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PYRETHRINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pyrethrins are natural botanical insecticides extracted from the plant and dried flowers of Chrysanthemum spp., primarily C. cinerafolium. Pyrethrins are widely used for human and animal protection against indoor pest insects, such as cockroaches, flies, and mosquitoes.
    B) Pyrethrin I and II, cineron I and II, and jasmolin I and II are the main active principles of pyrethrum (the crude extract); these active constituents are often referred to collectively as PYRETHRINS. Pyrethrin I has potent insect killing properties while pyrethrin II causes rapid "knockdown" of insects.
    C) Pyrethrin-containing plants like Chrysanthemum cinerafolium allergenics, which may cause sneezing, rhinitis, coughing, and exacerbate symptoms of asthma. They are not considered toxic unless consumed in large quantities. Ingestion of the flower heads in large quantities may cause nausea, vomiting, and numbness of lips and tongue. Dermitis with pruritus and skin eruptions may result upon dermal contact with the plant.

Specific Substances

    A) CINERIN I
    1) C20H28O3
    2) 069010 (EPA)
    3) GZ1540000 (NIOSH)
    4) Chrysanthamummonocarboxylic acid, cinerolone ester
    5) Crysanthemummonocarboxilic acid, 3-(2-butenyl)-2-methyl-4-oxo-2- cyclopenten-1-yl ester
    6) Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methylpropenyl)-, ester with 2-(2-butenyl)-4- hydroxy-3-methyl-2-cyclopenten-1-one (TSCA)
    7) Cinerolone, chrysanthamummonocarboxylic acid ester
    8) Cinerolone ester of chrysanthemic acid
    9) CAS 25402-06-6
    CINERIN II
    1) C21H28O5
    2) 069009 (EPA)
    3) Cinerolone ester of pyrethric acid
    4) CAS 121-20-0
    CINEROLONE
    1) C10H14O2
    2) 2-Cyclopenten-1-one
    3) Cinerolon
    4) CAS 17190-74-8
    CYCLETHRIN
    1) C21H28O3
    2) GZ1575000 (NIOSH)
    3) Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methylpropenyl)-, ester with 2-(2-cyclopenten- 1-yl)-4-hydroxy-3-methyl-2-cyclopenten-1-one
    4) Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methylpropenyl)-, ester with 2-(2-cyclopenten- 1-yl)-4-hydroxy-3-methyl-2-cyclopenten-1-one
    5) Beilstein Reference Number: BRN 2672684
    6) Molecular Weight: 328.49
    7) CAS 97-11-0
    JASMOLIN I
    1) C21H30O3
    2) Jasmoline ester of chrysanthemic acid
    3) Jasmoline I
    4) CAS 4466-14-2
    JASMOLIN II
    1) C22H30O5
    2) Jasmoline ester of pyrethric acid
    3) CAS 1172-63-0
    PYRETHRIN
    1) C18H22O5
    2) CAS 88108-26-3
    PYRETHRINS
    1) 069001 (EPA)
    2) CAS 8003-34-7
    PYRETHRIN I
    1) C21H28O3
    2) 069001 (EPA)
    3) 3-09-00-00215 (Beilstein Handbook Reference)
    4) BRN 2004306
    5) GZ1725000 (NIOSH)
    6) 4963868, 4963872, 4963877, 4963881, 4963881, 4963886 (STCC)
    7) Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methylpropenyl)-, ester with 4-hydroxy-3-methyl-2-(2,4-pentadienyl)-2-cyclopenten-1-one
    8) Cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methylpropenyl)-, ester with 4-hydroxy-3- methyl-2-(2,4-pentadienyl)-2-cyclopenten-1-one (RTECS)
    9) Chrysanthemum monocarboxylic acid pyrethrolone ester
    10) Piretrina 1 (Portuguese)
    11) Pyrethrolone, chrysanthemum monocarboxylic acid ester
    12) Pyrethrolone ester of chrysanthemic acid
    13) (+)-Prethronyl (+)-trans-chrysanthemate
    14) CAS 121-21-1
    PYRETHRIN II
    1) C22H28O5
    2) 069006 (EPA)
    3) GZ0700000 (NIOSH)
    4) 4963872 (STCC)
    5) Cyclopropanecarboxylic acid, 3-[(1E)-3-methoxy-2-methyl-3-oxo-1-propenyl]-2,2-dimethyl-, (1S)-2-methyl-4-oxo-3-(2Z)-2,4-pentadienyl-2-cyclopenten-1-yl ester, (1R,3R) (TSCA)
    6) Cyclopropaneacrylic acid, 3-carboxy-alpha,2,2-Trimethyl-, 1-methyl ester, ester with 4-hydroxy-3-methyl-2-(2,4-pentadienyl)-2-cyclopenten-1-one
    7) Chrysanthemumdicarboxylic acid monomethyl ester pyrethrolone ester
    8) Pyrethrolone, chrysanthemum dicarboxlic acid methyl ester ester
    9) Pyrethrolone ester of chrsanthemumdicarboxylic acid monomethyl ester
    10) Pyrethrolone ester of pyrethric acid
    11) CAS 121-29-9
    PYRETHROLONE
    1) C11H14O2
    2) Pyrethrolon
    3) CAS 487-67-2
    PYRETHRUM
    1) C21H28O3
    2) C22H28O5
    3) 069007 (EPA)
    4) UR4200000 (NIOSH)
    5) Pyrethrum powder
    6) Pyrethrum marc
    7) Pyrethrum (insecticide)
    8) Pyrethrum extract
    9) Pyrethrum flowers
    10) Pyrethrum, pyrethrins, pyrethroids
    11) Pyrethrins and pyrethroids
    12) Pyrethrins
    13) CAS 8003-34-7
    GENERAL TERMS
    1) Anacyclus pyrethrum (India herb)
    2) Botanical insecticide
    3) Chrysanthenum dicarboxlic acid methyl ester
    4) Chrysanthemum monocarboxylic acid pyrethrolone ester
    5) Cinerin 1 allyl homolog
    6) Cinerin I or II
    7) Crysanthemum
    8) Cycklethrin
    9) Cyclopentenylrethonyl chrysanthemate
    10) Dalmation insect flowers
    11) Dalmation-insect powder
    12) Insect powder
    13) Jasmolin I or II
    14) Pallethrine
    15) Persian insect powder
    16) Piretrina 1 (Portuguese)
    17) Pynamin
    18) Pyresin
    19) Pyrethrin 1
    20) Pyrethrin 2
    21) Pyrethrin I or II
    22) Pyrethrin
    23) Pyrethrins
    24) Pyrethrolone, chrysanthemum monocarboxylic acid ester
    25) Pyrethrolone ester of chrsanthemumdicarboxylic acid-monomethyl ester
    26) Pyretrin II
    27) Pyrprethrin
    28) Trieste flowers
    CHRYSANTHEMUM SPECIES
    1) Chrysanthemum cinerareaefolium
    2) Chrysanthemum coccineum (painted daisy)

