Inhibitor of 5-enolpyruvateshikimate-3-phosphate synthase (EPSPS), an enzyme of the aromatic acid biosynthesis pathway (shikimate pathway) found in plants, not present in animals. [1]

Glyphosate is a broad-spectrum, extremely effective, low-toxic herbicide. The environment frequently contains cyanide chemicals, which are residues left over from glyphosate herbicides. Exposure to glyphosate may disrupt oocyte maturation by causing the generation of early cells and oxidants. In mouse oocytes, glyphosate triggers early cell staining and autophagy [2].

---

Its focus is on the review of existing animal carcinogenicity studies, genotoxicity data, and epidemiological evidence. [1]

In rodents, exposure to glyphosate or GBH (various doses and routes) induced neurotoxic effects including: impaired sensorimotor development, decreased locomotion, increased anxiety and depressive-like behavior, cognitive and memory deficits, alterations in social and maternal behavior, decreased acetylcholinesterase (AChE) activity in brain regions, disruption of glutamatergic, cholinergic, dopaminergic, and serotonergic neurotransmission, oxidative stress (increased lipid peroxidation, altered antioxidant enzyme activities), neuroinflammation (microglia and astrocyte activation, increased TNF-α), and neuronal death.
In fish (e.g., zebrafish), exposure to environmentally relevant concentrations of glyphosate or GBH caused developmental malformations, altered locomotion and behavior (increased anxiety, decreased social interaction, memory impairment), oxidative stress, mitochondrial dysfunction, neuroinflammation, and disruptions in brain energy metabolism.
In humans, occupational or accidental exposure to glyphosate or GBH has been associated with visual memory impairment, increased risk of autism spectrum disorder (with prenatal/infant exposure), and delayed neurological complications (peaking 1-2 days post-exposure) indicated by elevated serum S100B protein levels.

This review summarizes 14 chronic/carcinogenicity rodent studies (9 rat, 5 mouse).
In rat studies, technical grade glyphosate (acid, purity typically >94%) was administered ad libitum via the diet for 18-24 months. Dose levels varied across studies, with high doses often set at or above the regulatory limit dose of 1000 mg/kg bw/day due to the compound's low toxicity. For example, in Study 2 (Monsanto 1990), Sprague Dawley rats (50/sex/dose) received diets containing 0, 2000, 8000, or 20,000 ppm glyphosate for 24 months, achieving mean doses of 0, 89, 362, and 940 mg/kg bw/day (males) and 0, 113, 457, and 1183 mg/kg bw/day (females). Interim sacrifice groups (e.g., at 12 months) were often included for chronic toxicity assessment. [1]
In mouse studies, technical grade glyphosate was similarly administered via the diet for 18-24 months. For example, in Study 10 (Monsanto 1983), CD-1 mice (50/sex/dose) received diets containing 0, 1000, 5000, or 30,000 ppm for 24 months, achieving mean doses of 157/190, 814/955, and 4841/5874 mg/kg bw/day (males/females). [1]
Standard observations included clinical signs, body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weights, gross necropsy, and comprehensive histopathological examination of tissues. Studies were generally conducted following OECD Test Guidelines (e.g., TG 451, 453) and Good Laboratory Practice (GLP). [1]

