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PICLORAM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Picloram is a defoliant and herbicide used especially to control broadleaf and wood plants (Hayes & Laws, 1991; ACGIH, 1991a; IARC, 1991).

Specific Substances

    1) Amdon
    2) Amdon grazon
    3) ATCP
    4) Borolin
    5) Grazon
    6) K-Pin
    7) NCI-C00237
    8) Tordon
    9) 2-Pyridinecarboxylic acid, 4amino-3,5,6-trichloro-
    10) 2,5,6-Trichloro-4-aminopicolinic acid
    11) 4-Amino-3,5,6-trichloro-2-picolinic acid
    12) 4-Amino-3,5,6-trichloropicolinic acid
    13) 4-amino-3,5,6-trichlorpicolinsaeure (German)
    14) C6-H3-Cl3-N2-O2
    15) 4-amino-3,5,6-trichloropicolinic acid
    16) Chloramp
    17) CAS 1918-02-1
    18) NIOSH/RTECS TJ 7525000
    19) NCI-c 00237
    1.2.1) MOLECULAR FORMULA
    1) C6-H3-Cl3-N2-O2

Available Forms Sources

    A) FORMS
    1) Picloram is available in granules, pellets, aqueous concentrates, water-soluble liquid mixtures, and technical grades (ACGIH, 1991a; Hartley & Kidd, 1990a; Hayes & Laws, 1991; HSDB , 2002).
    2) Trade name picloram mixtures (Tordon 101 and Tordon RTU) often contain 2,4-dichlorophenoxyacetic acid (ACGIH, 1991a; Hayes & Laws, 1991; HSDB , 2002).
    B) SOURCES
    1) Picloram is produced by "chlorination of 2-methylpyridine, hydrolysis, and reaction with ammonia" (HSDB , 2002).
    2) Chlorine, ammonia, and alpha-picoline are used to produce picloram through a process of chlorination, ammoniation and acid-catalyzed hydrolysis (Ashford, 1994).
    3) Picloram liquid concentration ranges from 0.25-2.0 pounds of acid equivalent per gallon. The pellet formulations contain 2-10% acid equivalent by weight (EPA, 1990a).
    C) USES
    1) Picloram is used mainly as a defoliant and systemic herbicide to control annual and perennial broadleaf and woody plants. It may also be used as a flow stimulant for natural rubber and pine gum. Extremely low dosages of picloram may act as a growth regulator on certain fruits (ACGIH, 1991a; Ashford, 1994; Harbison, 1998; Hartley & Kidd, 1990a; HSDB , 2002; Lewis, 1997a; Lewis, 1998).
    2) Picloram is sold for non-crop use in broadleaf control along utility rights-of-way, in pastures, forestland, rangeland, and some grains (Harbison, 1998; HSDB , 2002; IARC, 1991).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Human overdose exposure data are limited. Nausea may occur following exposure to massive amounts. Its low vapor pressure makes inhalation toxicity unlikely. Picloram is not reported to be a sensitizer. The dust may be irritating to the eyes, skin, nose, throat and respiratory tract. Corneal injury is unlikely. Picloram has poor dermal absorption, but is rapidly absorbed from the gastrointestinal tract. It is cleared swiftly via the kidneys with >90% of the absorbed dose excreted unchanged in the urine. Systemic toxicity is thought to be low.
    B) Experimental animal exposures have produced skin rashes, hair loss, tachycardia, ataxia, diarrhea, leukopenia, vaginal bleeding, prostration, seizures, and liver and kidney lesions.
    C) IARC has classified picloram as not classifiable as to its carcinogenicity to humans (Group 3). Mutations have been observed in microorganisms. Developmental abnormalities have been noted in experimental animals.
    0.2.4) HEENT
    A) Eye irritation may occur with exposure to picloram.
    0.2.6) RESPIRATORY
    A) Picloram dust is irritating to the respiratory tract.
    0.2.7) NEUROLOGIC
    A) Although seizures have not been reported in humans, seizures have developed in animals exposed to fatal amounts.
    0.2.8) GASTROINTESTINAL
    A) Nausea is possible after ingestion of massive amounts of picloram.
    B) Picloram is rapidly absorbed from the gastrointestinal tract.
    0.2.13) HEMATOLOGIC
    A) Leucocyte levels may decrease.
    0.2.14) DERMATOLOGIC
    A) Picloram is mildly irritating to skin.
    B) Picloram is absorbed slowly through the skin.
    0.2.20) REPRODUCTIVE
    A) No teratogenicity was observed in several studies. However, there are reports that Tordon 202c (a picloram and 2,4-D combination herbicide) showed teratogenesis and fetal growth depression in mice by paternal exposure and combined preconceptional and gestational exposure.

