CHLOROPHENOXY COMPOUNDS

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Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2,4-Dichlorophenoxyacetic acid
2) Dichlorophenoxyacetic acid

1) 2,4,5-Trichlorophenoxyacetic acid
2) Trichlorophenoxyacetic acid

1) Methylchlorophenoxy acetic acid

1) 4-Chloro-2-methyl phenoxypropionic acid
2) Mecoprop

Available Forms Sources

1) 2,4,5-T - Most commercial products no longer contain 2,4,5-T. Propionic and butyric acid homologues of 2,4-D have similar chemical and presumably toxicologic properties.

1) The free acids, esters, and salts are formulated in water suspensions or solutions or in various organic solvents for application as systemic herbicides. Some esters are fairly volatile; salts are not.
2) There are many commercial formulations available for weed and brush control along rights-of-way, for certain agricultural uses, and for lawn and garden weed control.

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Chlorophenoxy compounds are mixed into commercial fertilizers to restrict the growth of broadleaf weeds. Several hundred commercial products contain chlorophenoxy compounds in various forms, concentrations, and combinations. Agent Orange was a mixture of chlorophenoxy compounds. Other chlorophenoxy compounds include MCPA (methylchlorophenoxy acetic acid) and MCPP (Mecoprop, 4-Chloro-2-methylphenoxypropionic acid).
B) TOXICOLOGY: In animals, chlorophenoxy compounds have been shown to demyelinate peripheral nerves, depress ribonuclease synthesis, uncouple oxidative phosphorylation, and increase hepatic peroxisomes. They are also moderately irritating to skin and mucous membranes.
C) EPIDEMIOLOGY: Thousands of exposures to chlorophenoxy compounds are reported to poison centers every year. The majority of cases have no or only minor effects, but major effects and even death does occur after exposures, usually with deliberate, large ingestions.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Inadvertent/exploratory ingestions by children generally only cause mild irritation of the exposed tissue (eg, gastrointestinal mucosa, skin, eyes, respiratory tract).
2) SEVERE TOXICITY: Large, deliberate ingestions can cause mucosal ulceration, miosis, coma, fever, hypotension, emesis, tachycardia, bradycardia, ECG abnormalities, muscle rigidity, rhabdomyolysis, renal failure, acute lung injury, and respiratory failure. Deaths have occurred secondary to cardiopulmonary arrest, but are rare. After ingestion, fever of sudden but delayed onset may occur. Electrolyte abnormalities, such as hypocalcemia, hyperkalemia, and hypophosphatemia, can develop. Thrombocytopenia and leukopenia have been reported. Hyperglycemia has also been reported in cases of acute 2,4-D poisoning. Direct dermal contact may cause skin irritation. Some chlorophenoxy compounds are also moderately irritating to eyes and respiratory and gastrointestinal linings.
3) CHRONIC EXPOSURE: Local depigmentation has resulted from protracted dermal contact. Albuminuria and porphyria may occur. Chlordioxin may produce chloracne with heavy exposures.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Fever of sudden but delayed onset may occur following ingestion.

0.2.20)

A) 2,4-D and 2,4,5-T have caused adverse reproductive effects in experimental animals. Allegations of human birth defects due to these compounds have not been confirmed.

0.2.21)

A) Human studies show conflicting results. Some studies have suggested a relationship between chlorophenoxy herbicides and both soft tissue sarcoma and non-Hodgkin's lymphoma, while others have not. There is limited evidence of an association with prostate carcinoma.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The mainstay of managing mild to moderate toxicity is removal/decontamination and supportive care.

B) MANAGEMENT OF SEVERE TOXICITY

1) For severe toxicity, treatment should be targeted towards symptoms. Hypotensive patients should be given boluses of isotonic fluids and pressors as necessary. Correct electrolyte abnormalities. Treat cardiac dysrhythmias with standard antidysrhythmics including lidocaine and amiodarone. Patients with severe respiratory symptoms may require intubation.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal may be considered if the patient is awake, alert, and cooperative. Remove contaminated clothing and wash exposed skin. Irrigate exposed eyes.
2) HOSPITAL: Activated charcoal may be beneficial, if the patient presents early and is alert. Airway protection should be considered prior to giving activated charcoal in large ingestions because of the risk for CNS depression and seizures. Remove contaminated clothing and wash exposed skin. Irrigate exposed eyes.

D) AIRWAY MANAGEMENT

1) Early intubation may be indicated in patients who develop respiratory issues or severe CNS depression.

E) ANTIDOTE

1) None

F) ENHANCED ELIMINATION

1) Alkaline diuresis can increase elimination of chlorophenoxy compounds, but has not been shown to affect outcome. It may be useful if performed early in the course of treatment. Administer 1 to 2 milliequivalent/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5% in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration, additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 mL/kg/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5. Administer potassium as necessary. Monitor urine pH hourly.
2) Hemodialysis is likely not useful because of the high degree of protein binding. For 2,4-D, hemoperfusion may be useful as volume of distribution is small, but human studies are not available to evaluate efficacy.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with unintentional exposures with minimal to no symptoms may be managed at home.
2) OBSERVATION CRITERIA: Patients should be sent to a healthcare facility if their exposure to chlorophenoxy compounds was in a self-harm attempt or if they are symptomatic. They should be observed for 6 to 12 hours (potential for delayed symptoms) and be clearly improving or asymptomatic prior to discharge.
3) ADMISSION CRITERIA: Patients with severe symptoms or getting worse after an observation period of 6 to 12 hours should be admitted to the hospital. Depending on the severity of their symptoms, ICU admission may be warranted (eg, intubated patients). Patients should not be discharged until they are clearly improving or asymptomatic.
4) CONSULT CRITERIA: Physicians who practice occupational medicine may be useful for patients with workplace exposures to chlorophenoxy herbicides.

H) PITFALLS

1) Concentrated formulations of 2,4-D-esters may contain petroleum (hydrocarbon) solvents that can contribute to the overall toxicity.

I) PHARMACOKINETICS

1) Well absorbed orally, dermal absorption 5% to 10% over 24 to 144 hours. Highly protein bound, volume of distribution of 2,4-D is small (0.1 L/kg). Metabolized by acid hydrolysis to phenoxy acids which are eliminated in urine. These compounds are strongly acidic (pKa 2.6) and show dose-dependent elimination (plasma half-lives 10 to 20 hours, rising to 80 to 120 hours in larger doses). Half-life is decreased by urine alkalinization. the half-life of 2,4-D is about 18 hours after oral ingestion, 13 hours after IV administration, 39.5 hours after dermal absorption, and 70 to 90 hours in overdose. 2,4-D amine had a half-life in overdose of 39.5 hours without alkaline diuresis and 2.7 hours with a urine pH greater than 7.5. 2,4,5-T has half-lives from 23 to 33 hours while MCPP had a half-life of 17 hours in an overdose case.

J) DIFFERENTIAL DIAGNOSIS

1) Other substances that may mimic chlorophenoxy compound exposures include other irritant chemicals or substances.

0.4.3)

A) Administer oxygen for respiratory distress. Administer inhaled beta adrenergic agents for bronchospasm.

0.4.4)

A) Eye exposures should be treated with removal of contact lenses and irrigation of eyes with water for at least 15 minutes. Patients with persistent irritation, pain, swelling, lacrimation or photophobia should have a slit lamp examination.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and jewelry, and wash skin, hair, and nails vigorously with soap and water. Dermal irritation or burns can be treated with standard topical therapy. Hypersensitivity reactions may require treatment with topical or systemic antihistamines and/or corticosteroids.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Fever of sudden but delayed onset may occur following ingestion.

3.3.3)

A) FEVER: Fever of sudden but delayed onset may occur following ingestion. About 18% of patients had fever in one study.
B) WITH POISONING/EXPOSURE

1) CASE REPORT: Sudden onset of fever was reported 17 hours postingestion in a case of MCPP poisoning (Dickey et al, 1988).
2) CASE REPORTS: Fever was reported in 3 of 27 cases in one series (Flanagan et al, 1990).
3) CASE REPORT: Profound diaphoresis and hyperthermia were reported in a 39-year-old patient who intentionally ingested a large amount of 10% 2,4-D and 20% mecoprop (Prescott et al, 1979).
4) CASE REPORT: Hyperthermia (38.8 degrees C) occurred in a 35-year-old man approximately 2 days after ingesting 50 g of a chlorophenoxy herbicide solution, containing 2,4-D and MCPP (Berthelot-Moritz et al, 1997).
5) CASE REPORT: A 37-year-old man developed tachypnea (30 breaths/min) approximately 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Prior to the tachypnea, the patient had developed nausea, vomiting, diarrhea, tachycardia, diaphoresis, and agitation. Despite supplemental oxygen, his tachypnea worsened (greater than 50 breaths/min). Following rapid sequence intubation, approximately 16 hours post-ingestion, his respiratory rate decreased from 56 to 36, however his tachycardia and diaphoresis persisted, and he developed hyperthermia (40 degrees C) and hypotension. Despite symptomatic therapy, his temperature continued to increase (42.5 degrees C), and 20 hours post-ingestion, he died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) IRRITATION: DURATION: Resolves in a few days.
2) MIOSIS was reported in several patients ingesting 2,4-D (Bhalla et al, 2008; McGuigan, 1986) in one patient ingesting dichlorprop, 2,4-DP (West et al, 1997), and in a patient ingesting a herbicide solution containing 2,4-D and MCPP (Berthelot-Moritz et al, 1997).
3) COLOR VISION: Alterations were seen in one case involving an herbicide composed of 2,4-dichlorophenoxyacetic acid and 2,4-dichlorophenoxypropionic acid (Anon, 1971).
4) LACRIMATION: Miosis with increased lacrimation has been reported following an ingestion of dichlorprop, 2,4-DP (West et al, 1997).

3.4.5)

A) WITH POISONING/EXPOSURE

1) Exposure to dust containing these agents may produce nasal irritation.

