Briefing Note: IARC Monograph 113 From June 2 – 9, 2015 the International Agency for Research on Cancer (IARC) Working Group 113 met to evaluate 2,4-D and classified the compound as “possibly carcinogenic to humans” (Group 2B). This review can now be found in the IARC Monograph for 2,4-D published on August 1, 2016.1 The full 126-page text is included below. IARC reached this conclusion based on “inadequate evidence” in humans and “limited evidence” in experimental animals.2 Other Group 2B possible carcinogens include aloe vera and pickled vegetables. Consistency between IARC and Regulators IARC’s finding of “inadequate evidence” in humans aligns with the repeated findings of agencies mandated with protecting human health including the United States Environmental Protection Agency (20073 & 20124 & 20145), European Food Safety Authority (20156), and more than 90 other countries as well as the World Health Organization (19967 & 20038). These agencies have consistently concluded 2,4-D does not present a human cancer risk. Similarly, IARC’s evaluation concluded, “…epidemiological studies did not find strong or consistent increases in risk of [non-Hodgkin’s lymphoma] NHL or other cancers in relation to 2,4-D exposure.” Differences between IARC and Regulators In IARC’s news release announcing their classification of 2,4-D, the agency states clearly in a “Note to the Editors” the important difference between Cancer Hazard Identification and Cancer Risk Assessment: “…the Monographs Programme identifies cancer hazards even when risks are very low at current exposure levels.” In contrast, the US EPA and other national regulators use hazard identification as one step of a rigorous four-step process.9 For example, in March 2016, Health Canada’s Pest Management Regulatory Agency (PMRA) published an evaluation of 2,4-D, which considered the IARC findings, and concluded: “The IARC hazard classifications are not health risk assessments and the levels of human exposure, which determine the actual risk, are not taken into account in the IARC assessments.”10 www.24d.org 1 What Regulatory Authorities Have Determined US EPA: In considering the same data in 2014 after a much longer review than the eight days IARC 113 panelists looked at the data, EPA determined: “…[B]ased on weight of evidence consideration of the available data, 2,4-D would be classified as ‘Not Likely to be Carcinogenic to Humans’.” Health Canada’s PMRA: In 2008 PMRA conducted its re-evaluation of 2,4-D and determined: “that 2,4-D meets Canada’s strict health and safety standards. …No other international regulatory body considers 2,4-D to be a human carcinogen. Based on all available and relevant data, Health Canada agrees with this position…Health Canada found that 2,4-D does not increase the risk of cancer and can be used safely by homeowners, provided label directions are followed.” 2015 European Food Safety Authority (EFSA): Following the peer review of the initial risk assessments carried out by the competent authority of the Rapporteur Member State Greece, for the pesticide active substance 2,4-D the conclusions were reported: “it was therefore agreed that 2,4-D, as currently manufactured, is unlikely to have a genotoxic potential or pose a carcinogenic risk to humans.” Furthermore, “no conclusive association can be established between exposure to phenoxy-herbicides (including 2,4-D acid) and human carcinogenicity.” Outcome Regulatory authorities worldwide have indicated that they will consider IARC hazard assessment as part of the normal full evaluation processes going forward, but there is no new evidence that has not already been evaluated. 18 August 2016 1 See Summary of Data, pp 105 – 108 http://monographs.iarc.fr/ENG/Monographs/vol113/mono113-03.pdf 2 http://www.iarc.fr/en/media-centre/pr/2015/pdfs/pr236_E.pdf 3 2,4-D, 2,4-DP, and 2,4-DB; Decision Not to Initiate Special Review. (2007) http://24d.org/govtrev/federal2007.pdf 4 EPA Denies Petition on 2,4-D Pesticide. (2012) http://www.epa.gov/oppfead1/cb/csb_page/updates/2012/2-4d-petition.html 5 EPA Memorandum, “Response to public comments received regarding new uses of Enlist DUOTM on corn and soybeans” EPA-HQ-OPP-2014-0195-2414 (2014) 6 European Food Safety Authority. Conclusion on Pesticide Peer for the active substance 2,4-D. (2015) 7 Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group. (1996) http://www.fao.org/fileadmin/templates/agphome/documents/Pests_Pesticides/JMPR/Reports_1991- 2006/Report1996.pdf 8 Guidelines for Drinking-water Quality. Third Edition. Geneva. World Health Organization. (2003) 9 http://epa.gov/riskassessment/health-risk.htm 10 Re-evaluation Note 2016-08, Special Review of 2,4-D: Proposed Decision for Consultation. (2016) http://www.hc-sc.gc.ca/cps-spc/pest/part/consultations/_rev2016-08/rev2016-08-eng.php#s4.1 www.24d.org 2 