017 |quote=Agriculture: Eleven farmers will seek $250 million from '60 Minutes' and an environmental group. They charge 'product disparagement.'}}</ref><ref>{{Cite news |last=Egan |first=Timothy |date=July 9, 1991 |title=Apple Growers Bruised and Bitter After Alar Scare |work=The New York Times |url=https://www.nytimes.com/1991/07/09/us/apple-growers-bruised-and-bitter-after-alar-scare.html?pagewanted=all}}</ref> The suit was moved from state to federal court at the request of CBS.<ref>{{Cite news |date=4 January 1991 |title=CBS Seeks to Move Alar Suit |work=[[Lewiston Morning Tribune]] |agency=[[Associated Press]] |url=http://lmtribune.com/northwest/cbs-seeks-to-move-alar-suit/article_a12e43e6-0dec-5e7a-be40-0c08f7f40081.html |access-date=30 April 2017 |quote=Lawyers for the network and its affiliates said the issue involved freedom of speech and should be heard in federal court.}}</ref> U.S. District Judge [[William Fremming Nielsen]] ruled in 1993 that the apple growers had not proved their case,<ref>{{Cite news |date=14 September 1993 |title=Apple Growers' Lawsuit Against CBS Thrown Out |work=[[Orlando Sentinel]] |url=https://www.orlandosentinel.com/1993/09/14/apple-growers-lawsuit-against-cbs-thrown-out/ |access-date=30 April 2017 |archive-url=https://web.archive.org/web/20200309211759/https://www.orlandosentinel.com/news/os-xpm-1993-09-14-9309140117-story.html |archive-date=March 9, 2020 |url-status=live |quote=First Amendment law requires plaintiffs bringing such lawsuits to prove media reports were false.}}{{better source needed|date=August 2022}}</ref>{{better source needed|date=August 2022}} and it was subsequently dismissed by the [[United States Court of Appeals for the Ninth Circuit]].<!--<ref>{{Cite web |title=Appellate Brief (1994) for CBS in Alar Case |url=http://www.cspinet.org/foodspeak/laws/cbsbrief.htm |url-status=dead |archive-url=https://web.archive.org/web/20100615222457/http://cspinet.org/foodspeak/laws/cbsbrief.htm |archive-date=June 15, 2010 |access-date=April 4, 2012 |website=Food Speak: Coalition for Free Speech |publisher=CSPI}}{{third-party inline|date = August 2022}}</ref> The Appellate Brief, standing alone, does not support the statement in the text regarding the disposition of the case, so represents immaterial (and one-sided) sourcing.--><ref name="Bernard">{{Cite news |last=Bernard |first=Mitchell S. |date=2 June 2013 |title=The Natural Resources Defense Council was right on Alar in 1989 and it still is |work=[[The Washington Examiner]] |url=http://www.washingtonexaminer.com/the-natural-resources-defense-council-was-right-on-alar-in-1989-and-it-still-is/article/2530942 |access-date=30 April 2017 |quote=Mitchell S. Bernard is litigation director for the Natural Resources Defense Council.}}{{third-party inline|date = August 2022}}</ref>{{better source needed|date = August 2022}}

<!--This opinion piece by a party interested in the disposition of the case is not a good source to cite for this judicial result, which will appear in many better news (non-opinion) published venues.-->

[[Elizabeth Whelan]] and her organization, the [[American Council on Science and Health]] (ACSH), which had received $25,000 from Alar's manufacturer,<ref name="Neff2005">{{Cite journal |vauthors=Neff RA, Goldman LR |year=2005 |title=Regulatory parallels to Daubert: stakeholder influence, "sound science," and the delayed adoption of health-protective standards |url=http://www.ajph.org/cgi/content/full/95/S1/S81 |journal=Am J Public Health |volume=95 |issue=Suppl 1 |pages=S81–91 |doi=10.2105/AJPH.2004.044818 |pmid=16030344 |hdl-access=free |hdl=10.2105/AJPH.2004.044818 |s2cid=10175577}}</ref> stated that Alar and its breakdown product [[UDMH]] had not been shown to be carcinogenic.<ref>{{Cite web |last1=Kroll |first1=Andy |last2=Schulman |first2=Jeremy |date=28 October 2013 |title=Leaked Documents Reveal the Secret Finances of a Pro-Industry Science Group |url=https://www.motherjones.com/politics/2013/10/american-council-science-health-leaked-documents-fundraising |access-date=30 April 2017 |website=[[Mother Jones (magazine)|Mother Jones]] |publisher=Foundation for National Progress |quote=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.}}</ref> 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.<ref name="Imprimis">{{Cite journal |last=Whelen |first=Elizabeth |date=June 1991 |title=Cancer Scares and Our Inverted Health Priorities |journal=[[Imprimis]] |volume=20 |issue=6}}</ref>{{page needed|date = August 2022}}<!--For a print journal, absent URL, need to include page number range of journal article.-->