Laboratory Monitoring

    A) No toxic levels have been established. The limits of detection are about 10 ng/mL.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) No specific treatment is recommended. Treatment is symptomatic and supportive. Seizures were observed in fatally poisoned animals, but have not been reported in humans.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    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. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Human volunteers have ingested 5 mg/kg without adverse effects.

Clinical Effects

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS1918-02-1 (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) IARC Classification
    a) Listed as: Picloram
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available from studies in humans (HSDB , 2000). Picloram is considered not classifiable as a human carcinogen (IARC, 1991; ACGIH, 2000).
    3.21.4) ANIMAL STUDIES
    A) CARCINOGENICITY RISK
    1) Picloram has shown limited evidence of carcinogenicity in experimental animals (ACGIH, 1991); it is considered carcinogenic by RTECS criteria (RTECS , 2000).
    B) CARCINOMA
    1) Rats and mice given 7,437 or 14,875 (rats) or 2,531 or 5,062 ppm (mice) for 80 weeks developed no carcinogenic changes (ACGIH, 1981) Robens, 1980).
    2) When the data from the National Cancer Institute study were reviewed by Reuber (1981), he found multiple neoplasms in the tissue samples examined, including pituitrary, thyroid, mammary and adrenal tumors. Further studies are needed to confirm or negate picloram's carcinogenic potential.
    3) Sax (1984) stated that carcinogenicity studies were positive in rats but negative in the mouse. Other negative studies include those by Lynn (1965) and McCollister & Leng (1969); Stott et al (1990) showed no increase in the rate of tumor development or incidence of tumor types.

Genotoxicity

    A) Picloram showed no evidence of genotoxicity in humans and only one positive result in other species, in a forward mutation test in Streptomyces coelicolor.

Summary Of Exposure

    A) Human overdose exposure data are limited. Nausea may occur following exposure to massive amounts. Its low vapor pressure makes inhalation toxicity unlikely. Picloram is not reported to be a sensitizer. The dust may be irritating to the eyes, skin, nose, throat and respiratory tract. Corneal injury is unlikely. Picloram has poor dermal absorption, but is rapidly absorbed from the gastrointestinal tract. It is cleared swiftly via the kidneys with >90% of the absorbed dose excreted unchanged in the urine. Systemic toxicity is thought to be low.
    B) Experimental animal exposures have produced skin rashes, hair loss, tachycardia, ataxia, diarrhea, leukopenia, vaginal bleeding, prostration, seizures, and liver and kidney lesions.
    C) IARC has classified picloram as not classifiable as to its carcinogenicity to humans (Group 3). Mutations have been observed in microorganisms. Developmental abnormalities have been noted in experimental animals.

Heent

    3.4.1) SUMMARY
    A) Eye irritation may occur with exposure to picloram.
    3.4.3) EYES
    A) Picloram induces moderate eye irritation without corneal damage, which heals readily (Hayes & Lawes, 1991; (HSDB , 2000).
    3.4.5) NOSE
    A) Picloram is irritating to the nose (Sittig, 1991).
    3.4.6) THROAT
    A) Picloram is irritating to the throat (Sittig, 1991).

Respiratory

    3.6.1) SUMMARY
    A) Picloram dust is irritating to the respiratory tract.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Picloram is mildly irritating to the respiratory tract, especially as dust, but is unlikely to cause illness (Morgan, 1993; HSDB , 2000).

Neurologic

    3.7.1) SUMMARY
    A) Although seizures have not been reported in humans, seizures have developed in animals exposed to fatal amounts.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures were the primary cause of death in acutely poisoned animals; these animals also had ataxia and tremors (Hayes et al, 1986). Seizures have NOT been reported in human overdose cases. Seizures should prompt suspicion of mixed poisoning, head injury, or cerebral anoxia.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea is possible after ingestion of massive amounts of picloram.
    B) Picloram is rapidly absorbed from the gastrointestinal tract.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) After a massive ingestion of picloram, nausea is possible (HSDB , 2000).
    B) INTESTINAL ABSORPTION
    1) Picloram is rapidly absorbed from the gastrointestinal tract (Hayes & Lawes, 1991).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VOMITIING
    a) High doses of picloram given to beagles produced vomiting and weight loss (ACGIH, 1991).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Animals fatally exposed developed nonspecific liver lesions.
    b) Fatally exposed rats developed nonspecific liver lesions (Hayes et al, 1986) or moderate liver changes (ACGIH, 1991). Picloram seemed to exacerbate hepatic lesions commonly found in rats of the tested age.
    c) Dietary picloram exposure produced centrolobar hepatocellular hypertrophy and increased liver weight in rats (ACGIH, 1991).

