Glyphosate isopropylammonium exposure can interfere with mouse oocyte maturation by producing oxidative stress and early apoptosis. Glyphosate isopropylammonium induces early apoptosis and autophagy in mouse oocytes[2].

Absorption, Distribution and Excretion
Glyphosate and its isopropylamine salts have extremely low oral toxicity. Glyphosate is incompletely absorbed from the gastrointestinal tract in rats (especially male rats) after oral administration. Glyphosate is primarily excreted unchanged in the urine, but there is also evidence that it can be excreted via bile and enterohepatic circulation. The transdermal absorption of 14C-labeled glyphosate from three glyphosate formulations was determined using in vitro techniques on isolated human abdominal skin. Results showed that glyphosate absorption was extremely low under these conditions, with the epidermis being the primary absorption barrier. This study also investigated the transdermal absorption of glyphosate in vivo and in vitro. The ability of the commercial glyphosate formulation Roundup (undiluted and diluted 1:20 to 1:32) to penetrate human thigh skin samples obtained from autopsies was evaluated using a flow cell with human plasma as the receiving fluid. Simultaneously, the binding ability of 14C-labeled Roundup and its 1:20 and 1:32 dilutions to human keratinocyte powder was investigated. Adult female rhesus monkeys received topical application of 500 or 5400 μg/200 cm² labeled glyphosate, or intravenous injection of 9 or 93 μg glyphosate. Blood and urine samples were collected from 24 hours before administration to 8 days after administration, and 14C activity was measured. Some monkeys were sacrificed 7 days after topical exposure to determine the distribution of glyphosate-derived 14C activity in tissues. Other monkeys were topically treated with a 1:20 dilution of 14C-labeled glyphosate solution. The application sites were washed with soap and water or clean water 0 to 24 hours later to evaluate the glyphosate removal capabilities of these treatments. In vitro studies showed that less than 2% of topical glyphosate penetrated human skin. Glyphosate (in Roundup herbicide form or diluted form) does not bind to stratum corneum powder. Approximately 95% to 99% of intravenously injected glyphosate is excreted in urine, mostly within the first 24 hours. Following topical application, only 2.2% of the 5400 μg/200 cm² dose and 0.8% of the 500 μg/200 cm² dose were excreted in urine within 8 days. Based on intravenous injection data, an estimated 0.8% to 2.2% of the topical dose was absorbed. Glyphosate was detected in blood after intravenous injection but not after topical application. No glyphosate-derived radioactive material was detected in any internal organs after topical application. 89.6% and 83.6% of the administered dose were removed 12 hours after administration with soap and water or plain water, respectively. Both methods removed approximately 50% of the administered dose within 24 hours of exposure. The conclusion is that the amount of glyphosate absorbed through the skin of rhesus monkeys is very low, approximately 0.8% to 2.2%. Since rhesus monkeys are a good model for studying transdermal absorption in humans, the skin toxicity of glyphosate in humans should be minimal. /Roundup/
The interaction of glyphosate with the skin and its potential systemic bioavailability via transdermal absorption were investigated through skin binding, skin absorption, residual tissue distribution, and skin decontamination. Glyphosate in the final formulation (Roundup), whether undiluted or diluted with water at 1:20 and 1:32, did not partition into human keratinocyte powder (<1%). In vitro transdermal absorption studies showed that, within a concentration range of 0.5–154 μg/cm² and a topical application volume range of 0.014–0.14 mL/cm², the proportion of glyphosate absorbed through the skin into human plasma (receptor fluid) did not exceed 2%. Following intravenous injection of 93 μg and 9 μg doses of glyphosate into rhesus monkeys, it was primarily excreted via urine, with excretion rates of 95 ± 8% and 99 ± 4% within 7 days, respectively. In rhesus monkeys, the percutaneous absorption rate was 0.8 ± 0.6% in the low-dose group (25 μg/cm²) and 2.2 ± 0.8% in the high-dose group (270 μg/cm²). Monkeys were euthanized 7 days after topical application, and no residual 14C was detected in their organs. Washing the skin application site with soap and water removed 90 ± 4% of the applied dose, while washing with water alone removed 84 ± 3%. During the 24-hour skin application period, soap and water were comparable to water alone in removing glyphosate from the skin. Approximately 50% of the initial applied dose could be recovered after 24 hours. Glyphosate is highly soluble in water but insoluble in most organic solvents (octanol/water log P = -1.70), thus it is incompatible with the lipid-rich stratum corneum. This is consistent with its low skin binding and absorption rates, and with the fact that it can be effectively removed from the skin by washing with soap and water or water alone. /Roundup/
In lactating goats, capsules containing a 9:1 mixture (14C-glyphosate and 14C-aminomethylphosphonic acid (AMPA)) were administered for 5 consecutive days at a dose equivalent to 120 mg/kg of diet (based on free acid), after which the concentration of the carbon-14 label in milk was measured. During the trial, the concentration in milk (in milligrams of glyphosate equivalent per kilogram of whole milk) ranged from 0.019 to 0.086 mg/kg; on day 5 after the last administration, the plasma concentration was 0.006 mg/kg.