3.4.6)

A) WITH POISONING/EXPOSURE

1) Irritation is common and usually resolves within a few days of exposure. Ingestions involving high concentrations or exposures of long duration may produce burning in the mouth, esophagus, and stomach. Burning pain in the mouth was reported on presentation to the emergency department in a young man following ingestion of 100 to 200 mL of MCPA (Schmoldt et al, 1997).
2) A pungent odor on the breath may be apparent following ingestions (West et al, 1997).
3) According to a retrospective review of pesticide poisonings reported to a northern India hospital from January 2000 to December 2005, diffuse oral ulcerations were reported in 2 of 4 patients on presentation after intentionally ingesting 2,4-D (within 8 hours post-ingestion). One of the other patients developed oral ulcerations 24 hours post-presentation, and the fourth patient experienced brownish discoloration of the lips after 48 hours post-presentation (Bhalla et al, 2008).

Cardiovascular

3.5.2)

A) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) In a prospective case series of 181 patients self-poisoned with MCPA, 7 patients died within 48 hours of cardiorespiratory arrest, and one died of asystolic arrest with failed resuscitation. Most patients (85%), however, developed only mild toxicity (Roberts et al, 2005).
b) CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Tachycardia, bradycardia, and ECG abnormalities occur commonly. Other cardiac dysrhythmias occurred in one suicidal ingestion case.

1) CASE SERIES: In a prospective case series of 181 patients self-poisoned with MCPA, tachycardia (up to 180 beats/min) was relatively common in the 8 fatalities (Roberts et al, 2005).
2) CASE REPORT: A 37-year-old patient who ingested about 20 grams of MCPP developed asystole 17 hours postingestion (Dickey et al, 1988).
3) CASE REPORT: Several hours following the ingestion of dichlorprop, 2,4-DP, a 49-year-old man was admitted to the hospital with tachycardia of 140 beats/ minute. The patient became increasingly cyanotic, developed dysrhythmias, and died the same day (West et al, 1997).
4) CASE REPORT: A 60-year-old man developed ventricular dysrhythmias, severe hypotension, and progressive cardiogenic shock, and subsequently died approximately 3 hours after ingesting 0.5 liters of an agent containing 2,4-D (Jorens et al, 1995).
5) CASE REPORT: A 35-year-old man developed persistent tachycardia after ingesting 50 g of a chlorophenoxy herbicide solution, containing 2,4-D and MCPP. The tachycardia resolved with supportive care (Berthelot-Moritz et al, 1997).
6) CASE REPORT: Persistent tachycardia was reported in a 37-year-old man who intentionally ingested 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent (Berling et al, 2015).

b) ECG abnormalities, including flattening or inversion of the T wave(Bronstein & Sullivan, 1992)or QT interval prolongation (Brahmi et al, 2003) may occur with acute poisoning.
c) CASE SERIES: Tachycardia occurred in 4 patients within 8 hours after intentionally ingesting 2,4-D (ethyl ester) (Bhalla et al, 2008).

C) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension occurs after ingestion of various chlorophenoxy compounds, including MCPP, MCPA and 2,4-D (Hwang et al, 2015; Berling et al, 2015; Bhalla et al, 2008; Roberts et al, 2005; Meulenbelt et al, 1988).
b) CASE REPORT: Seven of 27 patients with chlorophenoxy compound overdose had hypotension (Flanagan et al, 1990).
c) CASE REPORT: Hypotension was reported in a 61-year-old patient who ingested 7.5 to 50 grams (521 to 694 mg/kg) of 2,4-D amine (Friesen et al, 1990).
d) CASE REPORT: Severe hypotension requiring aggressive vasopressor support developed in a 49-year-old man who ingested 2,4-D (Keller et al, 1994).
e) CASE REPORT: Hypotension (systolic BP 80 mmHg) was reported in a young man following an intentional ingestion of 100 to 200 mL of a 50% solution of MCPA-dimethyl-ammonium salt with 0.1 g/L silicone antifoam emulsion in aqueous solution. The patient recovered following aggressive therapy and was discharged 10 days after the ingestion (Schmoldt et al, 1997).
f) CASE REPORT: Severe hypotension and progressive cardiogenic shock developed in a 60-year-old man who ingested a one-half liter of an agent containing 2,4-D. The patient expired despite aggressive treatment (Jorens et al, 1995).

D) NECROSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: At autopsy, signs of disseminated muscle cell necrosis were discovered in myocardial fibers, focal with reactive cellular infiltration, in a 49-year-old man following a fatal ingestion of 2,4-dichlorophenoxypropionic acid. The man died within 12 hours of the ingestion (West et al, 1997).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Noncardiogenic pulmonary edema has occasionally been reported after ingestion (Meulenbelt et al, 1988; Friesen et al, 1990; Jorens et al, 1995).
b) CASE REPORT: Fluid filled lungs with large quantities of edema fluid expressible from cut surfaces were described at autopsy in one fatal ingestion case (Smith & Lewis, 1987).
c) CASE REPORT: Massive hemostasis of the lungs in all capillaries and severe alveolar edema was reported at autopsy in a 49-year-old man following a suicidal ingestion of 2,4-dichlorophenoxypropionic acid (West et al, 1997).

B) APNEA

1) WITH POISONING/EXPOSURE

a) At least four patients have been reported to develop respiratory failure after ingestion.

1) CASE REPORT: Meulenbelt et al (1988) reported two cases of respiratory failure after MCPP ingestion, complicated by non-cardiogenic pulmonary edema and aspiration 5 days postingestion. Assisted ventilation was required for 7 weeks (Meulenbelt et al, 1988).
2) CASE REPORT: Respiratory paralysis occurred in a 61-year-old patient who ingested 37.5 to 50 grams (521 to 694 mg/kg) of 2,4,D amine (Friesen et al, 1990).
3) CASE REPORT: Prolonged apnea was seen in a 70-year-old patient who ingested an unknown amount of MCPP (Meulenbelt et al, 1988).
4) CASE REPORT: Respiratory depression requiring mechanical ventilation developed in a 49-year-old man who ingested 2,4-D (Keller et al, 1994).

b) CASE REPORT: A 76-year-old woman presented to the emergency department comatose and with respiratory failure approximately 3 hours after ingesting 100 mL of an herbicide solution containing MCPA (52%), polyoxyethylene tridecyl ether (PTE) and polypropylene glycol (PPG) as the surfactants (approximately 5%), dimethylamine with water as the solvent (approximately 24%), and 1-methoxy-2-propanol (approximately 10%). In addition to the presenting symptoms, the patient also developed hypotension and metabolic acidosis, and her urine output decreased to less than 10 mL/hour. Following treatment with continuous renal replacement therapy, norepinephrine, and lipid emulsion therapy, the patient gradually recovered (Hwang et al, 2015)

1) Tests of in vitro MTT cell viability and LDH cytotoxicity assays were conducted, using human brain neuroblastoma SK-N-SH cells, in order to determine the causative agent responsible for the patient's symptoms. The MTT cell viability assay revealed slight decreases in cell viability with MCPA, 1-methoxy-2-propanol, dimethylamine, and PPG; however, there was a significant decrease in the cell viability with PTE. Similarly, the LDH cytotoxicity assay showed a low or minimal percentage of released LDH with MCPA, 1-methoxy-2-propanol, dimethylamine, and PPG indicating very low or no cytotoxicity against the SK-N-SH cells; however, there was a significantly higher percentage of LDH released with PTE. Results of these tests demonstrated that PTE may have been the agent responsible for the patient's toxicity. It is suggested that the patient may have developed a "surfactant syndrome" that occurs with acute pesticide intoxication and is a symptom complex consisting of hypotension, loss of consciousness, and respiratory failure (Hwang et al, 2015).

C) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Hyperventilation may occur (Flanagan et al, 1990).
b) CASE REPORT: Tachypnea was reported in a 69-year-old patient who ingested an unknown amount of MCPP (Meulenbelt et al, 1988).
c) CASE REPORT: A 37-year-old man developed tachypnea (30 breaths/min) approximately 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Prior to the tachypnea, the patient had developed nausea, vomiting, diarrhea, tachycardia, diaphoresis, and agitation. Despite supplemental oxygen, his tachypnea worsened (greater than 50 breaths/min). Following rapid sequence intubation, approximately 16 hours post-ingestion, his respiratory rate decreased from 56 to 36, however his tachycardia and diaphoresis persisted, and he developed hyperthermia (40 degrees C) and hypotension. Despite symptomatic therapy, his temperature continued to increase (42.5 degrees C), and 20 hours post-ingestion, he died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).

D) RESPIRATORY DISTRESS

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Respiratory distress, necessitating mechanical ventilation, was reported in 4 patients following intentional ingestion of 2,4-D . Three of the patients died within 24 hours of hospital admission (approximately 26 to 30 hours post-ingestion), despite supportive therapy. The patient who survived experienced respiratory muscle paralysis that resolved after 5 days of mechanical ventilation (Bhalla et al, 2008).

Neurologic

3.7.2)

A) COMA

1) WITH POISONING/EXPOSURE

a) Coma has been reported in all fatal cases in the literature and frequently in nonfatal cases. In a case series, altered level of consciousness (drowsiness) was reported in 3 out of 3 cases of 2,4-D poisoning. It was attributed to blood brain barrier compromise, allowing central nervous system accumulation (Brahmi et al, 2003).
b) Coma, associated with severe muscle weakness has been reported (Meulenbelt et al, 1988).