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Animals fatally exposed developed nonspecific kidney lesions.
    b) Fatally exposed rats developed nonspecific kidney lesions (Hayes et al, 1986), or moderate kidney changes (ACGIH, 1991).

Hematologic

    3.13.1) SUMMARY
    A) Leucocyte levels may decrease.
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LEUKOPENIA
    a) RATS given 0.1 to 0.01% picloram in their diet had a slight fall in leucocytes (Suschetet & Causeret, 1973) Suchetet et al, 1974).

Dermatologic

    3.14.1) SUMMARY
    A) Picloram is mildly irritating to skin.
    B) Picloram is absorbed slowly through the skin.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Picloram may cause mild skin irritation (HSDB , 2000). It is not known as a skin sensitizer to humans
    B) POISONING
    1) Picloram is absorbed slowly through the skin (Hayes & Lawes, 1991).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RASH
    a) Feeding rats and mice doses of 7,400 ppm or 14,000 ppm for 80 weeks produced an increased incidence of skin rashes and hair loss (National Cancer Institute, 1978).

Reproductive

    3.20.1) SUMMARY
    A) No teratogenicity was observed in several studies. However, there are reports that Tordon 202c (a picloram and 2,4-D combination herbicide) showed teratogenesis and fetal growth depression in mice by paternal exposure and combined preconceptional and gestational exposure.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Blakley et al (1989) studied Tordon 202c (a picloram and 2,4-D combination) paternal exposure in male mice and the combined preconceptional and gestational exposure in females.
    2) Teratogenesis and fetal growth depression resulted after feeding with the drinking water at 0.12, 0.42, and 0.84 percent for 60 days in males prior to mating with untreated virgin female in the prenatal toxicity test and/or in females prior to mating with untreated males and subsequently continuing treatment to pregnant females throughout gestation in the combined test.
    3) Malformed fetuses and a decrease in fertility were reported (Harbison, 1998).
    B) LACK OF EFFECT
    1) Picloram alone has not been shown to produce a teratogenic effect (Harbison, 1998).
    2) No teratogenicity was seen in a study by Thompson et al (1972) done on rats, up to doses of 1000 mg/kg/day. This dose; however, resulted in a 40 percent mortality in the pregnant rats. NO neonatal adverse effects were noted (HSDB , 2000).
    3) Rats given 0.3 percent (3000 ppm) in their diet developed NO adverse fertility, reproduction, or lactation effects (ACGIH, 1991).
    4) John-Greene et al (1985) tested pregnant rabbits at doses of 40, 200, and 400 mg picloram/kg on day 6 to 18 of gestation. No dose-related embryotoxic or teratogenic effects were observed.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No toxic levels have been established. The limits of detection are about 10 ng/mL.

Methods

    A) CHROMATOGRAPHY
    1) Picloram in whole blood can be quantified using gas chromatography. The limits of detection are about 10 ng/mL (Nolan et al, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) No toxic levels have been established. The limits of detection are about 10 ng/mL.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) 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
    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) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) No specific treatment is recommended. Treatment is symptomatic and supportive. Seizures were observed in fatally poisoned animals.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    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.

Eye Exposure

    6.8.1) DECONTAMINATION
    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) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) DECONTAMINATION
    1) Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Human volunteers have ingested 5 mg/kg without adverse effects.

Minimum Lethal Exposure

    A) HUMAN DATA
    1) The minimum lethal human dose to this agent has not been delineated.
    B) ANIMAL DATA
    1) Lethality occurred in 4 of 20 male and 2 of 20 female rats given 600 mg/kg of potassium picloram in a 90-day drinking water study. A dose of 1070 mg/kg in this study was lethal to 9 of 10 male and 7 of 10 female rats (ACGIH, 1991).
    2) Approximately one g/kg of picloram is a lethal oral dose for rats (ACGIH, 1991; Hayes & Laws, 1991).
    3) Picloram at 36 mg/kg combined with 2,4-D at 134 mg/kg resulted in livestock fatalities (HSDB , 2002).