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Biological Half-Life
The elimination kinetics of glyphosate in Sprague Dawley rats were estimated by measuring radioactivity (carbon-14) in urine and feces following a single oral dose of (14)C-glyphosate (10 or 1000 mg/kg body weight). Since glyphosate does not undergo biotransformation, its kinetics can be determined 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). The half-life of the β-phase was 79 hours (male) or 106 hours (female) at 10 mg/kg body weight; at 1000 mg/kg body weight, the half-life of the β-phase was 181 hours (male) or 337 hours (female).

Toxicity Summary
Identification and Uses: Glyphosate isopropylamine salt is a white, odorless powder commonly used as a herbicide to control broadleaf and grass weeds in a variety of food and non-food crops. It is the active ingredient in the herbicide Roundup. Human Exposure and Toxicity: Researchers have reported clinical experiences of patients accidentally or intentionally ingesting Roundup. Symptoms of accidental skin contact with the product include periorbital and conjunctival edema, cardiovascular effects (tachycardia and elevated blood pressure), swelling and paresthesia at the site of skin contact, and prolonged duration of skin irritation. Intentional ingestion can lead to more serious consequences, including death from respiratory and cardiac arrest. For glyphosate-containing herbicides, abdominal pain with nausea, vomiting, and/or diarrhea are the most common manifestations of acute poisoning. These symptoms may be mild and resolve spontaneously, but in severe cases, inflammation, ulceration, or infarction may occur. Severe diarrhea and repeated vomiting can lead to dehydration. High doses of concentrated formulations can cause gastrointestinal burns and necrosis, possibly accompanied by bleeding. Extensive erosion of the upper gastrointestinal tract is associated with more severe systemic poisoning and longer hospital stays. Severe poisoning from glyphosate herbicides manifests as hypotension, arrhythmias, renal and hepatic dysfunction, hyperkalemia, pancreatitis, pulmonary edema or pneumonia, altered mental status, and metabolic acidosis. These effects can be transient or severe, progressing to shock and death within 12 to 72 hours. The mechanism of hypotension may be related to hypovolemia (increased fluid shift and loss) and direct cardiotoxicity. Death following Roundup ingestion alone is caused by hypotensive syndrome, which is unresponsive to intravenous fluids or vasopressors and sometimes presents with pulmonary edema but normal central venous pressure. Animal experiments: Six groups of male rabbits, 10 per group, were treated with undiluted glyphosate isopropylamine salt at doses of 76 or 114 mg/kg body weight, 5 days a week for 21 days. Toxicity manifested only as skin changes, more pronounced at sites of skin abrasion, but all cases healed by the end of the 28-day recovery period. In glyphosate isopropylamine formulations containing surfactants, acute toxicity was caused by the surfactants. In an acute study in female dogs, the combined effect of glyphosate and surfactants in Roundup formulations led to cardiac depression, primarily due to the surfactants, as glyphosate itself enhances myocardial contractility. A 4-week inhalation study was conducted in rats using a 1:3 dilution of Roundup formulation. Diluted formulations at test concentrations of 50, 160, and 360 mg/m³ were administered via aerosol spray for 6 hours daily, 5 days a week. Increased incidence of nasal turbinate (subacute inflammation), tracheal (monocyte infiltration), and lung (perivascular lymphocyte infiltration/aggregation) irritation was observed only in female rats in the high-dose group. No signs of systemic toxicity were observed (assessment measures: survival, growth, limited hematologic and blood biochemical parameters, organ weight, limited histopathological examination). The genotoxicity of the herbicide Roundup and glyphosate isopropylamine salt was investigated using three different experimental methods. In the mouse bone marrow micronucleus assay, neither formulation showed chromosome breakage. Only Roundup was tested in the Salmonella assay. Weak mutagenic effects were observed at a concentration of 360 μg/plate in TA98 medium (without metabolic activation) and at a concentration of 720 μg/plate in TA100 medium (with metabolic activation). Late-terminal Allium studies showed no effect from glyphosate isopropylamine salt, but Roundup treatment at concentrations of 1.44 and 2.88 mg/L (based on glyphosate isopropylamine) significantly increased chromosomal aberrations. The most common aberrations observed were attributable to spindle dysfunction. Ecotoxicity studies: One year after Roundup treatment in forests, there were no significant adverse effects on the reproduction, growth, or survival of deer mice. Although the response was short-lived, the population density of Townsend's chipmunks (Eutamias townsendii) in the treated area initially appeared to decrease. Adult rainbow trout showed no change in fertility or gonadal index at concentrations up to 2.0 mg/L of glyphosate isopropylamine. In avoidance experiments, rainbow trout did not exhibit avoidance behavior at concentrations up to 10.0 mg/L of isopropylamine. The egg stage is the least sensitive period in the early life stages of rainbow trout and channel catfish. Overall, the Roundup formulation is 3 to 42 times more toxic than the technical grade formulation.