1) CASE REPORT: Coma was seen in 15 of 27 patients reported by Flanagan et al (1990).
2) CASE REPORT: Coma was the most commonly reported finding in 6 of 7 cases after ingestion of 2,4-D (McGuigan, 1986).
3) CASE REPORT: Aggressive behavior, confusion, and coma were reported in a 39-year-old patient who intentionally ingested a large, unknown amount of 10% 2,4-D and 20% mecoprop (Prescott et al, 1979).
4) CASE REPORT: Coma lasting 12 hours occurred in one fatal case (Smith & Lewis, 1987).
5) CASE REPORT: Disorientation developed in a 49-year-old man with severe 2,4-D poisoning (Keller et al, 1994).
6) CASE REPORT: A 35-year-old man presented one hour after ingesting 50 g of a chlorophenoxy herbicide solution, containing 2,4-D and MCPP. He initially presented with pinpoint pupils, myoclonus and tachycardia. One and half hours after ingestion he became comatose (Glasgow Coma Score of 3). He was treated with intubation and mechanical ventilation, decontamination with activated charcoal and gastric lavage, and urinary alkalinization. The patient awoke 2 days later with significant muscular weakness, hyperthermia, and persistent tachycardia. Over the next few days, the patient gradually recovered and was discharged on hospital day 5 (Berthelot-Moritz et al, 1997).

c) CASE REPORT: A 76-year-old woman presented to the emergency department comatose and with respiratory failure approximately 3 hours after ingesting 100 mL of an herbicide solution containing MCPA (52%), polyoxyethylene tridecyl ether (PTE) and polypropylene glycol (PPG) as the surfactants (approximately 5%), dimethylamine with water as the solvent (approximately 24%), and 1-methoxy-2-propanol (approximately 10%). In addition to the presenting symptoms, the patient also developed hypotension and metabolic acidosis, and her urine output decreased to less than 10 mL/hour. Following treatment with continuous renal replacement therapy, norepinephrine, and lipid emulsion therapy, the patient gradually recovered (Hwang et al, 2015)

1) Tests of in vitro MTT cell viability and LDH cytotoxicity assays were conducted, using human brain neuroblastoma SK-N-SH cells, in order to determine the causative agent responsible for the patient's symptoms. The MTT cell viability assay revealed slight decreases in cell viability with MCPA, 1-methoxy-2-propanol, dimethylamine, and PPG; however, there was a significant decrease in the cell viability with PTE. Similarly, the LDH cytotoxicity assay showed a low or minimal percentage of released LDH with MCPA, 1-methoxy-2-propanol, dimethylamine, and PPG indicating very low or no cytotoxicity against the SK-N-SH cells; however, there was a significantly higher percentage of LDH released with PTE. Results of these tests demonstrate that PTE may have been the agent responsible for the patient's toxicity. It is suggested that the patient may have developed a "surfactant syndrome" that occurs with acute pesticide intoxication and is a symptom complex consisting of hypotension, loss of consciousness, and respiratory failure (Hwang et al, 2015).

B) NEURITIS

1) WITH POISONING/EXPOSURE

a) Paresthesias and protracted polyneuropathy have been caused by herbicide mixtures containing chlorophenoxy compounds. Onset may be delayed for up to a month, and some have occurred after only slight dermal exposure (O'Reilly, 1984). This association is controversial, as animal and human experiments have failed to reproduce this effect (Mattsson & Eisenbrandt, 1990).

1) Decreased vibratory and proprioceptive sensation, decreased deep tendon reflexes, and additional superficial reflexes have been seen (Smith & Oehme, 1991).

b) CAUSES: May be due to hypersensitivity or concurrent exposure to other neurotoxicants.
c) CASE REPORT: Herbatox(R), an herbicide containing 2,4-dichlorophenoxyacetic acid and 2,4-dichlorophenoxy acetic acid, was associated with a long-lasting polyneuritis (Anon, 1971).
d) CASE REPORT: An unspecified ester of 2,4-D produced polyneuritis when absorbed dermally (Goldstein et al, 1959).
e) CASE REPORT: A case of severe polyneuropathy was reported in a 3-year-old child following exposure to Chwastox (dichlorophenoxyacetic acid). By the 3rd post-exposure day, neurologic examination revealed the presence of flaccid quadriparesis and sensory deficits of touch, pain, and temperature. An EMG showed denervation and extremely low velocity of conduction in ulnar and median nerves by the 5th day. The patient improved following plasmapheresis therapy (Lankosz-Lauterbach et al, 1997).

C) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Moderate cerebral edema was seen on CT scan in a 13-year-old boy after intentional ingestion of 2,4-D. The patient required respiratory support with mechanical ventilation, sedation, alkaline diuresis and mannitol infusion (Brahmi et al, 2003).

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache may occur and may be associated with malaise and vertigo.
b) SOURCES: Most cases were in persons occupationally exposed.

E) INCREASED MUSCLE TONE

1) WITH POISONING/EXPOSURE

a) Stiff legs, muscle twitching, and muscle spasms have been seen with high doses. Profound muscle weakness and coma may follow (Flanagan et al, 1990).
b) Hyperreflexia and cervical rigidity were observed in 2 cases of 2,4-D poisoning (Brahmi et al, 2003).

3.7.3)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) IV ADMINISTRATION: Doses up to 28 mg/kg of 2,4-D have been injected without neuropathic effects or other serious symptomatology. Extreme doses had to be given to produce effects (Seabury, 1963).
b) INTRAPERITONEAL: 2,4,D was given intraperitoneally in large doses to rats over 3 months. No neuropathic symptoms were seen, including gait, toe-spreading reflexes, distal motor latencies, and motor and mixed nerve conduction velocities and amplitudes (Toyoshima, 1985).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting occurred in 11 of 27 patients in one study (Flanagan et al, 1990).
b) CASE REPORT: Repeated vomiting occurred for 24 hours after ingestion of an unknown amount of MCPP by a 70-year-old patient.
c) CASE SERIES: Nausea and vomiting occurred in 4 patients after intentionally ingesting 2,4-D (Bhalla et al, 2008).
d) CASE REPORT: Vomiting and diarrhea occurred in a 35-year-old man immediately following ingestion of 50 g of a chlorophenoxy herbicide solution, containing 2,4-D and MCPP (Berthelot-Moritz et al, 1997).
e) CASE REPORT: Nausea, vomiting, and diarrhea occurred in a 37-year-old man who intentionally ingested 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent (Berling et al, 2015).

B) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea has been reported (Berling et al, 2015; Berthelot-Moritz et al, 1997; Flanagan et al, 1990).

C) ASCITES

1) WITH POISONING/EXPOSURE

a) Fluid may be found in the abdominal cavity.
b) CASE REPORT: One fatally poisoned patient had abdominal and thoracic cavities containing a thin reddish watery fluid (Smith & Lewis, 1987).

D) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Abdominal pain and bloody diarrhea developed in a 49-year-old man who ingested 2,4-D (Keller et al, 1994). Endoscopy revealed massive hemorrhage and mild necrosis of the gastric mucosa.
b) CASE REPORT: Significant erosion of the stomach lining was discovered at autopsy in a 49-year-old man who died within 12 hours following the ingestion of 2,4-dichlorophenoxypropionic acid (dichlorprop, 2,4-DP) (West et al, 1997).
c) CASE REPORT: A 60-year-old man developed gastrointestinal hemorrhage of the mouth, esophagus, and stomach after ingestion of approximately a one-half liter of an agent containing 2,4-D. The patient died 3 hours after admission from cardiogenic shock. Blood levels of 2,4-D were 192 mg/liter (Jorens et al, 1995).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Elevated serum LDH and AST have been reported and may reflect moderate liver injury (Berwick, 1970; Jones et al, 1967).
b) CASE REPORT: Liver function tests were slightly elevated, peaking at 36 hours after ingestion of 37.5 to 50 grams by a 61-year-old patient (Friesen et al, 1990).
c) CASE SERIES: Vietnam veterans potentially exposed to phenoxy herbicides were noted to have chronic liver abnormalities. A study of 350 patients suggested that viral and alcoholic complications, rather than herbicides, were causal (Tamburro, 1992).
d) Some chlorophenoxy compounds are inducers of cytochrome P-450 mixed function oxidase.

B) STEATOSIS OF LIVER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Fatty liver was reported at autopsy in a 49-year-old man 3 days following the fatal ingestion of 2,4-dichlorophenoxypropionic acid (West et al, 1997).

Genitourinary

3.10.2)

A) ALBUMINURIA

1) WITH POISONING/EXPOSURE

a) Albuminuria has been reported and may reflect glomerular and/or tubular injury. Hemoglobinuria may also be present (Friesen et al, 1990).

B) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE

1) WITH POISONING/EXPOSURE

a) Porphyria has been seen after chronic industrial exposure to 2,4-D and 2,4-T (Bleiberg, 1964).

1) DURATION: Symptoms disappeared on cessation of exposure.

C) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure secondary to rhabdomyolysis has been described after ingestion of MCPP (Meulenbelt et al, 1988) and 2,4-D (Berwick, 1970; Flanagan et al, 1990).
b) CASE REPORT: A 69-year-old patient ingested an unknown amount of MCPP and developed rhabdomyolysis and renal failure that necessitated hemodialysis for 30 days (Meulenbelt et al, 1988).
c) CASE REPORT: Acute renal failure developed in a 49-year-old man with severe 2,4-D poisoning complicated by gastrointestinal bleeding and hypotension (Keller et al, 1994).

D) SERUM CREATININE RAISED

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Elevated serum creatinine concentrations, ranging from 3.6 to 7.8 mg/dL, were reported in 4 patients who intentionally ingested 2,4-D. Three of the 4 patients also had elevated serum creatine phosphokinase concentrations as well (range 1200 to 4500 units/L). Despite supportive therapy, three of the patients died within 24 hours after hospital admission (approximately 26 to 30 hours post-ingestion). The fourth patient developed worsening renal function that improved following 3 hemodialysis sessions. She was discharged approximately 3 weeks post-presentation (Bhalla et al, 2008).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis may be seen in severe cases (Hwang et al, 2015; Brahmi et al, 2003; Jorens et al, 1995; Flanagan et al, 1990; Osterloh, 1983) .

Hematologic

3.13.2)

A) THROMBOCYTOPENIC DISORDER

1) WITH POISONING/EXPOSURE

a) Thrombocytopenia has been reported in a few cases.
b) MCPP CASE REPORT: Thrombocytopenia was seen in two cases (Meulenbelt et al, 1988). The nadir in one case was on day 5.
c) MCPA CASE REPORT: Cases have been reported by Kancir et al (1988) and Jones et al (1967) (Kancir et al, 1988; Jones et al, 1967).