==Current views==

{{Cite check |section |date=August 2022}}

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"<ref name = ZeiseJackson1991/><!--OKAY-->—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.<ref name = ShawLATimes940912/><!--OKAY--><ref name = ZeiseJackson1991/><!--OKAY-->{{update after|2022|8|12}}{{citation needed|date = August 2022}}

<!--This strong, general, conclusive statement requires more citations to make this claim.-->

[[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|date=August 2022}}<!--FAILED CHECK.--> (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.{{clarify|date = August 2022}}<ref>{{Cite journal |last1=Sadowitz, March |last2=Graham, John D. |date=January 1995 |title=A Survey of Residual Cancer Risks Permitted by Health, Safety and Environmental Policy |url=https://scholars.unh.edu/cgi/viewcontent.cgi?article=1218&context=risk |journal=RISK: Health, Safety & Environment |volume=6 |issue=1 |at=article no. 4 |access-date=11 August 2022}}</ref>{{verify source|date = August 2022}})<!--FIXED. OKAY.--> 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".<ref name = ZeiseJackson1991/><!--OKAY.--> As late as 1995, results continued to appear (e.g., from a medium-term carcinogenicity assay approved for use by the [[International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use|ICH]])<ref>{{Cite journal |vauthors=Ito N, Tamano S, Shirai T |date=January 2003 |title=A Medium-Term Rat Liver Bioassay for Rapid in vivo Detection of Carcinogenic Potential of Chemicals |journal=Cancer Sci. |volume=94 |issue=1 |pages=3–8 |doi=10.1111/j.1349-7006.2003.tb01343.x |pmid=12708466 |s2cid=337527 |quote=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.|doi-access=free |pmc=11160283 }}</ref><!--OKAY.-->—supporting ''in''significant levels of "carcinogenicity of daminozide, alone or in combination with... 1,1-dimethylhydrazine".<ref>{{Cite journal |vauthors=Cabral R, Hakoi K, Hoshiya T, Hasegawa R, Ito N |date=1995 |title=Lack of Carcinogenicity of Daminozide, Alone or in Combination with its Contaminant 1,1-Dimethylhydrazine, in a Medium-Term Bioassay |journal=Teratog. Carcinog. Mutagen. |volume=15 |issue=6 |pages=307–312 |doi=10.1002/tcm.1770150607 |pmid=8732881 |quote=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.}}</ref><!--OKAY.-->{{update after|2022|8|12}}

As of 2005, daminozide remained classified as a probable human carcinogen by the EPA, and listed as a known carcinogen under [[California]]'s [[California Proposition 65 (1986)|Prop 65]].<ref name=Neff2005/>{{update after|2022|8|13}}

{{reflist}}

==Further reading==

* {{Cite journal |last=Groth III, Edward |date=19 May 1989 |title=Alar in Apples [Response to "Scare of the Week" (editorial), by Daniel E. Koshland, Jr., ''Science'', 7 April 1989, p. 9] |journal=Science |publisher=[[American Association for the Advancement of Science]] |volume=244 |issue=4906 |page=755 |doi=10.1126/science.2727678 |jstor=1703501|pmid=2727678 }} This is a formal response of Edward Groth III of the Consumers Union, reflecting the back-and-forth debate on this matter, at the highest levels of American science. See also the original Koshland editorial, and other responses on the pages following this.

* {{Cite journal |last=Marshall, Eliot |date=7 July 1989 |title=Science Advisers Need Advice [News & Comment: Ethics in Science] |url=https://www.science.org/doi/abs/10.1126/science.2740907?sid=09e6ec10-e614-43a0-8c1b-08d14f09a953 |journal=Science |publisher=[[American Association for the Advancement of Science]] |volume=245 |issue=4913 |pages=20–22 |doi=10.1126/science.2740907 |pmid=2740907 |access-date=13 August 2022}} This article is ''Science'''s formal reporting, months after, regarding the Lieberman-Reid hearings into the ethics and ties of the EPA SAP to the chemical manufacturing industry, a hearing which resulted in institutional reviews of the rules (but no formal charges against any SAP member).

* {{Cite web |last=Gordon, Wendy |date=March 30, 2011 |title=The True Alar Story [Part 1 of 4] |url=https://www.huffpost.com/entry/the-true-alar-story_b_838974 |access-date=13 August 2022 |website=HuffPost.com |format=self-published blog; HuffPost Contributor platform, defunct}} This extensive self-published work (this the first of a four-part series) is an attempt on the part of a former NRDC staffer to correct what she perceives to be the false narrative that has emerged, that pulling Alar from the market was an overreaction based on incomplete or poor science.

*[https://www.fda.gov/media/112989/download FDA Report RISK COMMUNICATION ADVISORY COMMITTEE pdf]

*[https://web.archive.org/web/20121003173526/http://www.epa.gov/aboutepa/history/topics/food/02.html EPA: Daminozide (Alar) Pesticide Canceled for Food Uses]

{{hydrazines}}

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[[Category:Plant growth regulators]]

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