    1.2.1) MOLECULAR FORMULA
    1) Cinerin I: C20H28O3
    2) Cinerin II: C21H28O5
    3) Jasmolin I: C21H30O3
    4) Jasmolin II: C22H30O5
    5) Pyrethrin I: C21H28O3
    6) Pyrethrin II: C22H28O5

Available Forms Sources

    A) FORMS
    1) Pyethrin-pyrethroid insecticides are commonly extracted in petroleum distillates (kerosene, acetone, alcohol, ethylene dichloride) for use as household sprays or dusts. They usually contain synergists (piperonyl butoxide) and some are marketed in cans pressurized by propellants (HSDB, 2006; Meister, 2003).
    2) Pyrethrum is a mixture of cinerin, jasmolin, and pyrethrin at varying concentrations. The standardized pyrethrum extract is 45-55% w/w total pyrethrins (NIOSH, 2006; Krieger, 2001).
    3) Pyrethrin I and II are esters of chrysanthemic and pyrethric acids, respectively. They are formed from three keto alcohols: pyrethrolone, cinerolone, and jasmolone (HSDB, 2006; Agency for Toxic Substances and Disease Registry (ATSDR), 2003).
    4) Pyrethrins are generally brown or tan in color. Their various physical forms include viscous liquid (pyrethrin I and II, cinerin II), viscous oil (cinerin II), solid, and dust (HSDB, 2006; NIOSH, 2006; Pohanish, 2002; Krieger, 2001; Lewis, 2001).
    5) Pyrethrum's unrefined extract is a mobile oil; the refined extract is a liquid. Its color ranges from an unrefined dark greenish brown to a refined pale yellow. The powdered ground flowers are tan (HSDB, 2006).
    B) SOURCES
    1) Pyrethrins are botanical insecticides obtained by grinding flowers of Chrysanthemum cinerariifolium. Pyrethrum refers to the crude extract obtained from the flowers. The dried flowers contain approximately 0.9-1.3% pyrethrins (Meister, 2003).
    2) The chrysanthemum plant (C. cinerariifolium) and its flowers are the source of the active insecticidal principles: pyrethrin I and II, cinerin I and II, and jasmolin I and II. Other active constituents include the chemicals syrethrolone and cineroline (HSDB, 2006; Meister, 2003; Tech Info, 1986).
    3) The chrysanthemum flowers for producing pyrethrins are native to Kenya, Ecuador, Rwanda, Tanzania, and Japan (HSDB, 2006; Meister, 2003).
    C) USES
    1) Pyrethrum extracts are chiefly used as a residential insecticide because of their safety. Household formulations typically contain about 0.5% active pyrethrum. Constituents of the insecticidal extract are collectively termed "pyrethrins" or "natural pyrethrins" (HSDB, 2006; Ray, 1991; Proctor et al, 1988).
    2) Pyrethrins are used in human and veterinary medicine to treat lice and flea infestations (HSDB, 2006; Proudfoot, 2005).
    3) Pyrethrum extracts are used extensively in stock sprays, aerosols, and in industrial sanitation sprays for protecting stored food in warehouses and treating paper bags used in shipping cereals (HSDB, 2006).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pyrethrins are naturally occurring compounds produced by chrysanthemums. Pyrethrins are used as insecticides to treat parasitic infections such as scabies and lice. Pyrethroids are synthetic chemicals that are structurally similar to pyrethrins. Pyrethrin-pyrethroid combination insecticides are commonly mixed with petroleum distillates (kerosene, acetone, alcohol, ethylene dichloride) for use as household sprays or dusts. They usually contain synergists (piperonyl butoxide) and some are marketed in cans pressurized by propellants. Please refer to "PYRETHROIDS" management for more information.
    B) TOXICOLOGY: Pyrethrins bind voltage-gated sodium channels preferentially in the open state allowing sodium influx, prolonged axonal firing, with repetitive stimuli and eventual muscle paralysis. Piperonyl butoxide and other compounds are often added to pyrethrin insecticides as synergists and may contribute to toxicity.
    C) EPIDEMIOLOGY: Exposures to pyrethrins are common, but significant toxicity is very rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Dermal exposure can cause mild erythematous dermatitis with vesicles, papules in moist areas, and intense pruritus; a bulbous dermatitis may also occur. Pyrethrins can cause allergic dermatitis. Ocular exposure can cause irritation. Inhalation exposure can cause congestion, rhinorrhea and other upper respiratory symptoms, headaches, paresthesia, and dizziness. Ingestion commonly cause nausea, vomiting, and abdominal pain.
    2) SEVERE TOXICITY: Severe asthma exacerbations and anaphylaxis have been reported, and can be fatal. Seizures are a rare manifestation of severe poisoning. Severe corneal injury can occur from ocular exposure.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no reproductive studies were found for pyrethrum in humans.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the potential carcinogenic activity of pyrethrum in humans.