B) PLATELET AGGREGATION

1) WITH POISONING/EXPOSURE

a) 2,4-D and MCPA inhibit human platelet aggregation in-vitro. The effect was confirmed in rabbit experiments in-vitro and in vivo with dosages of 100 to 150 mg/kg subcutaneously (Elo et al, 1991).

C) LEUKOPENIA

1) WITH POISONING/EXPOSURE

a) Leukopenia has been reported (Bronstein & Sullivan, 1992).

Dermatologic

3.14.2)

A) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Acute exposure may produce irritation, dependent on chemical, duration of contact, and concentration.

B) CHLORINE ACNE

1) WITH POISONING/EXPOSURE

a) Chlorodioxin contamination has produced chloracne.
b) EPIDEMIOLOGY: Chloracne has occurred in workers producing 2,4-T (Moses et al, 1984), but not in handlers of the commercially packaged herbicides.

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Elevated creatine kinase was associated with more severe poisoning following intentional MCPA (Roberts et al, 2005) and 2,4-D exposure (Bhalla et al, 2008).
b) CASE SERIES: Three patients developed elevated creatine phosphokinase concentrations (range 1200 to 2400 units/L) after intentionally ingesting 2,4-D (Bhalla et al, 2008).
c) CASE REPORT: Initial muscle cramping was followed within 1 to 2 hours by rhabdomyolysis, then renal failure in two adults who ingested MCPP (Meulenbelt et al, 1988).
d) CASE REPORT: Mild rhabdomyolysis (CK 822 Units/L) and mild spasticity was reported in a young man who ingested 100 to 200 mL of the liquid herbicide, MCPA (Schmoldt et al, 1997).
e) Muscle rigidity and elevated creatinine kinase (CPK) may be seen.
f) CASE REPORT: Dickey et al (1988), reported a fatal poisoning in which these effects were noted (Dickey et al, 1988). Elevated CPK (876 Units/L) was reported in a 21-year-old man following an intentional ingestion of an unknown quantity of 2-4-D. The patient died on hospital day 4 from multiorgan failure (Brahmi et al, 2003).
g) CASE REPORT: Elevated CPK (1562 International Units/L at 48 hours) occurred after an unknown amount of MCPP was ingested (Meulenbelt et al, 1988).
h) CASE REPORT: A peak CPK of 24,092 units/liter was seen the day after admission for ingestion of 37.5 to 50 grams of 2,4-D amine in a 61-year-old patient (Friesen et al, 1990).

B) EMG FINDING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: EMG abnormalities were described in a single case of 2,4-D ester exposure (Goldstein et al, 1959).

C) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Proximal muscle weakness was reported in 4 patients within 8 hours after intentionally ingesting 2,4-D. Three of the 4 patients also developed elevated creatine phosphokinase concentrations (range 1200 to 2400 units/L). Three of the patients died within 24 hours after hospital admission (approximately 26 to 30 hours post-ingestion). The fourth patient who survived continued to experience persistent muscle weakness at hospital discharge 3 weeks later (Bhalla et al, 2008).

3.15.3)

A) ANIMAL STUDIES

1) CHOLINESTERASE INHIBITION/MYOTONIA

a) 2,4-D at 200 mg/kg intraperitoneally resulted in inhibition of muscle (but not sciatic nerve) type cholinesterase and myotonia (Bernard et al, 1985).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hypoglycemia (1.7 mmol/L) was reported in an 18-year-old woman following an intentional ingestion of Illoxan(R) , a 2,4-D product. The authors felt this may have been induced by hepatic failure (Brahmi et al, 2003).

3.16.3)

A) ANIMAL STUDIES

1) THYROID FUNCTION

a) Subchronic exposure studies of 2,4-D in dogs at 1 to 300 mg/kg/d orally resulted in decreased T3 and T4 levels (Charles et al, 1996c). This effect has not been reported in exposed humans.

Reproductive

3.20.1)

A) 2,4-D and 2,4,5-T have caused adverse reproductive effects in experimental animals. Allegations of human birth defects due to these compounds have not been confirmed.

3.20.2)

A) CONGENITAL ANOMALY

1) Allegations of human birth defects related to 2,4-D and/or 2,4,5-T have not been confirmed (Wolfe et al, 1995).

a) However, some evidence from a report on Vietnam veteran's children shows a limited or suggestive level of evidence between exposure to 2,4-D and/or 2,4,5-T and spina bifida. A major limitation of the report was the inability to quantify levels of herbicide exposure in individual troops (Stephenson, 1996).
b) In a recent review article, relevant studies were identified through a computerized literature search of Medline and Embase from 1966 to 2002. It was concluded that parental exposure to Agent Orange appears to be associated with an increased risk of birth defects (Ngo et al, 2006).

2) MENTAL DEFICIENCY

a) There has been one documented case of mental retardation and facial defects in a child born to a mother who had very high-level occupational exposure to 2,4-D during pregnancy, but other possible causes were not ruled out (Casey & Collie, 1984).

B) ANIMAL STUDIES

1) 2,4-D

a) 2,4-D and all of its derivatives have been either embryotoxic, fetotoxic, or teratogenic in animals. Various salts and esters of 2,4-D were fetotoxic and teratogenic in rats only at doses high enough to be maternally toxic; no effects were evident in rabbits even a maternally toxic doses (Charles et al, 2001).
b) 2,4-D administered as the free acid induced urogenital malformations and increased postnatal mortality in rat pups (Fofana et al, 2002).
c) Offspring of CD-1 mice given 2,4-D on days 6 through 16 of gestation showed alterations in lymphocyte profiles, lower numbers of T cytotoxic or suppressor cells and higher relative counts of B cells (Lee et al, 2001).
d) 2,4-D when administered as the dimethylamine salt at levels up to 100 ppm in the diet, inhibited formation of teeth in fetal rats (Alpoz et al, 2001).

2) 2,4,5-T

a) Technical and purified grade 2,4,5-T administered during gestation to CD-1 mice produced fetal weight reduction, embryolethality, and an increased incidence of cleft palate (Nelson et al, 1992; Holson et al, 1992). Similar findings have been reported in outbred mice (Chen & Gaynor, 1992).
b) 2,4,5-T administered to pregnant Rhesus monkeys at 1 and 10 mg/kg/day on days 22 through 38 of gestation produced no maternal toxicity or teratogenic effects; the offspring were followed for a full year after birth (Dougherty et al, 1975).

3) Various neurodevelopmental abnormalities have been reported following intrauterine exposure to 2,4-D, 2,4,5-T, or combinations of these agents (St. Omer & Mohammad, 1987) (Mohammad & St. Omer, 1986; Crampton & Rogers, 1983).
4) Studies of 2,4-D, MCPA, and Mecoprop in mice revealed embryotoxic effects, embryolethality, and skeletal malformations (cleft palate, wavy ribs) with all three compounds, as well as with other chemically related substances (Roll & Matthiaschk, 1983).
5) Male and female Sprague-Dawley rats maintained on diets with a related agent, triclopyr, at doses from 3 to 30 mg/kg/day over three generations had no abnormalities of reproductive function (Hanley et al, 1984).

3.20.3)

A) DEATH IN UTERO

1) CASE SERIES - An increased rate of death was reported among twin offspring of Swedish laboratory workers with complex exposures including phenoxy herbicides (Ericson et al, 1985).
2) CASE SERIES - An increased rate of fetal death was reported in pregnancies between 1966 and 1977 in an area of Sweden located near a chlorophenoxy herbicide facility where air and water pollution are believed to have occurred (Kallen & Thorbert, 1985).

B) SPONTANEOUS ABORTION

1) In a two-stage case-control group study, there was an association between occupational exposure to 2,4-D in forestry and commercial workers and miscarriages (through either male or female exposure), but this association was not seen in farmers (3).

3.20.4)

A) ANIMAL STUDIES

1) 2,4-D is transferred in the breast milk in neonatal rats (Sturtz et al, 2000).
2) 2,4-D exposure of rat pups during lactation produced alterations of astroglial architecture, especially in serotonergic nuclei, hippocampus, and cerebellum (Brusco et al, 1997).
3) 2,4-D administered to dams at 100 mg/kg (single dose) on postnatal days 15 to 25 in rats resulted in deficient and abnormal myelination in nursing pups (Duffard et al, 1996).
4) Several studies have shown neurological effects in rodents.

a) Neuromotor and behavioral abnormalities occurred in rats given 2,4-D prenatally and postnatally (Bortolozzi et al, 1999).
b) Rats exposed to 2,4-D from day 16 of gestation to postpartum day 23 by oral administration of 70 mg/kg/day to the dams showed alterations in brain monoamine neurotransmitters, including elevated levels of serotonin (5-hydroxytryptamine) (Bortolozzi et al, 2003).
c) Neonatal rats given relatively high doses of 2,4-D (100 mg/kg) had reduced myelination in the brain (Duffard et al, 1996; Rosso et al, 2000).
d) Delayed CNS development, measured as reduced brain ganglioside levels, occurred in neonatal rats given relatively high doses of 70 or 100 mg/kg/day (Rosso et al, 1997).
e) Increased numbers of astrocytes were seen in the brains of neonatal rats exposed through lactation (Brusco et al, 1997).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS94-75-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

B) IARC Carcinogenicity Ratings for CAS93-76-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

C) IARC Carcinogenicity Ratings for CAS94-74-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

D) IARC Carcinogenicity Ratings for CAS93-65-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

3.21.3)

A) CARCINOMA

1) The causal relationship between the chlorophenoxy herbicides and cancer remains controversial (Armstrong, 1986; Coggon, 1987; Giri, 1986) and not sufficiently proven (Coggon et al, 1986; Bond et al, 1988). A review was done by Morrison et al (1992).
2) Another review stated that the overall available evidence from epidemiologic studies was not adequate to confirm any causal relationship between 2,4-D exposure and any form of cancer (Garabrant & Philbert, 2002).
3) An International Register of occupational exposure to phenoxy herbicides was established by IARC in 1984 and contains 18,972 workers from 10 countries. Analysis of cancer incidence from this study may provide a more accurate assessment of the risk from these compounds (IARC, 1990). The IARC has concluded there is limited evidence of carcinogenicity in humans (Morrison et al, 1992).

a) Two New Zealand cohorts of 1025 phenoxy herbicide producers and 703 sprayers were followed from January 1, 1969 and January 1, 1973 respectively to December 31, 2000. Calculation of standardized mortality rates revealed a non-significant excess of cancer related deaths of 24% in the producer cohort with a significant excess of multiple myeloma (SMR=5.51). All cancer mortality was higher in the producers involved in product synthesis. In the sprayer cohort, total cancer mortality was decreased compared to the production workers with increased mortality from colon cancer (SMR=1.94) ('t Mannetje et al, 2005).

