Glyphosate (IUPAC name: N-(phosphonomethyl)glycine) 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). Glyphosate-based herbicides (GBHs) are used to kill weeds, especially annual broadleaf weeds and grasses that compete with crops. American agricultural company 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.
Farmers quickly adopted glyphosate for agricultural weed control, especially after Monsanto introduced glyphosate-resistant Roundup Ready crops, enabling farmers to kill weeds without killing their crops. In 2007, glyphosate was the most used herbicide in the United States' agricultural sector and the second-most used (after 2,4-D) in home and garden, government and industry, and commercial applications. From the late 1970s to 2016, there was a 100-fold increase in the frequency and volume of application of GBHs worldwide, with further increases expected in the future.
Glyphosate is absorbed through foliage, and minimally through roots, and from there translocated to growing points. It inhibits EPSP synthase, a plant enzyme involved in the synthesis of three aromatic amino acids: tyrosine, tryptophan, and phenylalanine. It is therefore effective only on actively growing plants and is not effective as a pre-emergence herbicide. Crops have been genetically engineered to be tolerant of glyphosate (e.g. Roundup Ready soybean, the first Roundup Ready crop, also created by Monsanto), which allows farmers to use glyphosate as a post-emergence herbicide against weeds.
While glyphosate and formulations such as Roundup have been approved by regulatory bodies worldwide, concerns about their effects on humans and the environment have persisted. A number of regulatory and scholarly reviews have evaluated the relative toxicity of glyphosate as an herbicide. The WHO and FAO Joint committee on pesticide residues issued a report in 2016 stating the use of glyphosate formulations does not necessarily constitute a health risk, giving an acceptable daily intake limit of 1 milligram per kilogram of body weight per day for chronic toxicity.
The consensus among national pesticide regulatory agencies is that labeled uses of glyphosate are unlikely to be carcinogenic to humans. In March 2015, the World Health Organization's International Agency for Research on Cancer (IARC) classified glyphosate as "probably carcinogenic in humans" (category 2A) based on epidemiological studies, animal studies, and in vitro studies. In contrast, the European Food Safety Authority concluded in November 2015 that "the substance is unlikely to be genotoxic (i.e. damaging to DNA) or to pose a carcinogenic threat to humans", later clarifying that while carcinogenic glyphosate-containing formulations may exist, studies that "look solely at the active substance glyphosate do not show this effect". In 2017, the European Chemicals Agency (ECHA) classified glyphosate as causing serious eye damage and as toxic to aquatic life but did not find evidence implicating it as a carcinogen, a mutagen, toxic to reproduction, nor toxic to specific organs.
Discovery Glyphosate was first synthesized in 1950 by Swiss chemist Henry Martin, who worked for the Swiss company Cilag. The work was never published. Early studies found it to be a weak chemical chelating agent.
Glyphosate was independently discovered in the United States at Monsanto in 1970. About 100 derivatives of aminomethylphosphonic acid had been prepared as potential water-softening agents. Two were found to have weak herbicidal activity, and John E. Franz, a chemist at Monsanto, was asked to try to make analogs with stronger herbicidal activity. Glyphosate was the third analog he made. Franz received the National Medal of Technology of the United States in 1987 and the Perkin Medal for Applied Chemistry in 1990 for his discoveries.
Monsanto developed and patented the use of glyphosate to kill weeds in the early 1970s and first brought it to market in 1974 under the Roundup brandname. While its initial patent expired in 1991, Monsanto retained exclusive rights in the United States until its patent on the isopropylamine salt expired in September 2000.
In 2008, scientists at the United States Department of Agriculture Agricultural Research Service (USDA ARS) described glyphosate as a "virtually ideal" herbicide. In 2010 Stephen Powles stated: "glyphosate is a one in a 100-year discovery that is as important for reliable global food production as penicillin is for battling disease."
Chemistry
Glyphosate is a derivative of aminophosphonic acid and the amino acid glycine. Both the phosphonic acid and carboxylic acid moieties can be ionised (deprotonated) and the amine group can be protonated. Consequently the substance exists as a series of rapidly interchanging zwitterions. It was originally synthesized by the reaction of chloromethylphosphonate with glycine. Its name is a contraction of its constituents: glycine and a phosphonate.
The main degradation path for glyphosate is hydrolysis to aminomethylphosphonic acid.
Synthesis Two main approaches are used to synthesize glyphosate industrially, both of which proceed via the Kabachnik–Fields reaction. The first is to react iminodiacetic acid and formaldehyde with phosphorous acid (sometimes formed in situ from phosphorus trichloride using the water generated by the Mannich reaction of the first two reagents). Decarboxylation of the hydrophosphonylation product gives the desired glyphosate product. Iminodiacetic acid is usually prepared on-site by various methods depending on reagent availability.
The second uses glycine in place of iminodiacetic acid. This avoids the need for decarboxylation but requires more careful control of stoichiometry, as the primary amine can react with any excess formaldehyde to form bishydroxymethylglycine, which must be hydrolysed during the work-up to give the desired product.