Laboratory Monitoring

    A) Pyrethrin plasma concentrations are not clinically useful or readily available.
    B) Monitor vital signs and mental status.
    C) Monitor for allergic responses such as asthma or contact dermatitis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat vomiting with antiemetics.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Administer IV fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat bronchospasm with inhaled beta-2 agonists and corticosteroids. Monitor for and treat anaphylaxis.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not indicated; minor exposures generally do not cause toxicity and large ingestions can cause seizures with the risk of aspiration. Wash exposed skin and remove contaminated clothing. Irrigate exposed eyes.
    2) HOSPITAL: Gastrointestinal decontamination is not required for small ingestions. For large ingestions, the risk of aspiration may outweigh the benefits, and GI decontamination is not routinely recommended. Wash exposed skin and remove contaminated clothing. Irrigate exposed eyes.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress, persistent seizures, or severe acute allergic reaction.
    E) ANTIDOTE
    1) None
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Most unintentional exposures in patients who are asymptomatic may be watched at home.
    2) OBSERVATION CRITERIA: Patients with deliberate exposure, and those with more than mild symptoms or any evidence of bronchospasm or acute allergic reaction should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate supportive care may require admission.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) Failure to recognize that a product may contain pyrethrins and other more dangerous insecticides.
    I) PHARMACOKINETICS
    1) Well absorbed orally and via inhalation. These compounds are lipophilic and rapidly distribute to the CNS. They are then rapidly metabolized by human microsomal enzymes and thus do not accumulate in significant amounts. Then the parent compound and metabolites are eliminated renally.
    J) DIFFERENTIAL DIAGNOSIS
    1) Irritating gas exposures such as chlorine and chloramine. Also can mimic substances that can trigger bronchospasm especially in asthmatic patients.
    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).
    2) Vitamin E topical application is highly effective in relieving paresthesias.

Range Of Toxicity

    A) TOXICITY: The minimal lethal dose of pyrethrins is not established, but is probably in the range of 10 to 100 grams. THERAPEUTIC DOSE: RID lice killing shampoo contains pyrethrum extract (equivalent to 0.33% pyrethrins), applied for 10 minutes.

Clinical Effects

Summary Of Exposure

    A) USES: Pyrethrins are naturally occurring compounds produced by chrysanthemums. Pyrethrins are used as insecticides to treat parasitic infections such as scabies and lice. Pyrethroids are synthetic chemicals that are structurally similar to pyrethrins. Pyrethrin-pyrethroid combination insecticides are commonly mixed with petroleum distillates (kerosene, acetone, alcohol, ethylene dichloride) for use as household sprays or dusts. They usually contain synergists (piperonyl butoxide) and some are marketed in cans pressurized by propellants. Please refer to "PYRETHROIDS" management for more information.
    B) TOXICOLOGY: Pyrethrins bind voltage-gated sodium channels preferentially in the open state allowing sodium influx, prolonged axonal firing, with repetitive stimuli and eventual muscle paralysis. Piperonyl butoxide and other compounds are often added to pyrethrin insecticides as synergists and may contribute to toxicity.
    C) EPIDEMIOLOGY: Exposures to pyrethrins are common, but significant toxicity is very rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Dermal exposure can cause mild erythematous dermatitis with vesicles, papules in moist areas, and intense pruritus; a bulbous dermatitis may also occur. Pyrethrins can cause allergic dermatitis. Ocular exposure can cause irritation. Inhalation exposure can cause congestion, rhinorrhea and other upper respiratory symptoms, headaches, paresthesia, and dizziness. Ingestion commonly cause nausea, vomiting, and abdominal pain.
    2) SEVERE TOXICITY: Severe asthma exacerbations and anaphylaxis have been reported, and can be fatal. Seizures are a rare manifestation of severe poisoning. Severe corneal injury can occur from ocular exposure.

Vital Signs

    3.3.2) RESPIRATIONS
    A) Labored respirations were noted in an 11-month-old child following exposure to pyrethrum powder on his face. The child recovered in 1.5 hours (Ray, 1991; Proctor et al, 1988).
    3.3.5) PULSE
    A) Feeble heart sounds and slow pulse rate were noted in an 11-month-old infant whose face was accidentally covered with a pyrethrum powder when the top came off the container (Ray, 1991; Proctor et al, 1988).