B) SARCOMA

1) In humans, exposure to phenoxyacid herbicides has been said to be a possible cause of soft-tissue sarcoma (Vineis et al, 1986; Saracci et al, 1991; Kang et al, 1987).
2) CASE SERIES: In a Swedish case-control study of 20,245 pesticide applicators followed for a mean time of 13.9 years, there was no association between phenoxyacid herbicide exposure and soft-tissue sarcoma (Wiklund et al, 1988).
3) Although initially it was thought that TCDD contamination was responsible, Saracci et al (1991) found no association.
4) A study from the Netherlands found no statistical increase in soft tissue sarcoma (Bueno de Mesquita et al, 1993).
5) CASE SERIES: No deaths from soft tissue sarcoma were found in an 18-year follow-up of 1909 male pesticide applicators who had been exposed to 2,4-D and 2,4,5-T from 1955 through 1971. The low numbers of subjects limit the statistical power of this study (Asp et al, 1994).
6) CASE SERIES: Lynge et al (1998) conducted a retrospective study of workers in 2 Danish phenoxy herbicide factories, where MCPA (main product), 2,4-D, and MCPP were manufactured. Of 2,199 workers exposed from 1947 to 1993, 4 cases of soft tissue sarcoma were reported, which was not statistically different from the incidence in the Danish population (Lynge, 1998).
7) Four deaths from soft tissue sarcoma (STS; 3.3 expected deaths) occurred among men who had worked in jobs with more than background exposure to phenoxy herbicides and three (1.5 expected) were in those who had at least 1 year of job-related exposure in a case-control study with extended follow-up in the United Kingdom of 8036 men employed at 5 factories, of whom 15 had STS and 150 were controls. No significantly elevated risks or consistent trends across categories of potential exposure were found for STS; the highest odds ratio for STS in men who had at least 1 year of job-related exposure was 1.3 (95% CI, 0.3 to 5.62) (Coggon et al, 2015).

C) LYMPHOMA-LIKE DISORDER

1) NON-HODGKIN'S LYMPHOMA: In humans, exposure to phenoxyacid herbicides has been said to be a possible cause of non-Hodgkin's lymphoma (NHL) (Weininger, 1987). Not all studies are positive (Bueno de Mesquita et al, 1993; Pearce, 1989; Dalager et al, 1991; O'Brien et al, 1991; Pearce et al, 1986). Epidemiologists and toxicologists reviewing the association between exposure to 2,4-D and NHL have found that the data are insufficient to conclude a cause and effect relationship (Anon, 1997).

a) All available studies have design flaws, but some evidence supports a weak association between chlorophenoxy compounds and non-Hodgkin's lymphoma. Some evidence points to organic solvent diluents and inactive ingredients as risk factors, but further studies are needed (Kelly & Guidotti, 1989/90).

2) CASE SERIES: In a Western Washington state study (Woods et al, 1987), a small but significantly increased risk of developing a non-Hodgkin lymphoma was seen in workers who used phenoxy herbicides for 15 years or more in combination with other types of chemicals. The results of this study do not demonstrate a positive association between increased cancer risks and exposure to any specific phenoxy herbicide product alone.
3) CASE SERIES: A case control study of agricultural 2,4-D exposure in Nebraska using a telephone survey found an increased risk of non-Hodgkin's lymphoma with borderline statistical significance (Zahm et al, 1990).
4) CASE SERIES: No deaths from non-Hodgkin's lymphomas were found in an 18-year follow-up of 1909 male pesticide applicators who had been exposed to 2,4-D and 2,4,5-T from 1955 through 1971, and only one case of non-Hodgkin's lymphoma was found. The low numbers of subjects limit the statistical power of this study (Asp et al, 1994).
5) CASE SERIES: In a study of 32,600 employees of a lawn care company exposed to a wide variety of herbicides including 2,4-D and MCPP, there was no significant increase in the number of deaths from non-Hodgkin's lymphoma (NHL) in male lawn chemical applicators, with 3 cases of NHL reported compared to an expected rate of 2.1 cases in the general population (Zahm, 1997).
6) Lynge (1998) conducted a retrospective study of workers in 2 Danish phenoxy herbicide factories, where MCPA (main product), 2,4-D and MCPP were manufactured. Of the 2119 workers exposed from 1947 to 1993, 6 cases of non-Hodgkin's lymphoma were reported, an incidence consistent with that observed in the Danish population (Lynge, 1998).
7) An increased risk of non-Hodgkins lymphoma (NHL) in subjects exposed to herbicides (odds ratio [OR], 1.6, 95% confidence interval [CI], 1.0-2.5) and fungicides (OR, 3.7; 95% CI, 1.1-13.0) was found in a Swedish case control study of 404 males diagnosed with non-Hodgkin's lymphoma and 741 controls. Of the phenoxyacetic acids, 4-chloro-2-methyl phenoxyacetic acid (MCPA) was found to have the most significant association (OR, 2.7; 95% CI, 1.0-6.9) with NHL. In this study, the risk appeared to decrease with time since the last exposure (Hardell & Eriksson, 1999).
8) An excess of deaths from non-Hodgkin lymphoma (NHL; 19 deaths) was observed among men who had worked for at least 1 year in jobs with more than background exposure to phenoxy herbicides (standardized mortality ratio, 1.85; 95% CI, 1.12 to 2.89) in a case-control study with extended follow-up in the United Kingdom of 8036 men employed at 5 factories, of whom 74 had NHL or chronic lymphocytic leukemia (CLL) and 719 were controls. However, no significantly elevated risks or consistent trends across categories of potential exposure were found for NHL or CLL (Coggon et al, 2015).

D) NASAL ULCER

1) NASAL CANCER: A Swedish study (Hardell et al, 1982) found a 2-fold increased risk in persons exposed to phenoxy herbicides.
2) Cancer mortality was increased for cancers of the respiratory tract, buccal cavity/pharynx, and for non-Hodgkin's lymphoma, in a group of 2,479 German workers exposed to phenoxy herbicides and contaminants (Becher et al, 1996).

E) GASTRIC CARCINOMA

1) Results have been contradictory. A Swedish study (Axelson et al, 1980) found an increased risk, but a Saskatchewan, Canadian study (Wigle et al, 1990) did not.

F) COLON CARCINOMA

1) LACK OF EFFECT: According to a prospective study, conducted by the Agricultural Health Study, investigating the relationship between agricultural pesticides and colorectal cancer incidence, there appeared to be a lower risk of colon cancer among individuals occupationally exposed to 2,4-D (n=135; OR 0.6, 95% CI 0.4-0.8) (Lee et al, 2007).

G) PROSTATE CARCINOMA

1) A historic cohort study of veterans found that exposure to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin is associated with an increased risk of prostate cancer, especially high-grade prostate cancer (Gleason score of 7 or higher). Of the 2720 veterans who underwent a prostate biopsy, prostate cancer was detected in 896 men (32.9%), and 459 men (16.9%) had high-grade prostate cancer. The risk of prostate cancer was 52% higher (adjusted odds ratio [OR], 1.52; 95% CI, 1.07 to 2.13) in men with Agent Orange exposure (n=203) compared with those who had no exposure (n=2517). While Agent Orange exposure had no significant association with risk of low-grade prostate cancer (adjusted OR, 1.24; 95% CI, 0.81 to 1.91), a significant association was observed between exposure and risk of high-grade prostate cancer (adjusted OR, 1.75; 95% CI, 1.12 to 2.74). An even stronger association of 2.1 fold was shown between Agent Orange exposure and risk of detecting prostate cancer with a Gleason score of 8 or higher (adjusted OR, 2.1; 95% CI, 1.22 to 3.62) (Ansbaugh et al, 2013).

H) TESTIS NEOPLASM MALIGNANT

1) A few studies have shown increased risk, but the number of patients is small (Bond et al, 1988; Coggon et al, 1986).
2) CASE SERIES - NEGATIVE: In a case-control study of exposure to 2,4-D and 2,4,5-T (Agent Orange) in Vietnam veterans, no increased risk for testicular cancer was found. The study compared 97 veterans with testicular cancer to 311 matched controls. The study was limited by reliance on surrogate measures of herbicide exposure, such as branch/occupation in military service, geographic region stationed, and location of the unit in relation to spraying of herbicide (Bullman et al, 1994).

I) OTHER MALIGNANCIES

1) CASE SERIES-NEGATIVE: Case-control studies of Vietnam veterans did not reveal an association between Hodgkin's disease (Dalager et al, 1995) or lung cancer and dioxin-contaminated Agent Orange exposure (Mahan et al, 1997).
2) CASE SERIES-NEGATIVE: In a case-control study of women in Vietnam, exposure to Agent Orange was not associated with an increased risk of gestational trophoblastic disease. Cumulative exposure to the herbicide was estimated by residential history and data from U.S. crop spraying missions (Cordier et al, 1996).