Maximum Tolerated Exposure

    A) HUMAN DATA
    1) Volunteers receiving a dermal application of a 5% aqueous picloram solution experienced no skin sensitization (ACGIH, 1991).
    B) LACK OF EFFECT
    1) HUMAN DATA
    a) Six male volunteers ingested 0.5 or 5 mg/kg picloram dissolved in grape juice with no observed adverse effects (ACGIH, 1991).
    2) ANIMAL DATA
    a) No adverse effects were observed in rats and dogs with lifetime exposure to a daily oral dose of 150 mg/kg of picloram (HSDB , 2002).
    b) Multi-generational rat studies revealed no adverse effects resulting from oral exposure to picloram concentrations up to 3000 ppm (HSDB , 2002).
    c) No signs of toxicity were observed in rats exposed by inhalation to 150 mg/L for 15 days (HSDB , 2002).
    d) Single doses of picloram at 720 mg/kg did not result in overt toxic signs in sheep (HSDB , 2002).
    e) In a 2-year feeding trial, rats did not experience any effects of picloram at 150 mg/kg per day (Hartley & Kidd, 1990).
    f) No fatalities occurred when 4000 mg/kg of picloram was applied to the skin of rabbits (Hayes & Laws, 1991).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Toxic concentrations are unknown. In humans given 5.0 and 0.5 milligrams/kilogram orally, the mean blood picloram concentrations were 3.6 and 0.33 micrograms/milliliter respectively, one hour postingestion (Nolan et al, 1984).

Workplace Standards

    A) ACGIH TLV Values for CAS1918-02-1 (American Conference of Governmental Industrial Hygienists, 2010):
    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) Adopted Value
    1) Picloram
    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): Liver and kidney dam
    d) Molecular Weight: 241.48
    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) NIOSH REL and IDLH Values for CAS1918-02-1 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Picloram
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix D
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS1918-02-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Picloram
    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: Picloram
    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): 3 ; Listed as: Picloram
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Picloram
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS1918-02-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Picloram (Total dust)
    2) Table Z-1 for Picloram (Total dust):
    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: 15
    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
    3) Listed as: Picloram (Respirable fraction)
    4) Table Z-1 for Picloram (Respirable fraction):
    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: 5
    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

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ACGIH, 1991 Budavari, 2000 Hartley & Kidd, 1990 Hayes & Laws, 1991 HSDB, 2002 Lewis, 2000 RTECS, 2002 Verschueren, 2001
    1) LD50- (ORAL)MOUSE:
    a) 1061 mg/kg (Lewis, 2000)
    b) 1060 mg/kg (Verschueren, 2001)
    c) 2.0-4.0 g/kg (ACGIH, 1991)
    d) 2000-4000 mg/kg (Budavari, 2000; Hartley & Kidd, 1990; Hayes & Law, 1991)
    2) LD50- (ORAL)RAT:
    a) 8200 mg/kg
    b) 2898 mg/kg (Lewis, 2000)
    c) 2900 mg/kg (Verschueren, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) PLANTS -
    1) Picloram replaces the plant growth regulator indoleacetic acid and inhibits plant protein synthesis (Hamaker et al, 1963). It may persist in the environment for some time (Dennis et al, 1977).

Physicochemical

Physical Characteristics

    A) Picloram is a damp colorless to white, or off-white to brown crystalline solid or powder with a chlorine-like odor. The low vapor pressure makes it unlikely that vapors can be inhaled. At 190 degrees C under 12 mmHg, picloram will sublime. It is stable to alkalis and acids, but in hot alkalis it will decompose. Picloram readily forms water-soluble alkali-metal and amine salts (ACGIH, 1991; Budavari, 2000; EPA, 1990; Harbison, 1998; Hartley & Kidd, 1990; HSDB , 2002; NIOSH , 2002).
    B) Technical grades of picloram are off white to brown in color (HSDB , 2002).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 241.46

Animal Toxicology

Clinical Effects

    11.1.9) OVINE/SHEEP
    A) ADENOCARCINOMAS - A small increase in small intestine adenocarcinomas was seen in sheep in one study (Newell et al, 1984).

References

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