Absorption, Distribution and Excretion
This study investigated the toxicokinetics of glyphosate in rats following a single intravenous (iv) administration of 100 mg/kg and an oral administration of 400 mg/kg. Blood samples were collected after both intravenous and oral administration. Plasma concentrations of glyphosate and its metabolite aminomethylphosphonic acid (AMPA) were determined by high-performance liquid chromatography (HPLC). Plasma concentration-time curves conformed to a two-compartment open model after both intravenous and oral administration. The plasma elimination half-life (T_1/2β) of glyphosate was 9.99 hours after intravenous administration and 14.38 hours after oral administration. Total plasma clearance was 0.995 L/hr/kg, independent of dose concentration or route of administration. Following intravenous administration, the apparent volume of distribution (V₂) and steady-state volume of distribution (V_ss) in the second compartment were 2.39 and 2.99 L/kg, respectively, indicating sufficient diffusion of the herbicide in tissues. After oral administration, glyphosate was partially and slowly absorbed, with a peak time (T_max) of 5.16 hours. The oral bioavailability of glyphosate was 23.21%. Glyphosate can be converted to ampicillin (AMPA). The metabolite AMPA accounts for 6.49% of the parent drug's plasma concentration. The peak plasma concentrations of glyphosate and AMPA were 4.62 and 0.416 μg/mL, respectively. The peak plasma concentration of AMPA was reached at 2.42 hours. For AMPA, the elimination half-life (T_1/2β) after oral administration of the glyphosate parent compound was 15.08 hours.
The in vivo distribution of glyphosate was studied in mice. Male F344/N mice were administered 5.6 or 56 mg/kg of radiolabeled glyphosate by gavage. Urine and feces were collected every 24 hours for 72 hours, and their radioactivity was analyzed. Some mice were sacrificed 3 to 96 hours after administration to determine the tissue distribution of the radioactive material. Within 72 hours, approximately 20% to 30% of the dose was excreted in the urine and 70% to 80% in the feces. Only about 1% of the dose remained in the tissues, mainly distributed in the liver and small intestine.
…Glyphosate is rapidly cleared from a variety of animals, including mammals, birds, and fish, without biotransformation, and with very low tissue retention.
In laboratory animals, more than 90% of the dose of glyphosate is rapidly cleared within 72 hours after oral administration. …Generally, about 70% of the administered dose is excreted in the feces, and the remainder in the urine. In all cases, the doses detected in tissues and organs were less than 0.5%, indicating that glyphosate does not bioaccumulate in edible tissues. For more complete data on the absorption, distribution, and excretion of glyphosate (11 species), please visit the HSDB record page. Metabolites/Metabolites… In rats, following a single oral administration, over 97% of (14)C/glyphosate/ in excrement was confirmed as an unmetabolized compound. AMPA was the only metabolite, accounting for only 0.2–0.3% of the administered (14)C… Following a single oral administration of 14C-glyphosate, only aminomethylphosphonic acid (AMPA) metabolites were detected in the urine (0.2–0.3% of the administered dose) and feces (0.2–0.4% of the administered dose) of male and female Sprague-Dawley rats. Studies of glyphosate metabolism in experimental animals (rats, rabbits, lactating goats, and chickens) have shown that glyphosate does not undergo biotransformation, and almost all administered doses are excreted in the form of unchanged parent molecules. The biotransformation of glyphosate is extremely low. In rats, after a single oral administration of (14)C-glyphosate, all carbon-14 in urine and feces is present in the form of unchanged parent compounds. In rats, after a single oral administration, over 97% of the carbon-14 in feces is unmetabolized. AMPA is the only metabolite, accounting for only 0.2–0.3% of the carbon-14 used. In laying hens, AMPA is also the only metabolite, accounting for only a small fraction of the amount used.

---

Biological half-life
Male and female Sprague-Dawley rats received a single intraperitoneal injection of radiolabeled (14)C-glyphosate. The glyphosate dose for both male and female rats was 1150 mg/kg. Blood samples were collected at 0.25, 0.50, 1, 2, 4, 6, and 10 hours post-injection. Assuming first-order kinetics, the half-life of radioactivity reduction in bone marrow was 7.6 hours for males and 4.2 hours for females. Similarly, the half-life of radioactivity in plasma was approximately 1 hour in both sexes. Systemic elimination kinetics were estimated using the radioactivity of 14C in urine and feces following a single oral dose of 14C-glyphosate (10 or 1000 mg/kg body weight). Since glyphosate does not undergo biotransformation, it is reasonable to estimate kinetics based on total radioactivity. The elimination process was biphasic. At a dose of 10 mg/kg body weight, the half-life of the α-elimination phase was 5.87 hours (male) or 6.22 hours (female); at a dose of 1000 mg/kg body weight, the half-life of the α-elimination phase was 5.26 hours (male) or 6.44 hours (female). At a dose of 10 mg/kg body weight, the β-phase half-life is 79 hours (male) or 106 hours (female); at a dose of 1000 mg/kg body weight, the β-phase half-life is 181 hours (male) or 337 hours (female).
Toxicokinetics of glyphosate following a single intravenous injection of 100 mg/kg and oral administration of 400 mg/kg were studied in rats. ……For glyphosate, the plasma elimination half-life (T_1/2β) after intravenous injection was 9.99 hours and after oral administration was 14.38 hours.