3.21.4)

A) CARCINOMA

1) In sheep, phenoxy- and picolinic acid herbicides have been reported to cause small-intestinal adenocarcinoma (Newell et al, 1984).
2) MCPA at 40 ppm in the diet of mice resulted in the occurrence of leukemias (Takagi, 1990). The chlorophenoxy herbicides behave as peroxisome proliferators in mammalian liver (Vainio et al, 1983; Linnainmaa, 1984). Peroxisome proliferation agents generally have tumor promoter effects.

B) LACK OF EFFECT

1) LACK OF EFFECT

a) In chronic exposure studies of rats and mice at oral 2,4-D doses of up to 300 mg/kg/day, no oncogenic effect was noted (Charles et al, 1996b). Studies with three forms of oral 2,4-D given to dogs at up to 7.5 mg/kg/d were also negative (Charles et al, 1996a). Chronic dietary exposure studies of 2,4,5-T in mice at 80 ppm were negative (Muriani-Kovacs et al, 1976).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Monitor serum electrolytes, renal function, liver enzymes, CK, and serum pH after large exposures.
C) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
D) Monitor urine for pH, protein, RBCs, myoglobin and urinary output.
E) Monitor neurologic exam in symptomatic patients.
F) Patients with significant respiratory symptoms should have a chest X-ray.
G) These compounds can be measured in serum and urine, but these tests are not widely available and not useful to guide therapy, but can be used to confirm exposure.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor CPK levels and serum myoglobin levels (Hallenbeck & Cunningham-Burns, 1985). Monitor serum electrolytes and liver and kidney function tests.
2) Cholinesterase activity is not affected.

B) PLASMA LEVELS

1) Plasma chlorophenoxy herbicide levels appear to be poorly correlated with clinical effects (Roberts et al, 2005).

4.1.3)

A) URINARY LEVELS

1) Monitor urine for pH, protein, RBC's, myoglobin, and urine output.
2) A urinary analysis for chlorophenoxy compounds may also be useful as a confirmatory test (Arnold & Beasley, 1989). Limited data suggest that urinary 2,4-D levels may be useful in monitoring workers with industrial and commercial exposure (Knopp & Glass, 1991)(Kolomin-Hedman & Erne, 1980).
3) The level of detection of 2,4-dichlorophenoxyacetic acid, measured by urinalysis, was variable in family members living on a farm who were exposed to 2,4-D, and was dependent on the amount of direct contact with the pesticide (Alexander et al, 2007).

4.1.4)

A) OTHER

1) Monitor vital signs and mental status.
2) Monitor neurologic exam in symptomatic patients.
3) Monitor the patient for at least 6 to 12 hours as there is a potential for delayed onset of symptoms.
4) CARDIAC MONITORING

a) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.

Radiographic Studies

1) Monitor the chest x-ray in patients with significant exposure.

Methods

1) GC/MS: A method using acid hydrolysis, diazoethane derivatization, and silica gel column chromatography for sample preparation followed by combined capillary gas chromatography and mass spectrometry/mass spectrometry in the selective ionization modes of positive and negative chemical ionization was successful in improving the detection limit to 1 ppb for urine samples.

a) This method is designed for use in large epidemiologic studies to document exposure to chlorophenoxy herbicides (Holler et al, 1989).

2) GLC: This method is sensitive for residue analysis, but is a lengthy process and can create additional products during derivatization (Roseboom et al, 1982).
3) HPLC: Flanagan & Ruprah (1989) developed a method using methanolic hydrochloric acid extraction and resolution with a phenylsilyl-modified silica column/aqueous buffer acetonitrile eluent to partially quantify a variety of chlorophenoxy compounds in biological samples of acutely poisoned patients.

a) The limit of detection was 20 milligrams per liter.
b) Plasma/whole blood ratios ranged from 1.7 to 2.0. Therefore, whole blood measurements should be adjusted before comparing to plasma or serum data.

4) 2,4-D was quantitated in human autopsy material. Visceral samples were acidified, and blood and plasma deproteinized with methanol, followed by acidification, extraction with diethyl ether, and analysis using HPLC (Keller et al, 1994).
5) HPLC and CE: West et al (1997) compared high performance liquid chromatography and capillary electrophoresis in the analysis of 2,4-dichlorophenoxypropionic acid (2,4-DP) in body fluids and tissues obtained at autopsy. Both methods reported similar results of concentrations of 2,4-DP in cardiac blood, stomach contents, bile, liver, spleen, kidney and brain tissue (West et al, 1997).
6) Urinary levels of 2,4-D can be detected with gas chromatography with mass selective detection (GC/MSD) with a lower limit of detection of 5 ppb (Hughes et al, 2001).
7) Two methods for determining urinary 2,4-D levels, based on high performance liquid chromatography and gas chromatography, produced identical results in a group of ten occupationally exposed subjects (Aprea et al, 1997).

1) Quantitative estimates of total dermal exposure to 2,4-D for the past six days can be derived from two consecutive 24-hour urine samples (Harris et al, 2001).

1) ULTRAVIOLET SPECTROMETRY: This is an older and non-selective method which does not differentiate between chlorophenoxy and benzonitrile herbicides. These two herbicides types are often combined in commercial products.
2) Published values using this method are of dubious value (Flanagan & Ruprah, 1989a).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with severe symptoms or getting worse after an observation period of 6 to 12 hours should be admitted to the hospital. Depending on the severity of their symptoms, ICU admission may be warranted (eg, intubated patients). Patients should not be discharged until they are clearly improving or asymptomatic.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with unintentional exposures with minimal to no symptoms may be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Physicians who practice occupational medicine may be useful for patients with workplace exposures to chlorophenoxy herbicides.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients should be sent to a healthcare facility if their exposure to chlorophenoxy compounds was in a self-harm attempt or if they are symptomatic. They should be observed for 6 to 12 hours (potential for delayed symptoms) and be clearly improving or asymptomatic prior to discharge.

Monitoring

Oral Exposure

6.5.1)

A) Activated charcoal may be considered if the patient is awake, alert, and cooperative.

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) Remove contaminated clothing and wash exposed skin. Irrigate exposed eyes.

6.5.2)

A) SUMMARY

1) Ingestion of 2,4-D in quantities exceeding 40 mg/kg should be treated with gastric decontamination within 4 hours after ingestion (McGuigan, 1986).

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Monitor serum electrolytes, renal function, liver enzymes, CK, and serum pH after large exposures.
3) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
4) Monitor urine for pH, protein, RBCs, myoglobin and urinary output.
5) Monitor neurologic exam in symptomatic patients.
6) Patients with significant respiratory symptoms should have a chest X-ray.
7) These compounds can be measured in serum and urine, but these tests are not widely available and not useful to guide therapy, but can be used to confirm exposure.

B) AIRWAY MANAGEMENT

1) Early intubation may be indicated in patients who develop respiratory issues or severe CNS depression.

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

D) FLUID/ELECTROLYTE BALANCE REGULATION

1) Maintain adequate urine flow with intravenous fluids if the victim is dehydrated. Monitor fluid and electrolyte balance and replace as required.

E) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Manage hyperthermia with sponge baths.

F) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).
2) All hairy areas should be shampooed.

B) STUDIES

1) 2,4-D dimethylamine is more easily removed than 2,4-D (acid). In one study, 10 mg of 2,4-D dimethylamine and 2,4-D (acid) were applied to the dorsum of the hand with the following results:

a) 2,4-D DIMETHYLAMINE: 7.68 mg (+/- 0.493 mg) was washed off the skin at 6 hours postexposure (Harris & Solomon, 1992).
b) 2,4-D (ACID): 5.35 mg (+/- 0.384 mg) was washed off the skin at 6 hours postexposure (Harris & Solomon, 1992).

2) MULTIPLE WASHES: Moody et al (1992) showed that although roughly 20% of an applied dose was washed off with an initial soap and water wash, an additional 10% to 14% could be removed with 5 washings (Moody et al, 1992).

6.9.2)

A) IRRITATION SYMPTOM

1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Alkaline diuresis may be useful, particularly if begun early in the course of treatment. Hemodialysis is not more effective than alkaline diuresis. Plasmapheresis may be effective for late treatment of second stages of poisoning.

1) SODIUM BICARBONATE/INITIAL DOSE

a) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.

2) SODIUM BICARBONATE/REPEAT DOSES

a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

3) CAUTION

a) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.

4) LITERATURE REVIEW: A Cochrane review found no randomized controlled trials available regarding the use of urinary alkalinization in patients who presented 24 to 48 hours following poisoning with a chlorophenoxy herbicide. Although there have been anecdotal reports of urinary alkalinization being used successfully, according to this review there is insufficient evidence to support the routine use of urinary alkalinization for acute chlorophenoxy herbicide poisoning (Roberts & Buckley, 2007). The authors felt that it was reasonable to attempt urinary alkalinization (after establishing adequate urine output) in patients with significant poisoning, as these substances may cause prolonged toxicity with death after 24 hours in some cases, given the relatively few adverse effects reported with urinary alkalinization.
5) CASE REPORT: Mecoprop elimination was enhanced in one case of 2,4-D and mecoprop ingestion. For each 1 unit increase in urine pH, the renal clearance increased almost 5-fold (Prescott et al, 1979).
6) CASE REPORT: In one case, alkaline diuresis was associated with a decrease in the 2,4-D half-life from 39.5 to 2.7 hours and with reversal of coma. Diuresis was also credited with prevention of renal failure in this patient, who had rhabdomyolysis (Friesen et al, 1990).
7) CASE REPORT: MCPA excretion was markedly increased by urinary alkalinization in a young man after an ingestion. Plasma half-life of MCPA was reported to fall from 133 hr to 12.6 hr with forced alkaline diuresis. Improvement in symptoms paralleled with declining plasma concentrations. Concomitant supportive therapy was also necessary (Schmoldt et al, 1997).
8) ANIMAL DATA: Increases in urine volume and pH increased urinary clearance of 2,4,5-T in dogs, following infusion of acetate. Infusion of saline or mannitol was associated with an increase in the volume of urine voided, but did not increase 2,4,5-T clearance. A urinary pH in excess of 6.0 was associated with increased clearance (Hook et al, 1976).