This synthetic approach is responsible for a substantial portion of the production of glyphosate in China, with considerable work having gone into recycling the triethylamine and methanol solvents. Progress has also been made in attempting to eliminate the need for triethylamine altogether.
Impurities Technical grade glyphosate is a white powder that, according to FAO specification, should contain not less than 95% glyphosate. Formaldehyde, classified as a known human carcinogen,
and N-nitrosoglyphosate, have been identified as toxicologically relevant impurities. The FAO specification limits the formaldehyde concentration to a maximum of 1.3 g/kg glyphosate. N-Nitrosoglyphosate, "belonging to a group of impurities of particular concern as they can be activated to genotoxic carcinogens", should not exceed 1 ppm.
Formulations
Glyphosate is marketed in the United States and worldwide by many agrochemical companies in diverse strengths and with diverse adjuvants, under dozens of tradenames.Farm Chemicals International Glyphosate entry in Crop Protection Database As of 2010, more than 750 glyphosate products were on the market.National Pesticide Information Center. Last updated September 2010 Glyphosate General Fact Sheet In 2012, about half of the total global consumption of glyphosate by volume was for agricultural crops, with forestry comprising another important market.monsanto.ca: "Vision Silviculture Herbicide" , February 3, 2011 Asia and the Pacific was the largest and fastest growing regional market. As of 2014, Chinese manufacturers collectively are the world's largest producers of glyphosate and its precursorsChina Research & Intelligence, June 5, 2013. Research Report on Global and China Glyphosate Industry, 2013–2017 and account for about 30% of global exports. Key manufacturers include Anhui Huaxing Chemical Industry Company, BASF, Bayer CropScience (which also acquired the maker of glyphosate, Monsanto), Dow AgroSciences, DuPont, Jiangsu Good Harvest-Weien Agrochemical Company, Nantong Jiangshan Agrochemical & Chemicals Co., Nufarm, SinoHarvest, Syngenta, and Zhejiang Xinan Chemical Industrial Group Company.
Glyphosate is an acid molecule, so it is formulated as a salt for packaging and handling. Various salt formulations include isopropylamine, diammonium, monoammonium, or potassium as the counterion. The active ingredient of the Monsanto herbicides is the isopropylamine salt of glyphosate. Another important ingredient in some formulations is the surfactant polyethoxylated tallow amine (POEA). Some brands include more than one salt. Some companies report their product as acid equivalent (ae) of glyphosate acid, or some report it as active ingredient (ai) of glyphosate plus the salt, and others report both. Given that each salt has its own molecular weight, the acid equivalent is a more accurate method of expressing and comparing concentrations.
Glyphosate itself is not easily absorbed into plant leaves, and requires a "wetter" for proper absorption, by making sure the herbicide spreads out in evenly sized droplets. The most common wetter is tallow amine ethoxylate, typically 10–12% of a concentrated glyphosate formulation by weight. An Australian study also found alkyl amine ethoxylate being used, in amounts as low as 3%. Where comparable 12% tallow formulations achieved 87% weed control, the alkyl formulations achieved only 76%, and a formulation with 14% tallow achieved 97% control. All were applied at the same amount of glyphosate per acre on ryegrass weeds, and similar results were obtained on wild radish.
Adjuvant loading refers to the amount of adjuvant already added to the glyphosate product. Fully loaded products contain all the necessary adjuvants, including surfactant; some contain no adjuvant system, while other products contain only a limited amount of adjuvant (minimal or partial loading) and additional surfactants must be added to the spray tank before application.
Products are supplied most commonly in formulations of 120, 240, 360, 480, and 680 g/L of active ingredient. The most common formulation in agriculture is 360 g/L, either alone or with added cationic surfactants.Alberta Agriculture and Rural Development. April 26, 2006. Quick Guide to Glyphosate Products – Frequently Asked Questions
For formulations, European regulations allow applications of up to for control of perennial weeds such as couch grass. More commonly, rates of are practiced for control of annual weeds between crops.
Mode of action Glyphosate interferes with the shikimate pathway, which produces the aromatic amino acids phenylalanine, tyrosine and tryptophan in plants and microorganisms – but does not exist in the genome of animals, including humans. It blocks this pathway by inhibiting the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which catalyzes the reaction of shikimate-3-phosphate (S3P) and phosphoenolpyruvate to form 5-enolpyruvyl-shikimate-3-phosphate (EPSP). Glyphosate is absorbed through foliage and minimally through roots, meaning that it is only effective on actively growing plants and cannot prevent seeds from germinating. After application, glyphosate is readily transported around the plant to growing roots and leaves and this systemic activity is important for its effectiveness. Inhibiting the enzyme causes shikimate to accumulate in plant tissues and diverts energy and resources away from other processes, eventually killing the plant. While growth stops within hours of application, it takes several days for the leaves to begin turning yellow. Glyphosate may chelate Co, which contributes to its mode of action.