Heent

    3.4.3) EYES
    A) CORNEAL DAMAGE: Superficial corneal abrasions have been reported following the use of a 0.17% synergized pyrethrin shampoo to control head lice in children. It was suggested that the corneal damage may have been the result of ingredients (2% piperonyl butoxide, 5% kerosene, and 92.835% inert ingredients) other than pyrethrins (Pe'er & Ben Ezra, 1988).
    1) FINDINGS: Injury was mild in 3, moderate in 11, and severe in 11 of 25 children.
    2) PROGNOSIS: Complete corneal healing usually occurs within 2 weeks, but was delayed for more than 4 weeks in 1 case.
    B) VISUAL ACUITY: Corneal denudation and decreased visual acuity have been reported following ocular contact exposure during normal use of pediculicide shampoos containing pyrethrin (Quan & Anderson, 1989).
    C) PERIORBITAL EDEMA has been described during hypersensitivity reactions (Culver et al, 1988), and in homeowners after their houses were sprayed (Moretto, 1991).
    D) IRRITATION: Eye burning, itching and irritation may result from exposure to fumes or direct ocular contamination (Giacomo et al, 1994; Lessenger, 1992; (Ray, 1991). Pyrethrin I and II in pure form are irritating to the eyes and mucous membranes (Grant & Schuman, 1993). Chemical conjunctivitis was diagnosed in a patient after a pyrethrin-containing mist was inadvertently sprayed into the eyes (Anon, 2000). Pyrethrum insecticide powder may cause transient contact conjunctival edema and hyperemia (Grant & Schuman, 1993).
    3.4.5) NOSE
    A) RHINITIS and sneezing have been reported (Moretto, 1991; (Newton & Breslin, 1983; Proudfoot, 2005). Following inhalation, a stuffy, runny nose and scratchy throat are common.
    3.4.6) THROAT
    A) PHARYNGITIS: A sore, scratchy throat has been reported (Anon, 2000; Paton & Walker, 1988).
    B) TASTE PERVERSION: An oily taste and burning sensation of the mouth developed in a 74-year-old woman who inadvertently sprayed an insecticide containing pyrethrins, pyrethroids, kerosene and a chlorofluorocarbon propellant into her mouth (Grant & Schuman, 1993). The burning sensation resolved over 5 months but the taste disorder persisted.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension and tachycardia may occur as a result of an anaphylactoid reaction (Culver et al, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) Asthma or reactive airways disease syndrome is possible following inhalation exposures, as is hypersensitivity pneumonitis with chest pain, cough, dyspnea and bronchospasm (Fischer & Eikmann, 1996; Ray, 1991; Newton & Breslin, 1983; Proudfoot, 2005). Patients with ragweed sensitivity are more prone to allergic reactions following pyrethrum extract administration. Fatal asthma was reported in a child and an adult following the use of an animal shampoo containing pyrethrin (Wagner, 2000; Wax & Hoffman, 1994).
    a) PYRETHRUM: Hypersensitivity reactions characterized by pneumonitis, cough, dyspnea, chest pain, and bronchospasm have occurred (Carlson & Villaveces, 1977).
    b) PYRETHRINS: Asthma-like symptoms have been reported in susceptible individuals, especially those with a history of asthma (Newton & Breslin, 1983).
    B) RESPIRATORY FAILURE
    1) CASE REPORT (ADULT): A 37-year-old woman with a history of mild asthma requiring no chronic medication developed severe shortness of breath and died after a brief exposure to a pet shampoo containing 0.06% pyrethrin (Wax & Hoffman, 1994).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) APNEA
    a) Animal studies have demonstrated respiratory failure and resultant death following inhalation of pyrethrins (Ray, 1991).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PARESTHESIA
    1) Skin contamination with pyrethrins may cause localized paresthesia (Ray & Forshaw, 2000; Wilks, 2000).
    2) PYRETHROIDS VS PYRETHRINS: Paresthesias from natural pyrethrins are much less intense than those from synthetic pyrethroid agents (Ray, 1991; Martin & Hester, 1941).
    B) SEIZURE
    1) Seizures may occur following a massive ingestion, but are rare following any type of exposure to pyrethrins. An 11-month-old boy was reported to have intermittent seizures and vomiting after a box of pyrethrum powder opened and covered the child's mouth, nostrils, and entire face (Ray, 1991).
    a) A 14-year-old boy painted his throat with an extract of pyrethrum. Approximately 1 hour later, he vomited and convulsed several times (Proudfoot, 2005). Children are considered more sensitive to pyrethrin exposure due to their inability to hydrolyze pyrethrin esters effectively.
    C) DIZZINESS
    1) Dizziness has been reported following exposure to pesticide mists. CNS depression may occur following toxic exposure to pyrethrin-piperonyl butoxide preparations; the CNS depression is most likely due to piperonyl butoxide.
    2) CASE REPORT: Dizziness was reported by a restaurant cook after exposure to a pesticide mist containing pyrethrin and piperonyl butoxide (Anon, 2000).
    D) HEADACHE
    1) Headache may occur after exposure to pesticide mists.
    2) CASE REPORTS: Two customers of a restaurant developed headache after exposure to a pesticide containing pyrethrin and piperonyl butoxide (Anon, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) Nausea, vomiting, abdominal pain, and diarrhea may occur, especially following large ingestions, and may be due in part to piperonyl butoxide, which is often added as an adjunct in pyrethrum extract products (Ray, 1991).
    B) ABDOMINAL PAIN
    1) CASE REPORT: Abdominal cramps with vomiting and diarrhea were reported after an inhalation exposure to a pyrethrin-containing commercial-strength flea and tick spray (Paton & Waleker, 1988).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CHRONIC TOXICITY
    a) RATS: Following pyrethrin daily feedings of 1000 to 2000 ppm for 2 years to rats, liver lesions developed, which included bile duct proliferation and focal necrosis of the liver cells (Ray, 1991).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) Irritant contact dermatitis has been described, and is more common following pyrethrin exposures than pyrethroid exposures. Patients allergic to chrysanthemums may develop photosensitivity or chronic actinic dermatitis following repeated exposures (McGovern & Barkley, 1999; Fischer & Eikmann, 1996; Lisi, 1992) Kolmodin-Hedman et al, 1982).
    2) The usual lesion is a mild erythematous dermatitis with vesicles, papules in moist areas, and intense pruritus; a bulbous dermatitis may also develop (McGovern & Barkley, 1999; Ray, 1991; Proctor et al, 1988).
    3) Four types of lesions associated with pyrethrum dermatitis include erythema venenatum, vesicular dermatitis, papular dermatitis, and an anaphylactic type. Lesions developed on exposed skin and were associated with intense itching and a burning feeling. Erythema venenatum was reported in approximately 30% of 85 workers and was characterized by redness, roughness, and later desquamation of the skin. The anaphylactic type is the least common type of rash (Proudfoot, 2005).
    4) CASE REPORT: Erythematous papular lesions of the face and dorsum of the hands were reported in a farmer following the use of pesticide sprays containing pyrethrin. The skin eruption was described as an erythema-multiforme-like reaction. Patch tests showed a positive response to pyrethrum (Garcia-Bravo et al, 1995).
    B) ERYTHEMA MULTIFORME
    1) Generalized erythema multiforme developed in a neonate 12 to 24 hours after being placed in a crib that had been sprayed with pyrethrum insecticide (approximately 100g). Pyrexia and polymorphonuclear leucocytosis were also observed (Proudfoot, 2005).
    C) CELLULITIS
    1) CASE REPORT: Goldberg et al (1982) reported 2 cases of patients who injected (subcutaneously and intravenously) commercially available household spray insecticides and presented with cellulitis at and around the injection site, followed by an abscess which showed negative bacterial growth.
    a) The commercially available household insecticides contained chlorinated hydrocarbons, piperonyl butoxide, pyrethrins, carbamates, and hydrocarbons (petroleum distillates).
    D) HYPERSENSITIVITY REACTION
    1) Pyrethrin exposures can result in severe allergic dermatitis (Budavari, 1996; Lisi, 1992; Ray, 1991).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERCORTISOLISM
    1) Severe poisoning may result in marked adrenal activation, with increases in adrenaline and noradrenaline accompanying motor signs (Ray & Forshaw, 2000).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) Human injuries from pyrethrum and pyrethrins have most frequently resulted from allergenic properties of the material rather than its direct toxicity. Allergy usually has been associated with occupational or therapeutic contact. Dermatitis, and particularly allergy of the respiratory tract, may result from exposure to pyrethrum formulations intended for use in the home or workplace (Ray, 1991). Patients at highest risk for an allergic reaction are those who are sensitive to ragweed pollen, which may cross-react with chrysanthemums (Howland, 1998). Eosinophilia may accompany an acute allergic reaction (Ray, 1991).
    2) CASE REPORT: Hypersensitivity pneumonitis characterized by cough, shortness of breath, chest pain, and bronchospasm occurred in a chronically exposed person (Carlson & Villaveces, 1977).
    B) ANAPHYLACTOID REACTION
    1) Death from severe bronchospasm and respiratory failure has been reported rarely in patients with well controlled underlying asthma (Wagner, 2000; Wax & Hoffman, 1994).
    2) CASE REPORT: A nonfatal anaphylactoid reaction has been described following application of a shampoo for head lice. The patient developed hypotension, collapse, and required respiratory support (Culver et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no reproductive studies were found for pyrethrum in humans.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) EMBRYOTOXICITY
    a) Pyrethrum at 0, 50, 100 and 150 mg/kg was tested on pregnant rats. An increase in resorptions was seen at the higher doses (Khera et al, 1982).
    2) LACK OF EFFECT
    a) Rats given pyrethrum orally on days 6 to 15 of pregnancy experienced increased resorptions at doses of 100 and 150 mg/kg, but no increase in structural defects was seen (Khera et al, 1982; Khera, 1981).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) PYRETHRINS WITH PIPERONYL BUTOXIDE - US FDA Pregnancy Category C (Briggs et al, 1998).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS88108-26-3 (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 CAS8003-34-7 (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
    C) IARC Carcinogenicity Ratings for CAS121-21-1 (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) Not Listed
    D) IARC Carcinogenicity Ratings for CAS121-29-9 (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
    E) IARC Carcinogenicity Ratings for CAS121-20-0 (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
    F) IARC Carcinogenicity Ratings for CAS4466-14-2 (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
    G) IARC Carcinogenicity Ratings for CAS1172-63-0 (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
    H) IARC Carcinogenicity Ratings for CAS8003-34-7 (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
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the potential carcinogenic activity of pyrethrum in humans.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) One review mentioned that pyrethrum has caused tumors in laboratory animals (Anon, 1976); however, no original studies were found to confirm these assertions at the time of this review.

