IDENTIFICATION AND USE: Glyphosate isopropylamine salt is a white odorless powder that is commonly used as a herbicide to control broadleaf weeds and grasses, in many food and non-food crops. It is an active ingredient in the herbicide Roundup. HUMAN EXPOSURE AND TOXICITY: Clinical experiences with patients exposed to Roundup either accidentally or through deliberate ingestion have been reported by investigators. Symptoms resulting from dermal exposure incidental to the use of the product included periorbital edema and chemosis of the eye, cardiovascular effects (tachycardia and elevated blood pressure), swelling and paraesthesia at the site of dermal contact and prolonged skin irritation. Deliberate ingestion resulted in more severe effects, including lethality from apparent respiratory and cardiac arrest. In glyphosate-containing herbicides abdominal pain with nausea, vomiting, and/or diarrhea are the most common manifestations of acute poisoning. These may be mild self-resolving, but in severe poisoning there may be inflammation, ulceration, or infarction. Severe diarrhea and recurrent vomiting may induce dehydration. Gastrointestinal burns and necrosis occurs with high doses of concentrated formulations and may be associated with hemorrhage. Extensive erosions of the upper gastrointestinal tract are associated with more severe systemic poisoning and a prolonged hospitalization. Severe poisonings by glyphosate-containing herbicides manifests as hypotension, cardiac dysrhythmias, renal and hepatic dysfunction, hyperkalemia, pancreatitis, pulmonary edema or pneumonitis, altered level of consciousness, and metabolic acidosis. These effects may be transient or severe, progressing over 12 to 72 hours to shock and death. The mechanism of hypotension may relate to both hypovolemia (fluids shifts and increased losses) and direct cardiotoxicity. Deaths following ingestion of Roundup alone were due to a syndrome that involved hypotension, unresponsive to iv fluids or vasopressor drugs, and sometimes pulmonary edema, in the presence of normal central venous pressure. ANIMAL STUDIES: Six groups of 10 male rabbits were treated with 76 or 114 mg/kg b.w. undiluted glyphosate isopropylamine salt for 5 days/week for 21 days. Toxicity was apparent only as dermal changes, which were more pronounced on abraded skin, but which in all cases had healed by the end of a 28-day recovery period. In glyphosate isopropylamine formulations containing surfactants, acute toxicity was due to the surfactant. In acute female dog study the joint effect of both glyphosate and the surfactant in Roundup formulation resulted in cardiac depression, which was mostly due to the surfactant since glyphosate itself increased myocardial contractility. A 4-week inhalation study was carried out on rats with a 1:3 dilution of Roundup formulation. Test concentrations of 50, 160 and 360 mg/cu m of the diluted formulation were administered as an aerosol spray for 6 hr/day, 5 days/week. An increased incidence of irritation of the nasal turbinates (subacute inflammation), trachea (mononuclear cell infiltration) and lungs (perivascular lymphoid infiltrates/aggregates) was observed among the high-dose females only. No signs of systemic toxicity were found (parameters: survival, growth, limited hematology and blood biochemistry, organ weights, limited histopathology). The genotoxic potential of the herbicide Roundup and glyphosate isopropylamine salt was studied in three different assays. No clastogenic effects were found in the mouse bone marrow micronucleus test for either of the two agents. In the Salmonella assay only Roundup was tested. It showed a weak mutagenic effect for the concn 360 ug/plate in TA98 (without metabolic activation) and 720 ug/plate in TA100 (with metabolic activation). The anaphase-telophase Allium test showed no effect for the glyphosate isopropylamine salt, but a significant increase in chromosome aberrations appeared after treatment with Roundup at concn of 1.44 and 2.88 mg/L when calculated as glyphosate isopropylamine. The most frequent aberrations observed could be characterized as disturbances of the spindle. ECOTOXICITY STUDIES: Roundup had no apparent adverse effects on reproduction, growth, or survival of deer mice 1 year after treatment of forest. The population density of Townsend chipmunks (Eutamias townsendii) appeared to initially decline in the treated area, although this response was short lived. No changes in fecundity or gonadosomatic index were observed in adult rainbow trout treated with up to 2.0 mg/L of glyphosate isopropylamine salt. In avoidance studies, rainbow trout did not avoid concentrations of the isopropylamine salt up to 10.0 mg/L. The egg stage was the least sensitive early life stage for both rainbow trout and channel catfish. Overall, the Roundup formulation was 3 to 42 times more toxic than the technical grade material.
Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Glyphosate (Roundup) and Related Compounds/
Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Monitor body temperature and treat if necessary. Cover skin burns with dry sterile dressings after decontamination ... . /Glyphosate (Roundup) and Related Compounds/
Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Monitor and treat cardiac arrhythmias if necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Glyphosate (Roundup) and Related Compounds/
Glyphosate and its isopropylamine salt have extremely low oral toxicity. Orally administered glyphosate is incompletely absorbed from the gastrointestinal tract of rats, especially in males. It is excreted unchanged in the urine, although there is evidence of biliary excretion and enterohepatic circulation.
The percutaneous absorption of (14)C-labelled glyphosate from 3 formulations of glyphosate was measured in excised human abdominal skin using an in vitro technique. Glyphosate was found to be very poorly absorbed under these conditions, with the epidermis acting as the primary barrier /Glyphosate formulations/.
The percutaneous absorption of glyphosate was studied in vivo and in vitro. The ability of Roundup, a commercial glyphosate formulation, applied neat and in 1:20 to 1:32 dilutions to penetrate human thigh skin samples obtained at autopsy was evaluated using flow through cells containing human plasma as the receptor fluid. The ability of 14C-labeled Roundup and the 1:20 and 1:32 dilutions to bind to powdered human stratum corneum was investigated. Adult female rhesus monkeys were administered 500 or 5400 ug per 200 sq cm labeled glyphosate topically or 9 or 93 ug glyphosate iv. Blood and urine samples were collected starting 24 hr before dosing and up to 8 days post dosing and assayed for carbon-14 activity. Selected monkeys were killed 7 days after topical exposure to determine the tissue distribution of glyphosate derived carbon-14 activity. Other monkeys were topically administered a 1:20 dilution of 14C-labeled glyphosate.The application sites were washed with soap and water or water 0 to 24 hr later to assess the ability of these treatments to remove glyphosate. In vitro, less than 2% of the applied glyphosate penetrated human skin. Glyphosate as Roundup or in diluted form did not bind to powdered stratum corneum. Around 95 to 99% of iv administered glyphosate was excreted in the urine, mostly within the first 24 hr. Following topical application only 2.2% of the 5400 ug/200 sq cm dose and 0.8% of the 500 ug/200 sq cm dose were excreted in the urine over 8 days. Based on the iv data, 0.8 to 2.2% of the applied doses was estimated to have been absorbed. Glyphosate was detected in the blood after iv administration, but not topical application. No glyphosate derived radioactivity was detected in any internal organs after topical application. Soap and water, or water removed 89.6 and 83.6% of the applied dose, respectively, 12 hr after treatment. Both treatments removed about 50% of the applied dose 24 hr after exposure. It was concluded that the amounts of glyphosate absorbed through the skin of rhesus monkeys is low, on the order of 0.8 to 2.2%. Since the rhesus monkey is a good model for percutaneous absorption relevant to humans, glyphosate should have little dermal toxicity for humans. /Roundup/
Interactions /of glyphosate/ with skin and potential systemic availability through percutaneous absorption was studied by skin binding, skin absorption, residual tissue distribution, and skin decontamination. Glyphosate in a final formulation (Roundup) undiluted and diluted with water 1:20 and 1:32, would not partition into powdered human stratum corneum (<1%). In vitro percutaneous absorption through human skin into human plasma as receptor fluid was no more than 2% over a concentration range of 0.5-154 ug/sq cm and a topical volume range of 0.014-0.14 mL/sq cm. Disposition of glyphosate following iv administration of 93 and 9 ug doses to rhesus monkeys was mainly through urine excretion, 95 + or - 8 and 99 + or - 4% in 7 days, respectively. Percutaneous absorption in vivo in rhesus monkey was 0.8 + or - 0.6% for the low dose (25 ug/sq cm) and 2.2 + or - 0.8% for the high dose (270 ug/sq cm). No residual (14)C was found in organs of the monkeys euthanized 7 days after the topical application. Washing the skin application site with soap and water removed 90 + or - 4% of applied dose, and washing with water only removed 84 + or - 3% of applied dose. Both soap and water and water only were equal in ability to remove glyphosate from skin over a 24 hr skin application period. About 50% of the initially applied dose could be recovered after 24 hr. Glyphosate is very soluble in water and insoluble in most organics (octanol/water log P = -1.70) and therefore not compatible with the lipid-laden stratum corneum. This is consistent with the low skin binding and skin absorption and also consistent with the efficient removal from skin with soap and water or water-only wash. /Roundup/
In lactating goats concentrations of carbon-14 label in milk were measured after giving capsules containing a 9:1 mixture of (14)C-glyphosate and (14)C-aminomethylphosphonic acid (AMPA) to a dose level equivalent to 120 mg/kg diet (expressed as free acid) for 5 days. Concentrations in milk (as mg equivalents glyphosate/kg whole milk) ranged from 0.019 to 0.086 mg/kg during the test period; at day 5 after the last dose the concentration was 0.006 mg/kg.