---

Absorption of glyphosate in the mammalian gastrointestinal tract is low, ranging from 20 to 40%. [1]
Metabolism is very limited. Only a small amount of a single metabolite, aminomethylphosphonic acid (AMPA), is produced, which is likely produced by the gut microbiota rather than by the mammalian itself. [1] Systemic elimination is biphasic, with an α-phase half-life of 6–14 hours. Glyphosate is rapidly excreted unchanged in the urine. [1]

Glyphosate has low acute toxicity. The oral LD50 in rats is >2000 mg/kg body weight. The dermal LD50 in rats is >2000 mg/kg body weight. The inhalation LC50 in rats is >5 mg/L. [1] It does not irritate the skin, but may be mild or non-irritating to the eyes depending on the salt form (moderate to severe irritation in the acid form). It is not sensitizing. [1] Subchronic and chronic toxicity studies in dogs and rats have found that glyphosate can cause reduced weight gain, increased liver weight, changes in salivary glands (considered an adaptive response to oral irritation caused by organic acids), and occasional effects on clinical chemistry indicators. In a two-year chronic toxicity study in rats, the no adverse effect dose (NOAEL) was 100 mg/kg body weight/day (this study is not detailed in this review). The acceptable daily intake (ADI) was 0.5 mg/kg body weight/day, and the acceptable operator exposure dose (AOEL) was 0.1 mg/kg body weight/day, both with a safety margin of 100. [1] In the 14 rodent carcinogenicity studies reviewed, no treatment-related neoplasms (i.e., cancers) associated with glyphosate administration were found at doses up to and exceeding 1000 mg/kg body weight/day. The observed tumors were sporadic, lacked dose-response relationships, and were within the historical control incidence range for the corresponding strains. [1]
Glyphosate is not genotoxic based on a weighted assessment of evidence from a large number of in vitro and in vivo studies. It is not neurotoxic and has no effect on prenatal development and fertility at doses not exceeding the maximum tolerated dose. [1]

[1]. Evaluation of carcinogenic potential of the herbicide glyphosate, drawing on tumor incidence data from fourteen chronic/carcinogenicity rodent studies. Crit Rev Toxicol. 2015;45(3):185-208.

[2]. Zhang JW, et al The toxic effects and possible mechanisms of glyphosate on mouse oocytes. Chemosphere. 2019 Dec;237:124435.

[3]. Toxic Effects of Glyphosate on the Nervous System: A Systematic Review. Int J Mol Sci. 2022 Apr 21;23(9):4605.

Glyphosate is the active ingredient in herbicide products such as RoundUp™. Glyphosate products are among the most widely used herbicides on farms, home gardens, and lawns worldwide. These products typically contain glyphosate and are used in combination with other ingredients to enhance plant uptake of glyphosate. Glyphosate formulations (GBF) are readily available in most stores. These products may contain different combinations of other ingredients or different concentrations of glyphosate. According to California labor laws and the International Agency for Research on Cancer (IARC) of the World Health Organization, glyphosate may be carcinogenic. Glyphosate is an odorless white powder. Its decomposition temperature is approximately 419°F (darkening of color). The pH value (1% aqueous solution) is 2.5. (NTP, 1992) Glyphosate is a phosphonic acid, formed by the oxidative coupling of the methyl group of methylphosphonic acid with the amino group of glycine. It is one of the most commonly used herbicides globally and the only one that targets 5-enolpyruvate-3-shikimate phosphate synthase (EPSPS). It is both an agrochemical and an EC 2.5.1.19 (3-phosphoshikimate-1-carboxyvinyltransferase) inhibitor and herbicide. It is a phosphonic acid and glycine derivative, the conjugate acid of glyphosate (2-) and glyphosate (1-). Glyphosate has been reported and data are available for detection in soybean (Glycine max) and common bean (Phaseolus vulgaris). Glyphosate is a synthetic organophosphorus compound that blocks the activity of enolpyruvate-3-phosphate (EPSP) synthase and is used as a broad-spectrum insecticide. It is a volatile, moderately toxic, colorless, odorless crystalline solid or powder, exposed via inhalation, ingestion, or contact. It is the active ingredient in herbicide formulations that inhibits 3-phosphoshikimate-1-carboxyvinyltransferase.
See also: ...View more...