Genotoxicity

    A) Pyrethrum is not mutagenic in bacterial reversion tests (Ray, 1991).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Pyrethrin plasma concentrations are not clinically useful or readily available.
    B) Monitor vital signs and mental status.
    C) Monitor for allergic responses such as asthma or contact dermatitis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Pyrethrin plasma concentrations are not clinically useful or readily available.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor for allergic responses (eg, asthma, contact dermatitis) in patients following toxic exposures. Patients with sensitivity to chrysanthemums may be at increased risk for allergic reactions.
    1) Patients experiencing an allergic reaction should have vital signs and respiratory function monitored.
    b) Rarely, tremors may occur following marked toxic exposures. Monitor for tremors and signs of sympathetic activation following substantial exposures.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) PYRETHRINS: A color test with 2-2 (2-aminoethylamine) ethanol produces red to violet color in the presence of pyrethroidal substances. It is not suitable for analysis of pyrethrins in body fluids, except, possibly at extraordinary concentrations.
    2) PYRETHRINS: Were analyzed in pyrethrum extract by HPLC (McEldowney & Menary, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate supportive care may require admission.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Most unintentional exposures in patients who are asymptomatic may be watched at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate exposure, and those with more than mild symptoms or any evidence of bronchospasm or acute allergic reaction should be referred to a healthcare facility.

Monitoring

    A) Pyrethrin plasma concentrations are not clinically useful or readily available.
    B) Monitor vital signs and mental status.
    C) Monitor for allergic responses such as asthma or contact dermatitis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not indicated; minor exposures generally do not cause toxicity and large ingestions can cause seizures with the risk of aspiration. Wash exposed skin and remove contaminated clothing. Irrigate exposed eyes.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination is not required for small ingestions.
    B) If the pyrethrin is formulated in an organic solvent, activated charcoal is unlikely to be of benefit (Bateman, 2000). If the pyrethrin is formulated in a petroleum base, the risk of hydrocarbon pneumonitis may exceed the toxic hazard of the insecticide. Gastric decontamination is not recommended.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Pyrethrin plasma concentrations are not clinically useful or readily available.
    2) Monitor vital signs and mental status.
    3) Monitor for allergic responses such as asthma or contact dermatitis.
    B) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    C) BRONCHOSPASM
    1) BRONCHOSPASM SUMMARY
    a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
    2) ALBUTEROL/ADULT DOSE
    a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    3) ALBUTEROL/PEDIATRIC DOSE
    a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    4) ALBUTEROL/CAUTIONS
    a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.
    5) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).
    D) SEIZURE
    1) Seizures may occur following a massive ingestion, but are rare. Children are considered more sensitive to pyrethrin exposure due to their inability to hydrolyze pyrethrin esters effectively.
    2) 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).
    3) 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 .
    4) 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).
    5) 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).
    6) 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).
    7) 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) VITAMIN E
    1) Oil of vitamin E preparations appear effective for treatment of paresthesias as long as they contain vegetable oils such as corn oil sesame oil, safflower oil or wheat germ oil (Ray & Forshaw, 2000; Ray, 1991).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) INFANT
    1) PYRETHRUM: Symptoms in an 11-month-old infant who ingested pyrethrum powder included pallor, intermittent convulsions, vomiting, and bradycardia; there was extreme reddening of the lips and tongue and slight inflammation of the conjunctivae (Proctor et al, 1988). The initial report of this case is from the late 1800's, it's accuracy is uncertain.
    B) ADULT
    1) PYRETHRINS
    a) One hour following application of a pyrethrin-containing pediculicide shampoo, a burning sensation in the eyes and puffiness were noted by a 43-year-old asthmatic woman.
    1) At 2.5 hours postexposure wheezing and shortness of breath developed. At 8.5 hours postexposure she complained of chest tightness, dysphagia, paresthesias, and puffy closed eyes.
    2) During transportation to the hospital, she became unresponsive. On arrival she was hypotensive, with shallow respirations. Intubation was performed with artificial ventilation for 3 hours (Culver et al, 1988).
    b) A 24-year-old man developed vomiting, abdominal cramps, and shortness of breath 30 minutes after heavy spraying of a floor with an aerosol spray containing 0.15% pyrethrin.
    1) Other symptoms included nasal and pharyngeal stinging, clear rhinorrhea, productive cough, rectal urgency, fatigue, dizziness, and tingling of both hands. Episodes of fecal incontinence developed after arrival at the hospital. Recovery ensued rapidly over 2 to 4 hours (Paton & Walker, 1988).
    c) A 36-year-old woman developed severe shortness of breath 5 minutes after she began bathing her dog with a shampoo containing 0.06% pyrethrin.
    1) The patient had a 10-year history of mild asthma without exacerbation in over 2 years. Shortness of breath progressed to cardiopulmonary arrest and death. Post mortem pulmonary findings were consistent with asthma (Wax & Hoffman, 1994).