1) In late stages of poisoning, alkaline forced diuresis may not be effective. One case report suggests that plasmapheresis may be an effective elimination treatment for the second stage of poisoning, with increased symptoms of polyneuropathy, and should be considered (Lankosz-Lauterbach et al, 1997).

a) CASE REPORT: A 3-year-old child was admitted to the hospital with vomiting, dehydration, apathy and weakness. A diagnosis was not established until after the 3rd day, when a urine toxicologic screen revealed the presence of chloro- phenoxy compounds. By the 5th day, clinical symptoms of polyneuropathy, similar to Guillain-Barre Syndrome, were evident. Plasmapheresis was started on day 10, with immediate improvement of symptoms. Subsequent plasmapheresis was administered on days 16 and 23. The child was discharged after 14 weeks of hospitalization with normal muscle strength, but absent tendon reflexes (Lankosz-Lauterbach et al, 1997).

Abstracts

Case Reports

1) 2,4-D/MCPP: Aggressive behavior, confusion, coma, profound diaphoresis, and hyperthermia were reported in a 39-year-old man who intentionally ingested a large but unknown amount of 10% of 2,4-D and 20% mecoprop (Prescott et al, 1979).
2) 2,4-D/MCPP: In a fatal case, the combined blood level of 2,4-D and MCPP was 71.5 mg/100 mL; a blood level of 66.9 mg/dL had been reported in a prior case (Osterloh, 1983).
3) 2,4-D: In a reported case of 2,4-D ingestion, the patient developed hyperthermia, rhabdomyolysis, and acute tubular necrosis secondary to myoglobinuria (Berwick, 1970).
4) 2,4-D: A 64-year-old woman was found deeply comatose and expired 12 hours after admission for acute 2,4-D ingestion. The significant pathological findings were distinctly edematous lungs with large quantities of edema fluid expressible from cut surfaces.

a) The abdominal and thoracic cavities contained a thin reddish watery fluid. Large quantities of 2,4-D were detected in all samples submitted to the laboratory. Blood level was 72 mg/100 mL (Smith & Lewis, 1987).

5) 2,4-D: A 60-year-old man developed severe gastrointestinal hemorrhage, metabolic acidosis, ventricular tachycardia, and progressive cardiogenic shock and respiratory failure following ingestion of approximately 0.5 liters of solution containing 2,4-D. The patient expired 3 hours after admission despite aggressive treatment with inotropes, ventilatory support, sodium bicarbonate, and other supportive measures (Jorens et al, 1995).
6) MCPP: A 69-year-old man ingested an unknown amount of MCPP and developed muscle cramps and tachypnea within 1 to 2 hours. Mechanical ventilation was required for 7 weeks due to respiratory failure complicated by pulmonary aspiration of gastric contents 5 days postingestion and pulmonary edema.

a) Hypotension developed shortly after admission. Rhabdomyolysis and renal failure subsequently developed and necessitated hemodialysis for 30 days. The patient recovered and was discharged 10 weeks postingestion (Meulenbelt et al, 1988).

7) MCPP: A 70-year-old man ingested an unknown amount of MCPP and was comatose shortly thereafter with muscle cramping and twitching. Prolonged apnea occurred.

a) Laboratory abnormalities included thrombocytopenia (nadir on day 5), decreased white cell count (nadir on day 5), elevated serum LDH (peak 72 hours), hyperkalemia (peak 6.6 mmol/L), elevated CPK (1562 International Units/L at 48 hours), and elevated serum myoglobin. Abrupt hypotension occurred 2 hours post-admission and was followed by anuria.
b) Repeated vomiting occurred for 24 hours postingestion. Recovery was uneventful (Meulenbelt et al, 1988).

8) 2,4-D AMINE: A 61-year-old woman who ingested 37.5 to 50 grams (521 to 694 mg/kg) of 2,4-D amine in an aqueous solution presented with respiratory paralysis, miosis, coma, and hypotension.

a) Laboratory abnormalities included transient hyperkalemia, slight elevation of liver function tests peaking at 36 hours after admission, creatine kinase of 24,092 Units/L peaking the day after admission, and hemoglobinuria.
b) Serum 2,4-D concentrations were measured serially by gas chromatography with a peak of 392 mg/L on the first day.
c) The calculated half-life was 39.5 hours before initiation of alkaline diuresis and 2.7 hours after 30 hours of diuresis. Coma resolved when serum 2,4-D levels decreased to 126 mg/L on the second day. No sequelae were found at 5 weeks after hospital discharge (Friesen et al, 1990).

9) MCPA: A young male patient ingested a massive amount of MCPA and developed oral burning, spasmodic pain in the extremities, and severe hypotension.

a) Plasma MCPA concentration two hours post-ingestion was 546 mg/L. Forced diuresis was said to be ineffective until urine was alkalinized, following which a rapid decrease in plasma levels occurred (Schmoldt et al, 1997).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Limited data are available to determine the lethal dose in humans. In several reported cases the amount ingested is unknown, but blood/serum levels are available (See below).
2) 2,4-D: Human fatalities have been reported after ingestion of amounts ranging from 80 mg/kg to 3 g/kg (McGuigan, 1986; Mullison, 1986; Jorens et al, 1995).
3) Two adults died within 3 days of intentional oral exposure to 2,4-D diethyl ester. One patient ingested 100 grams (the amount ingested was unknown in the second patient) and became drowsy within one hour of ingestion, and soon became restless and incoherent. Despite aggressive supportive care, both patients deteriorated and died of cardiac arrest. Autopsy revealed pulmonary edema and hemorrhage in both patients (Singh et al, 2003).
4) MCPA: The lowest reported oral dose (LDLo) causing a human male fatality was reported to be 814 mg/kg (RTECS , 1999).
5) MCPP: Limited data are available to determine the lethal dose in humans.

a) ADULT CASE: A 37-year-old patient died after ingestion of 20 grams of MCPP and 6.65 grams of ioxynil (Dickey et al, 1988).

6) CASE REPORT: A 37-year-old man developed nausea, vomiting, diarrhea, diaphoresis, tachycardia, tachypnea, and agitation within 8 hours after intentionally ingesting 200 mL of an herbicide containing MCPA 200 g/L and bromoxynil 200 g/L, mixed with a hydrocarbon solvent. Despite supportive care, including continuous veno-venous hemodialysis, his condition deteriorated, with development of hyperthermia with hypotension. Approximately 20 hours post-ingestion, the patient died following development of asystolic cardiac arrest with failed resuscitation. Serum MCPA concentrations obtained 2 hours post-ingestion and 19 hours post-ingestion were 83.9 mcg/mL and 100 mcg/mL, respectively (Berling et al, 2015).

Maximum Tolerated Exposure

1) Limited data are available to determine the toxic doses of these agents. Oral doses of up to 694 milligrams/kilogram have been survived. Intravenous doses of 51 milligrams/kilogram produced symptoms; 28 milligrams/kilogram did not.

1) 2,4-D

a) ADULT CASE (ORAL): A 61-year-old patient ingested between 37.5 and 50 grams (521 to 694 milligrams/kilogram) of 2,4-D amine and developed respiratory paralysis, miosis, coma, hypotension, hyperkalemia, elevated liver functions, elevated CPK, and hemoglobinuria (Friesen et al, 1990). Following treatment with gastrointestinal decontamination, alkaline diuresis, and supportive care, this patient survived without sequelae (Friesen et al, 1990).
b) ADULT CASE (ORAL): Accidental ingestion of 110 milligrams/kilogram of 2,4-D isooctyl ester resulted in twitching and rib muscle paralysis, with recovery (Berwick, 1970).
c) ADULT CASES (PARENTERAL): Parenteral injections of 2,4-D sodium salts were administered to two patients with terminal cases of coccidioidomycosis. Case 1 received 40 mg intramuscular 2,4-D over 4 days without exhibiting any signs of toxicity. Death occurred on the 5th day post Injection, but was not felt to be related to 2,4-D.

1) Case 2 received a total of 12,712 mg 2,4-D parenterally over a period of 34 days. On the 36th day, he received an intravenous dose of 3,600 mg and developed stupor, ataxia, weakness, hyporeflexia and urinary incontinence lasting 24 hours. The patient expired 17 days following the last 2,4-D infusion. Autopsy showed coccidioidomycosis, but no findings related to 2,4-D (Seabury, 1963)

d) Plasma 2,4-D levels in human toxicity cases at the time of observed clinical effects have been reported as 389.6 and 520 mg/L (Dickow et al, 2000).

2) CASE REPORT: A 35-year-old man developed gastrointestinal irritation, miosis, hyperthermia, persistent tachycardia, and muscle weakness, and became comatose (Glasgow Coma Scale score of 3) after ingesting 50 g of a chlorophenoxy herbicide solution, containing 100 g/L of 2,4-D and 400 g/L of MCPP. With aggressive decontamination and supportive care, the patient completely recovered and was discharged approximately 5 days post-ingestion (Berthelot-Moritz et al, 1997).

1) CASE REPORT: A 76-year-old woman presented to the emergency department comatose and with respiratory failure approximately 3 hours after ingesting 100 mL of an herbicide solution containing MCPA. In addition to the presenting symptoms, the patient also developed hypotension and metabolic acidosis, and her urine output decreased to less than 10 mL/hour. Following treatment with continuous renal replacement therapy, norepinephrine, and lipid emulsion therapy, the patient gradually recovered (Hwang et al, 2015).

1) ACCEPTABLE DAILY INTAKE

a) The World Health Organization (WHO) and the Food and Agricultural Organization (FAO) have established an Acceptable Daily Intake (ADI) of 0.3 milligrams/kilogram for 2,4-D (CAST, 1987).