---

Mechanism of Action
Previous studies have shown that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, it is necessary to determine the mechanism by which glyphosate induces neurotoxicity. This study aimed to investigate whether acute (30 minutes) and chronic (pregnancy and lactation) exposure to the glyphosate herbicide Roundup leads to hippocampal neurotoxicity in young mice. This study simulated maternal exposure to the pesticide by administering 1% Roundup (0.38% glyphosate) orally to mother mice during pregnancy and lactation (until 15 days after birth). Hippocampal sections from 15-day-old pups were acutely exposed to Roundup solutions at concentrations ranging from 0.00005% to 0.1% for 30 minutes, and experiments were conducted to determine whether glyphosate affects Ca2+ influx and cell viability. Furthermore, this study investigated the effects of pesticides on oxidative stress parameters, 14C-α-methylaminoisobutyric acid (14C-MeAIB) accumulation, and glutamate uptake, release, and metabolism. The results showed that acute exposure to Roundup (30 min) increased 45% Ca2+ influx by activating NMDA receptors and voltage-dependent Ca2+ channels, leading to oxidative stress and neuronal death. The mechanism of Roundup-induced neurotoxicity also involved the activation of CaMKII and ERK. In addition, acute exposure to Roundup increased the release of (3)H-glutamate in the synaptic cleft, decreased GSH levels, and increased lipid peroxidation, all characteristic of excitotoxicity and oxidative damage. This study also observed that both acute and chronic exposure to Roundup reduced the uptake and metabolism of (3)H-glutamate in the hippocampus of young rats, while inducing (45)Ca(2+) uptake and (14)C-MeAIB accumulation. In summary, these results suggest that Roundup may lead to excessive extracellular glutamate levels, thereby causing glutamate excitotoxicity and oxidative stress in the rat hippocampus. Glyphosate is the main active ingredient in the commercial herbicide Roundup. The results of this study indicate that acute exposure to low doses (36 ppm, 0.036 g/L) of glyphosate for 30 minutes can induce oxidative stress in the testes of pre-pubertal rats and activate multiple stress response pathways, ultimately leading to Sertoli cell death. This pesticide increases intracellular Ca²⁺ concentration by opening L-type voltage-dependent Ca²⁺ channels and endoplasmic reticulum IP₃ and rymnesine receptors, leading to intracellular Ca²⁺ overload, which in turn triggers oxidative stress and necrotic cell death. Similarly, incubation of testes with glyphosate alone (36 ppm) for 30 minutes also increases ⁴⁵Ca²⁺ uptake. The antioxidants Trolox and ascorbic acid inhibit these responses. Activated protein kinase C, phosphatidylinositol 3-kinase, and mitogen-activated protein kinases (such as ERK1/2 and p38MAPK) play roles in inducing Ca²⁺ influx and cell death. Roundup reduces levels of reduced glutathione (GSH) and increases the content of thiobarbituric acid reactants (TBARS) and protein carbonyl groups. Furthermore, exposure to glyphosate-Roundup stimulates the activity of glutathione peroxidase, glutathione reductase, glutathione S-transferase, gamma-glutamyl transferase, catalase, superoxide dismutase, and glucose-6-phosphate dehydrogenase, thereby supporting the downregulation of GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular mechanisms of its toxicity remain to be elucidated. We propose that glyphosate toxicity, associated with calcium overload, dysregulation of cell signaling, endoplasmic reticulum stress response, and/or decreased antioxidant defense capacity, may lead to the destruction of supporting cells during spermatogenesis, thereby affecting male fertility. Dysregulation of programmed cell death mechanisms in human epidermis leads to