Range Of Toxicity

Summary

    A) TOXICITY: The minimal lethal dose of pyrethrins is not established, but is probably in the range of 10 to 100 grams. THERAPEUTIC DOSE: RID lice killing shampoo contains pyrethrum extract (equivalent to 0.33% pyrethrins), applied for 10 minutes.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) PYRETHRINS (Oral) - Prior to 1940 pyrethrins were used as anthelmintics, with suggested oral adult dose of 20 milligrams given daily for 3 days in the form of an emulsion (Ray, 1991).
    2) PYRETHRINS (Topical) - The topical liquid or topical gel should be applied, undiluted, to dry hair and scalp or to any infested area until entirely wet. The liquid should not be used on the eyelashes or eyebrows (Prod Info Rid(R), pyrethrins/piperonyl butoxide, 2001).
    3) PYRETHRUM EXTRACT (Shampoo)- Apply shampoo to affected area until all hair is thoroughly wet and allowed to stand for no longer than 10 minutes. Then wash the area with warm water and shampoo or soap. The treatment should be repeated in 7 to 10 days to assure eradication of unhatched nits. (Prod Info Rid(R), pyrethrins/piperonyl butoxide, 2001).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) PYRETHRINS (Topical) - The topical liquid or topical gel should be applied, undiluted, to dry hair and scalp or to any infested area until entirely wet. The liquid should not be used on the eyelashes or eyebrows (Prod Info Rid(R), pyrethrins/piperonyl butoxide, 2001).
    2) PYRETHRUM EXTRACT (Shampoo)- Apply shampoo to affected area until all hair is thoroughly wet and allowed to stand for no longer than 10 minutes. Then wash the area with warm water and shampoo or soap. The treatment should be repeated in 7 to 10 days to assure eradication of unhatched nits. (Prod Info Rid(R), pyrethrins/piperonyl butoxide, 2001).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) PYRETHRUM: Oral LD50 of pyrethrum is greater than 1 g/kg. Most poisoning cases are the result of allergic reactions (Howland, 1998).
    2) PYRETHRUM: A 2-year-old girl died after ingesting one-half ounce (14,000 mg) of an insect powder containing pyrethrum (Ray, 1991; Anon, 1889).
    3) PYRETHRIN: One case of an extremely hypersensitive asthmatic patient resulted in death after a brief exposure to an insecticide shampoo containing 0.06 percent pyrethrin (Wax & Hoffman, 1994). In a similar case, an 11-year-old child with asthma developed severe symptoms of shortness of breath with wheezing 10 minutes after bathing her dog with a 0.2% pyrethrin shampoo. Despite aggressive treatment, including artificial respiration, the child died 2.5 hours after initial exposure (Wagner, 2000).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) CHRONIC FEEDING STUDIES in animals also indicate that the toxicities of pyrethrins are of a low order in mammals (Ray, 1991).
    2) An oral toxic dose is estimated to be 100 to 1000 mg/kg (Dart, 2000).

Workplace Standards

    A) ACGIH TLV Values for CAS88108-26-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS8003-34-7 (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) Pyrethrum
    a) TLV:
    1) TLV-TWA: 5 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 dam; LRT irr
    d) Molecular Weight: 345 (avg.)
    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 CAS121-21-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    D) ACGIH TLV Values for CAS121-29-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    E) ACGIH TLV Values for CAS121-20-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    F) ACGIH TLV Values for CAS4466-14-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    G) ACGIH TLV Values for CAS1172-63-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    H) ACGIH TLV Values for CAS8003-34-7 (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) Pyrethrum
    a) TLV:
    1) TLV-TWA: 5 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 dam; LRT irr
    d) Molecular Weight: 345 (avg.)
    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:

    I) NIOSH REL and IDLH Values for CAS88108-26-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    J) NIOSH REL and IDLH Values for CAS8003-34-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Pyrethrum
    2) REL:
    a) TWA: 5 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: 5000 mg/m3
    b) Note(s): Not Listed

    K) NIOSH REL and IDLH Values for CAS121-21-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    L) NIOSH REL and IDLH Values for CAS121-29-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    M) NIOSH REL and IDLH Values for CAS121-20-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    N) NIOSH REL and IDLH Values for CAS4466-14-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    O) NIOSH REL and IDLH Values for CAS1172-63-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    P) NIOSH REL and IDLH Values for CAS8003-34-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Pyrethrum
    2) REL:
    a) TWA: 5 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: 5000 mg/m3
    b) Note(s): Not Listed

    Q) Carcinogenicity Ratings for CAS88108-26-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    R) Carcinogenicity Ratings for CAS8003-34-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Pyrethrum
    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 Listed
    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: Pyrethrum
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    S) Carcinogenicity Ratings for CAS121-21-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    T) Carcinogenicity Ratings for CAS121-29-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    U) Carcinogenicity Ratings for CAS121-20-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    V) Carcinogenicity Ratings for CAS4466-14-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    W) Carcinogenicity Ratings for CAS1172-63-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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