2,4-DICHLOROPHENOXYACETIC ACID 1. Exposure Data 1.1.2 Structural and molecular formulae, and relative molecular mass 1.1 Identification of the agent Cl 1.1.1 Nomenclature Chem. Abstr. Serv. Reg. No.: 94-75-7 Chem. Abstr. Serv. Name: 2,4-Dichlorophenoxy- Cl O acetic acid OH Preferred IUPAC Name: 2-(2,4-Dichloro- phenoxy) acetic acid O Synonyms: 2,4-D; 2,4 dichlorophenoxyacetic Molecular formula: C8H6Cl2O3 acid; 2,4-dichlorophenoxyacetic acid Relative molecular mass: 221.03 Trade Names: 2,4-Dichlorophenoxyacetic acid (2,4-D) has been used in many commer- cial product formulations. Selected trade 1.1.3 Chemical and physical properties of the names include: Hedonal; 2,4-D; Estone; pure substance Agrotect; Fernesta; Fernimine; Netagrone; Tributon; Vergemaster; Amoxone; Dicopur; Description: Colourless crystals or white Dormone; Ipaner; Moxone; Phenox; Pielik; powder Rhodia; Weedone; B-Selektonon. Solubility: Slightly soluble in water (g/100 mL Additional trade names are available in the at 25 °C, 0.031). Soluble in organic solvents PubChem Compound database (NCBI, 2015). (ethanol, acetone, dioxane) Octanol/water partition coefficient: log Pow, 2.81 Conversion factor: 1 ppm = 9.04 mg/m3, assuming normal temperature (25 °C) and pressure (101 kPa) See IPCS/ICSC (2015) 1 IARC MONOGraPhs – 113 Fig. 1.1 Production of 2,4-dichlorophenoxyacetic acid (2,4-D) via 2,4-dichlorophenol OH OH Cl Cl2 OCH2COOH Cl Phenol Cl 2,4-Dichlorophenol Cl CH2 COOH Cl Chloroacetic acid 2,4-Dichlorophenoxyacetic acid Reprinted from Chemosphere, 92(3), Liu et al. (2013) Formation and contamination of polychlorinated dibenzodioxins/dibenzofurans (PCDD/ Fs), polychlorinated biphenyls( PCBs), pentachlorobenzene (PeCBz), hexachlorobenzene (HxCBz), and polychlorophenols in the production of 2,4-D products, pp 304–308, Copyright (2013), with permission from Elsevier 1.1.4 Esters and salts of 2,4-D • 2,4-D isopropyl ester (CAS No. 94-11-1) Several esters and salts of 2,4-D with various • 2,4-D isooctyl ester (CAS No. 25168-26-7) properties have been manufactured and used in • 2,4-D choline salt (CAS No. 1048373-72-3) herbicide products (NPIC, 2008). In humans, Physical properties of these 2,4-D salts and esters and salts of 2,4-D undergo rapid acid esters have been reported elsewhere (NPIC, or enzymatic hydrolysis in vivo to yield 2,4-D 2008). (Garabrant & Philbert, 2002) (see Section 4.1). Esters and salts also undergo hydrolysis to the acid in environmental media at different rates 1.2 Production and use depending on specific conditions of pH, moisture, 1.2.1 Production and other factors (NPIC, 2008). Relevant ester and salt forms of 2,4-D include the following: Two processes are currently used for the production of 2,4-D. In the first process, phenol • 2,4-D salt (CAS No. 2702-72-9) is condensed with chloroacetic acid forming • 2,4-D diethanolamine salt (CAS No. phenoxyacetic acid, which is subsequently chlo- 5742-19-8) rinated (Fig. 1.1). In the second process, phenol • 2,4-D dimethylamine salt (CAS No. is chlorinated, generating 2,4-dichlorophenol, 2008-39-1) which is subsequently condensed with chloro- • 2,4-D isopropylamine salt (CAS No. acetic acid (Fig. 1.2). 5742-17-6) The butyl ester derivative of 2,4-D is produced • 2,4-D isopropanolamine salt (CAS No. by the esterification of the acid with butanol in 32341-80-3) the presence of a ferric chloride catalyst and chlorine (Liu et al., 2013). • 2,4-D butoxyethyl ester (CAS No. 1929-73-3) No reliable data on current global production • 2,4-D butyl ester (CAS No. 94-80-4) of 2,4-D were available to the Working Group. • 2,4-D 2-ethylhexyl ester (CAS No. 1928-43-4) 2 2,4-Dichlorophenoxyacetic acid Fig. 1.2 Production of 2,4-dichlorophenoxyacetic acid (2,4-D) via phenoxyacetic acid OH OCH2COOH OCH2COOH Cl Phenol Cl2 Cl CH2 COOH Cl Chloroacetic acid Phenoxyacetic acid 2,4-Dichlorophenoxyacetic acid Reprinted from Chemosphere, 92(3), Liu et al. (2013) Formation and contamination of polychlorinated dibenzodioxins/dibenzofurans (PCDD/ Fs), polychlorinated biphenyls( PCBs), pentachlorobenzene (PeCBz), hexachlorobenzene (HxCBz), and polychlorophenols in the production of 2,4-D products, pp 304–308, Copyright (2013), with permission from Elsevier In 2010, the production of 2,4-D reached 40 000 commonly formulated with other herbicides, tonnes in China (Liu et al., 2013). for example, dicamba (3,6-dichloro-2-meth- oxybenzoic acid), mecoprop (methylchloro- 1.2.2 Use phenoxypropionic acid, MCPP), mecoprop-P (the (R)-(+)-enantiomer of mecoprop), MCPA 2,4-D is a synthetic auxin, and was the first (2-methyl-4-chlorophenoxyacetic acid), picloram chemical that could selectively control dicot- (4-amino-3,5,6 trichloropicolinic acid), and yledons or broadleaf plants, but spare most clopyralid (3,6-dichloro pyridine-2-carboxylic monocotyledons, which include grasses and acid) (PubChem, 2015).