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Toxicity Data
LC50 (Rat)> 0.0013 mg/m3/4h

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Non-human Toxicity Values
LD50 Rat Oral > 5000 mg/kg
LD50 Goat Oral > 5700 mg/kg
LD50 Rabbit Dermal Contact > 5000 mg/kg
LC50 Rat Inhalation > 1.3 mg/L Air/4 hr
For more complete non-human toxicity data on glyphosate isopropylamine salts (6 in total), please visit the HSDB record page.

[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]. 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 isopropylamine is an organic molecular entity. It is the active ingredient in herbicide formulations, inhibiting shikimate-1-carboxyvinyltransferase (3-phosphate). Its mechanism of action includes cell membrane disruption and uncoupling of oxidative phosphorylation, although these mechanisms may be interconnected. In fact, the toxicity mechanisms of different glyphosate formulations can vary. In two cases of glyphosate trimethylammonium poisoning, patients experienced cardiopulmonary arrest within minutes of ingestion. Since no such reports have been found for glyphosate isopropylamine, the toxicity mechanisms of these products may differ. Experiments have shown that glyphosate itself has extremely low toxicity to mammals (if any)...LD50 greater than 4000 mg/kg. Surfactant adjuvants are considered to be more toxic components in glyphosate-containing herbicides. Polyoxyethylene amine (POEA; tallow amine; LD50 1200 mg/kg) is the most commonly used surfactant in these products, but other surfactants are also used. ...Combinations of potassium and isopropylamine may also lead to toxicity. The rat LD50 of isopropylamine ranges from 111 to 820 mg/kg. It can reduce vascular resistance and may increase or decrease myocardial contractility and heart rate. ... Disorders of oxidative phosphorylation can impair normal cellular function due to insufficient energy supply... Similarly, direct toxicity to cell membranes (including mitochondrial membranes) can interfere with normal cellular processes, such as ion channels. Both of these disorders can lead to multi-organ toxicity. Hypotension and arrhythmias can impair tissue perfusion, while hepatotoxicity and nephrotoxicity can lead to metabolic imbalances and acidosis, thereby impairing normal physiological processes. Pulmonary toxicity can lead to hypoxia, which in turn impairs normal cellular function. If these abnormalities are not corrected, irreversible cytotoxicity and death may result. /Glyphosate-containing herbicides/
/This study/tested the effects of low concentrations (non-toxic concentrations) of glyphosate and Roundup on aromatase (an enzyme responsible for estrogen synthesis). Glyphosate herbicides disrupt the activity and mRNA levels of aromatases and interact with the active sites of purified enzymes, but Roundup formulations enhance the effects of glyphosate in microsomes or cell cultures. The authors conclude that endocrine and toxic effects of the herbicide Roundup (not just glyphosate) can be observed in mammals, and that the presence of Roundup adjuvants may enhance the bioavailability and/or bioaccumulation of glyphosate. For more complete data on the mechanisms of action of glyphosate isopropylamine salts (6 in total), please visit the HSDB record page.

C6H17N2O5P

228.18

346.235

38641-94-0

38078

White powder

1.218 g/mL at 25ºC

465.8ºC at 760 mmHg

200ºC

235.5ºC

n20/D 1.435

5

7

4

14

173

0

ZEKANFGSDXODPD-UHFFFAOYSA-N

InChI=1S/C3H8NO5P.C3H9N/c5-3(6)1-4-2-10(7,8)9;1-3(2)4/h4H,1-2H2,(H,5,6)(H2,7,8,9);3H,4H2,1-2H3

2-(phosphonomethylamino)acetic acid;propan-2-amine

Glyphosate Isopropylamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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