2) NO OBSERVED EFFECT LEVEL: The lifetime NOEL in RATS and MICE is 1 mg/kg per day for 2,4-D (Mullison, 1986). Subchronic studies in mice and rats found a NOAEL of 5 mg/kg/day (Charles et al, 1996b), while dog studies found a NOAEL of 1 mg/kg/day (Charles et al, 1996b).
3) EXPOSURE VIA LAWN CARE

a) OCCUPATIONAL: Studies have shown that properly protected lawn care workers absorb about 100 times less than the Acceptable Daily Intake (ADI) during a 3-week workplace exposure, as measured by urinary excretion (Yeary, 1986).
b) CONSUMER: Approximately 50% of applied 2,4-D can be dislodged from a recently sprayed dry lawn.

1) Based on a dermal absorption rate of 6%, an infant weighing 10 kilograms who rolled on 10 square feet of lawn undressed would receive a dose of 0.02 milligram/kilogram. Measurements of urinary excretion of 2,4-D in exposed children would be needed to confirm this theoretical calculation (CAST, 1987).

c) TREATED LAWN EXPOSURE: It is recommended that entry to treated lawns be avoided for 48 hours under dry conditions and for 24 hours after watering, rainfall, or heavy dew. Inadvertent violations of these recommendations is not a cause for immediate concern in the absence of symptoms (Kelly & Guidotti, 1989/90).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ACUTE

a) SUMMARY

1) COMA: Plasma concentrations greater than 100 milligrams/liter have been associated with coma. Neuromuscular symptoms (stiffness, ataxia, paralysis) may occur at lower levels (Friesen et al, 1990).
2) POSTMORTEM: Fatal case blood levels reported were (all in milligrams/deciliter) 66.9 and 71.5 (Osterloh, 1983), and 72 (Smith & Lewis, 1987).

2) CASE REPORTS

a) 2,4-D and Mixtures:

1) TOXIC LEVELS 2,4-D/MCPP

a) CASE: A combined level of 2,4-D and MCPP in a fatal case was 71.5 milligrams/deciliter (Osterloh, 1983)
b) CASE: A blood level of 72 milligrams/deciliter was seen in a fatal case with coma and pulmonary edema (Smith & Lewis, 1987).
c) CASE: A patient with hemoglobinuria, elevated CPK, hyperkalemia, respiratory paralysis, miosis, coma, and hypotension had a 2,4-D serum concentration (GC method) of 392 milligrams/liter on the first day after ingestion of 37.5 to 50 grams of 2,4-D amine. The coma resolved when the serum level decreased to 126 milligrams/liter (Friesen et al, 1990).
d) A 2,4-D blood level of 192 milligrams/level was reported in a 60-year-old man who ingested approximately 0.5 liters of an agent containing 2,4-D. The patient developed arrhythmias, severe hypotension, and progressive cardiogenic shock, and subsequently died 3 hours after ingestion (Jorens et al, 1995).

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Under Study

1) 2,4-D

a) TLV:

1) TLV-TWA:
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s):
d) Molecular Weight:

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

b) Adopted Value

1) 2,4-D

a) TLV:

1) TLV-TWA: 10 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: Not Listed
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

c) TLV Basis - Critical Effect(s): URT and skin irr
d) Molecular Weight: 221.04

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) ACGIH TLV Values for CAS93-76-5 (American Conference of Governmental Industrial Hygienists, 2010):

a) Adopted Value

1) 2,4,5-T

a) TLV:

1) TLV-TWA: 10 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: Not Listed
3) Definitions:

c) TLV Basis - Critical Effect(s): PNS impair
d) Molecular Weight: 255.49

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

C) ACGIH TLV Values for CAS94-74-6 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

D) ACGIH TLV Values for CAS93-65-2 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

E) NIOSH REL and IDLH Values for CAS94-75-7 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: 2,4-D
2) REL:

a) TWA: 10 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

3) IDLH:

a) IDLH: 100 mg/m3
b) Note(s): Not Listed

F) NIOSH REL and IDLH Values for CAS93-76-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: 2,4,5-T
2) REL:

a) TWA: 10 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

3) IDLH:

a) IDLH: 250 mg/m3
b) Note(s): Not Listed

G) NIOSH REL and IDLH Values for CAS94-74-6 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

H) NIOSH REL and IDLH Values for CAS93-65-2 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

I) Carcinogenicity Ratings for CAS94-75-7 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: 2,4-D
2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: 2,4-D

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

3) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 2,4-Dichlorophenoxyacetic acid (2,4-D)
4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: 2,4-D
6) MAK (DFG, 2002): Not Listed
7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

J) Carcinogenicity Ratings for CAS93-76-5 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: 2,4,5-T

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T)
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: 2,4,5-T
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

K) Carcinogenicity Ratings for CAS94-74-6 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 2-Methyl-4-chlorophenoxyacetic acid (MCPA)
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

L) Carcinogenicity Ratings for CAS93-65-2 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 2-(2-Methyl-4-chlorophenoxy)propionic acid (MCPP)
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

M) OSHA PEL Values for CAS94-75-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: 2,4-D (Dichlorophenoxyacetic acid)
2) Table Z-1 for 2,4-D (Dichlorophenoxyacetic acid):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 10

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

N) OSHA PEL Values for CAS93-76-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: 2,4,5-T (2,4,5-trichlorophenoxyacetic acid)
2) Table Z-1 for 2,4,5-T (2,4,5-trichlorophenoxyacetic acid):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 10

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

O) OSHA PEL Values for CAS94-74-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

P) OSHA PEL Values for CAS93-65-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) 2,4,5-T

1) LD50- (ORAL)MOUSE:

a) 242 mg/kg (RTECS, 2004)

2) LD50- (ORAL)RAT:

a) 300 mg/kg (RTECS, 2004)

3) LD50- (SKIN)RAT:

a) 1535 mg/kg (RTECS, 2004)

B) 2,4-D

1) LD50- (ORAL)MOUSE:

a) 347 mg/kg (RTECS, 2004)

2) LD50- (INTRAPERITONEAL)RAT:

a) 666 mg/kg: spastic paralysis with or without sensory change, muscle weakness, coma (RTECS, 2004)

3) LD50- (ORAL)RAT:

a) 375 mg/kg (RTECS, 2004)
b) 3670 mg/kg for 18 hours (RTECS, 2004)

C) MCPA

1) LD50- (ORAL)MOUSE:

a) 439 mg/kg (RTECS, 2004)

2) LD50- (INHALATION)RAT:

a) 1370 mg/m(3) for 4 hours: somnolence, ataxia, dyspnea(RTECS, 2004)

3) LD50- (ORAL)RAT:

a) 700 mg/kg (RTECS, 2004)

D) MCPP

1) LD50- (ORAL)MOUSE:

a) 369 mg/kg (RTECS, 1999)

2) LD50- (INTRAPERITONEAL)RAT:

a) 402 mg/kg (RTECS, 2004)

3) LD50- (ORAL)RAT:

a) 650 mg/kg (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) ACUTE OVERDOSE - 2,4-D doses of 50 mg/kg orally produced myotonia, muscle stiffness, and lethargy lasting up to 3 days (Steiss et al, 1987).
B) LAWN EXPOSURE - Doses of 10 mL/kg orally of a fertilizer/herbicide combination delivering 6.5 mg/kg of 2,4-D, 3.26 mg/kg of MCPP, and 0.55 mg/kg of dicamba did not produce clinical illness.

1) This is the equivalent of an 8 kg dog ingesting the total amount applied to a 0.5 square meter area.
2) Since only 50% of lawn solutions or granules remain on the grass, and since dogs rarely eat more than 5 to 10 grams of grass, it is unlikely that symptoms would develop from this type of exposure (Yeary, 1984).

C) LIVER INJURY has been attributed to exposure to 2,4-D (Seabury, 1963; Drill & Hiratzka, 1953).
D) LYMPHOMA - A retrospective case control study of 588 canine patients and 583 controls found a weak association between the combined use of owner application of 2,4-D plus employment of a commercial lawn service and malignant lymphoma (odds ratio = 1.9; confidence interval 0.88 to 4.14).

1) No association was found with sole use of either owner application or lawn service.
2) Increased risk was also found for the subset of dogs exposed to 4 or more owner applications per year (odds ratio 2.0) (Hayes et al, 1991).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
4) ASPCA ANIMAL POISON CONTROL CENTER

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

5) SMALL ANIMALS: Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only.
6) In the case of a poisoning involving large animals, consult a veterinary poison control center.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE -

1) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
2) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
3) DOGS AND CATS

a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

4) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.

a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL/CATHARTIC -

1) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
2) CATHARTIC: Administer a dose of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

11.2.5)

A) GENERAL TREATMENT

1) VITAL FUNCTION -

a) MAINTAIN VITAL FUNCTIONS - as necessary.

2) LABORATORY -

a) This agent may cause hepatotoxicity. Monitoring liver function tests is suggested for patients with significant exposure.

3) SUPPORTIVE CARE -

a) Begin electrolyte and fluid therapy with isotonic solutions as needed at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.

4) MONITORING -

a) Admit all symptomatic patients and begin treatment.
b) Unless life threatening signs develop, these patients may be kept in the primary care clinic (24 hour monitoring is not necessary).

5) FOLLOW-UP -

a) Instruct the owner to return for a follow up appointment at which physical examination and appropriate laboratory tests will be repeated.

Range Of Toxicity

11.3.2)

A) DOG

1) Oral administration of up to 125 milligrams per kilogram to adult dogs did not result in lethality (Steiss et al, 1987).
2) Chronic administration of up to 500 ppm of 2,4-D in the diet for 2 years did not result in any adverse effects (Hansen et al, 1971).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE -

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

4) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.

a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL/CATHARTIC -

Kinetics

11.5.1)

A) LACK OF INFORMATION

1) There was no specific information on absorption at the time of this review.

11.5.2)

A) DOG

1) A dose of 5 mg/kg of 2,4,5-T resulted in a mean volume of distribution of 0.221 L/kg (Piper et al, 1973).

11.5.3)

A) GENERAL

1) MAMMALS - Phenoxy acid esters and salts are primarily metabolized by acid hydrolysis, and a minor amount is conjugated (Arnold & Beasley, 1989).

References

General Bibliography

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CHLOROPHENOXY COMPOUNDS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

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Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

General Bibliography