skin lesions. We have previously demonstrated that the widely used herbicide glyphosate has cytotoxic effects on cultured human keratinocytes, affecting their antioxidant capacity and impairing cell morphology and functional characteristics. This study, using the human epidermal cell line HaCaT, aimed to investigate the role of apoptosis in the cytotoxic effects of glyphosate and the intracellular mechanisms involved in apoptosis. This study revealed the specific process of glyphosate-induced cell death through different incubation times. The study observed an increase in the number of early apoptotic cells at low cytotoxicity levels (15%), while under more severe cytotoxic conditions, the number of early apoptotic cells decreased, and the number of late apoptotic and necrotic cells increased. This study also suggests that glyphosate-induced disruption of mitochondrial membrane potential may be one of the causes of apoptosis in keratinocyte cultures. Herbicides have been identified as a major environmental factor associated with human neurodegenerative diseases such as Parkinson's disease (PD). Previous studies have indicated that exposure to the widely used herbicide glyphosate may be associated with Parkinson's disease, but the underlying mechanisms remain unclear. We investigated the neurotoxic effects of glyphosate on differentiated PC12 rat cells and found that it inhibited the viability of differentiated PC12 cells in a dose- and time-dependent manner. Furthermore, the results showed that glyphosate, in addition to activating the apoptotic pathway, can also induce cell death through the autophagy pathway. Interestingly, in glyphosate-treated differentiated PC12 cells, inactivation of the Beclin-1 gene attenuated both apoptosis and autophagy, indicating that the Beclin-1 gene is involved in the interaction between these two mechanisms. For more complete data on the mechanisms of action of glyphosate (7 herbicides), please visit the HSDB record page. Glyphosate is a broad-spectrum, non-selective systemic herbicide introduced in the 1970s. It is an aminophosphonic acid analog of the amino acid glycine. [1] It inhibits the shikimic acid pathway enzyme EPSPS, which is essential for the synthesis of aromatic amino acids in plants, bacteria, and fungi but is absent in animals, providing a basis for its selective toxicity. [1] Existing epidemiological studies reviewed and cited herein by Mink et al. (2012) found no consistent positive correlation between exposure to glyphosate and cancer in humans as a whole or in any particular site. [1] Multiple regulatory agencies worldwide (the U.S. Environmental Protection Agency, the European Union, and the WHO/FAO) have agreed, based on substantial evidence from animal studies, genotoxicity data, and epidemiological surveys, that glyphosate does not pose a carcinogenic risk to humans. [1] This paper discusses and refutes the claims about the carcinogenic effects of glyphosate in a paper published by Séralini et al. (2012, later retracted and republished), highlighting its methodological flaws and lack of conclusive data. [1]

C3H8NO5P

169.07

169.014

1071-83-6

Glyphosate-d2;2733532-11-9;Glyphosate-13C2,15N;1185107-63-4;Glyphosate-d2-1

3496

White to off-white solid powder

1.7±0.1 g/cm3

465.8±55.0 °C at 760 mmHg

230 °C (dec.)(lit.)

235.5±31.5 °C

0.0±2.5 mmHg at 25°C

1.529

-2.36

4

6

4

10

162

0

XDDAORKBJWWYJS-UHFFFAOYSA-N

InChI=1S/C3H8NO5P/c5-3(6)1-4-2-10(7,8)9/h4H,1-2H2,(H,5,6)(H2,7,8,9)

2-(phosphonomethylamino)acetic acid

Glyphosate Folusen Atila Lancer

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~13.89 mg/mL (~82.16 mM)

Solubility in Formulation 1: 6.67 mg/mL (39.45 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

---

 (Please use freshly prepared in vivo formulations for optimal results.)