    X) Carcinogenicity Ratings for CAS8003-34-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Pyrethrum
    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 Listed
    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: Pyrethrum
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    Y) OSHA PEL Values for CAS88108-26-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    Z) OSHA PEL Values for CAS8003-34-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Pyrethrum
    2) Table Z-1 for Pyrethrum:
    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

    AA) OSHA PEL Values for CAS121-21-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AB) OSHA PEL Values for CAS121-29-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AC) OSHA PEL Values for CAS121-20-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AD) OSHA PEL Values for CAS4466-14-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AE) OSHA PEL Values for CAS1172-63-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AF) OSHA PEL Values for CAS8003-34-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Pyrethrum
    2) Table Z-1 for Pyrethrum:
    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) Pyrethrum
    1) LD50- (ORAL)MOUSE:
    a) 370 mg/kg -- tremor, excitement, ataxia (RTECS, 2006)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 189 mg/kg (RTECS, 2006)
    3) LD50- (ORAL)RAT:
    a) 200 mg/kg (RTECS, 2006)
    4) LD50- (SKIN)RAT:
    a) >1350 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) One of the chief virtues of the pyrethrins and pyrethroids is a much lower toxic effect in mammals than in insects. They are powerful paralytic poisons in insects, causing "quick knockdown", and in sufficient dosage, death.

Toxicologic Mechanism

    A) MAMMALS - Pyrethrum and the natural pyrethrins are sodium channel toxins. They produce typical type I motor symptoms in mammals. Low toxicity in mammals is due primarily to rapid metabolic breakdown, ester cleavage, then rapid oxidation (Ray, 1991).
    B) BIRDS are resistant to the action of pyrethrins and pyrethroids, but fish are extremely sensitive.
    C) ALLERGENICITY - Despite low systemic toxicity, natural pyrethrum contains impurities, such as pyrethrosin, which are allergenic, affecting the skin and the upper respiratory tract (Mitchell et al, 1972). Both immediate and delayed hypersensitivity reactions have been demonstrated in guinea pigs sensitized by a single subcutaneous injection of ground flowers (Ray, 1991).
    1) Two types of allergens present in crude pyrethrum oleoresin have been identified: glycoproteins or glycopeptides ranging in molecular weight from 60,000 to 200,000 (most important) and the sesquiterpene lactones, principally pyrethrosin (minor importance) (Ray, 1991).
    2) Refined pyrethrins and synthetic pyrethroids are said to have little or no allergenic effect. Contact dermatitis produced by crude pyrethrum extracts is due to impurities (Ray, 1991). Cross-reactivity to ragweed may occur (Carlson & Villaveces, 1977; Zucker, 1965).
    D) RODENTS - Given in extreme dosage to rats and mice, pyrethrins and pyrethroids cause irritability, tremors, ataxia, seizures, and respiratory depression. Bloody tears and diarrhea are evident. Surviving animals recover in 1 to 3 days (Cremer & Seville, 1985)
    1) Chronic feeding studies have demonstrated only a tendency to induce proliferation of bile duct epithelium, and hyperplasia of Peyer's patches. At extreme prolonged dosage, pyrethrum causes necrosis of liver and kidney cells of rats.
    2) Dermal and inhalation toxicities in experimental animals are low. Tests for teratogenicity and mutagenicity have so far been negative.
    E) PIPERONYL BUTOXIDE, which is often added to pyrethrins as a synergist, is a moderately active hepatic enzyme inducer in mammals. Halocarbon propellants, at high concentrations, cause increased ventricular irritability. Although esters, pyrethrins and pyrethroids do not inhibit cholinesterase.

Physicochemical

Physical Characteristics

    A) Pyrethrins are generally brown or tan in color. Their various physcial forms include viscous liquid (pyrethrin I and II, cinerin II), viscous oil (cinerin II), solid, and dust. They readily oxidize and are unstable in light and air (HSDB, 2006; NIOSH, 2006; Pohanish, 2002; Krieger, 2001; Lewis, 2001).
    B) Pyrethrum's unrefined extract is a mobile oil; the refined extract is a liquid. Its color ranges from an unrefined dark greenish brown to a refined pale yellow. The powdered ground flowers are tan (HSDB, 2006).

Molecular Weight

    A) Reported molecular weights are as follows (HSDB, 2006; NIOSH, 2006; Agency for Toxic Substances and Disease Registry (ATSDR), 2003):
    1) Cinerin I: 316.4
    2) Cinerin II: 360.4
    3) Jasmolin I: 330.5
    4) Jasmolin II: 357.7
    5) Pyrethrin I: 328.5
    6) Pyrethrin II: 372.5
    7) Pyrethrum: 316 to 374

Other

    A) ODOR THRESHOLD
    1) Pyrethrins have the characteristic odor of the carrier or solvent (HSDB, 2006).

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) Environmental exposure (fumigation of housing) has resulted in restlessness, hyperactivity, and decreased food intake within minutes following return to a previously treated area (Ray, 1991).
    11.1.3) CANINE/DOG
    A) As with cats, the most consistent sign is body tremors. Additional signs may include vomiting, diarrhea, dyspnea, disorientation, and seizures. The signs usually occur within a few hours of exposure (Dorman, 1987).
    11.1.6) FELINE/CAT
    A) Typically tremors will become apparent several hours following exposure. The tremors (mainly a peripheral effect) begin on the face and progress elsewhere, lasting up to 24 to 48 hours (Dorman, 1987). Usual effects of toxicosis in cats include primarily neurologic abnormalities of muscle tremors, agitation, ataxia, and seizures (Meyer, 1999). Seizures have developed within 24 hours, and in some cases by 2 hours, following a toxic dermal application.

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) SUMMARY -
    1) Exposure is usually related to topical application and secondary oral ingestion from grooming. Bathing may be helpful in limiting progression and/or duration of signs.
    2) Pyrethrins and pyrethroids are highly lipid soluble and of negligible water solubility; therefore, for bathing or washing to be most effective it should be carried out using a mild detergent.
    a) The ASPCA NAPCC recommends dermal decontamination using a mild hand dish detergent and water (Meyer, 1999).
    3) Emetics must be used with caution because of the prevalent signs and the presence of petroleum distillate solvents.
    4) DOGS AND CATS - If oral exposure is suspected, gastric lavage and/or administration of activated charcoal with an osmotic cathartic (magnesium or sodium sulfate) may be used.
    b) EMESIS -
    1) Emetics must be used with caution because of the prevalent signs and the presence of petroleum distillate solvents.
    2) If within 2 hours of exposure, emesis may be induced with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    3) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    4) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    c) ACTIVATED CHARCOAL -
    1) Dose: 2 grams/kilogram per os or via stomach tube.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) The signs due to effects on sodium channels are peripheral in nature and typically will not require therapy.
    2) Those due to central actions are more severe and may necessitate the use of sedatives.
    a) Diazepam (1 mg/kg, IV) may be the most specific agent for use in control of these effects (Valentine, 1990).
    b) Alternatively methocarbamol (50 to 150 mg/kg IV) or barbiturates may be used (Valentine, 1990).
    c) Phenothiazine tranquilizers should NOT be used (Valentine, 1990).
    3) DOGS AND CATS - Maintain vital functions: insure a patent airway, correct electrolyte/fluid imbalances and keep the animal warm and quiet.
    4) CATS - Tremors should be controlled with intravenous methocarbamol 55 to 220 mg/kg of body weight, administered rapidly at a rate not to exceed 2 mL/min. Discontinue briefly as cat relaxes, then resume until desired effect is achieved. Maximum dose is 330 mg/kg. If seizures are present, administer diazepam or pentobarbital, or mask induction with isoflurane prior to tremor control with methocarbamol (Meyer, 1999).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) GENERAL
    1) TOPICAL - The pyrethrins and pyrethroids are generally available for topical application in various concentrations ranging from 0.01% to 10% depending on the use and animal species involved.
    2) ORAL - At present, there are no preparations intended for internal use.
    11.3.2) MINIMAL TOXIC DOSE
    A) GENERAL COMMENTS -
    1) The pyrethrins and pyrethroids (synthetic pyrethrins) are generally considered to be among the most potent insecticides. Mammalian toxicity is relatively low compared to insects. They are, however, quite toxic to fish.
    2) Of great importance in determining toxicity is formulation of the product. The compounds have high lipid and low aqueous solubility and are 5 to 10 times more toxic in an organic solvent.
    3) Depending on the specific compound, dermal toxicity is somewhat less than oral.
    4) LD50 (Valentine, 1990)
    COMPOUNDORAL RAT LD50, mg/kg
    Pyrethrin900 to 1,200

Continuing Care

    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) SUMMARY -
    1) Exposure is usually related to topical application and secondary oral ingestion from grooming. Bathing may be helpful in limiting progression and/or duration of signs.
    2) Pyrethrins and pyrethroids are highly lipid soluble and of negligible water solubility; therefore, for bathing or washing to be most effective it should be carried out using a mild detergent.
    a) The ASPCA NAPCC recommends dermal decontamination using a mild hand dish detergent and water (Meyer, 1999).
    3) Emetics must be used with caution because of the prevalent signs and the presence of petroleum distillate solvents.
    4) DOGS AND CATS - If oral exposure is suspected, gastric lavage and/or administration of activated charcoal with an osmotic cathartic (magnesium or sodium sulfate) may be used.
    b) EMESIS -
    1) Emetics must be used with caution because of the prevalent signs and the presence of petroleum distillate solvents.
    2) If within 2 hours of exposure, emesis may be induced with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    3) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    4) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    c) ACTIVATED CHARCOAL -
    1) Dose: 2 grams/kilogram per os or via stomach tube.
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) CAT
    1) Maintain fluid and nutritional support. Normal body temperature should be maintained, as hypothermia may aggravate clinical signs of pyrethrin toxicosis (Meyer, 1999).

Kinetics

    11.5.1) ABSORPTION
    A) GENERAL
    1) All pyrethrins are absorbed from the gastrointestinal tract, especially when formulated in an organic solvent vehicle. Dermal absorption is usually somewhat lower than oral absorption.
    11.5.2) DISTRIBUTION
    A) GENERAL
    1) These compounds are highly lipid soluble and are well distributed throughout the body except brain (Marei Abd El-Salam et al, 1982).
    11.5.3) METABOLISM
    A) GENERAL
    1) All pyrethrins are subject to oxidative processes via mixed function oxidases mainly in the liver.
    11.5.4) ELIMINATION
    A) GENERAL
    1) There is limited information available on the specific kinetic parameters for the various pyrethrins and pyrethroids. Based on persistence of effects the elimination half-lives appear to be in the range of several hours; shortest for pyrethrin and longest for the alpha-cyanopyrethroids.

Pharmacology Toxicology

    A) GENERAL
    1) The predominant action of pyrethrins is on voltage dependent sodium channels (Dorman & Beasley, 1991). Pyrethrins bind to open sodium channels markedly prolonging sodium influx.
    a) These effects appear to be closely tied to the occurrence of repetitive discharges and the development of tremors in the animal (Clark & Brooks, 1989).

Sources

    A) GENERAL
    1) There are a variety of preparations available primarily for control of fleas, mites, and ticks. These preparations include dips, dusts, sprays, shampoos, lotions (ears), and foggers for use with dogs, cats, birds, and horses. Treated ear tags are available for cattle.
    a) The preparations may contain pyrethrins and/or synthetic pyrethroids; allethrin, permethrin, fenvalerate, and resmethrin (the latter two being alpha-cyanoderivatives).
    2) The pyrethrins and pyrethroids are very commonly formulated in combination with piperonyl butoxide, which is intended to inhibit pyrethrin metabolism by the insect, increasing insecticide potency. Organophosphates and/or carbamates may also be included.
    a) The clinical signs for the latter compounds are similar to those for pyrethroids. In cases of intoxication with the combination products, atropine may be useful in distinguishing the origin of the signs.

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