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DENATONIUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Denatonium benzoate is a taste aversive agent. It can be tasted at 10 parts per billion, and is bitter at 50 parts per billion (10 ppm=10 mg/L=0.001%) (Klein-Schwartz, 1991).

Specific Substances

    1) Denatonium benzoate
    2) lignocaine benzyl benzoate
    3) Bitrex(R)
    4) BITREX
    5) THS-839
    6) WIN 16568

Available Forms Sources

    A) FORMS
    1) Bitrex(R) Concentrate is available in the USA from Henley Chemicals, Inc. Macfarlan Smith, Inc., manufactures Bitrex(R) in Edinburgh, Scotland (Technical Information, 1989).
    a) Packaging: 4 oz, 50 oz tins of granular; 1 kg, 5 kg tins of powder. Solutions: 200-liter drums of 25% w/v in ethylene glycol; 22.5-liter drums of 21.45% w/v in ethyl alcohol (Technical Information, 1989).
    B) USES
    1) This taste aversion agent (trade name Bitrex(R)) is related to lidocaine and was discovered in 1958 during a search for new local anesthetics (Rogers, 1994; Klein-Schwartz, 1991).
    2) Denatonium has been used for over 20 years as an alcohol denaturant (6 to 100 parts per million); it is now being used on a limited basis as a bitter agent added to consumer products as a deterrent to ingestion (Klein-Schwartz, 1991).
    3) Denatonium is also being investigated as a nail biting and thumb sucking deterrent.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) In tests done with rats and monkeys using doses up to 16 mg/kg/day, no changes were seen in either general behavior or appearance. No microscopic lesions attributable to denatonium were seen.
    0.2.4) HEENT
    A) Rabbit tests have shown low ocular irritancy.
    0.2.6) RESPIRATORY
    A) Animal tests have shown very low respiratory irritancy.
    0.2.8) GASTROINTESTINAL
    A) Vomiting may be seen as a side effect of the intense bitter taste.
    0.2.13) HEMATOLOGIC
    A) Increased coagulation times were noted in one series of tests done on rats.
    0.2.14) DERMATOLOGIC
    A) In animal tests, low contact sensitivity has been noted. In humans, low acute irritancy has been noted with concentrations of under 0.05%.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) No routine laboratory test are needed unless otherwise clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) No treatment is necessary when ingested as part of a product where it is used as a bittering agent. Treatment would be as for the ingested agent without denatonium.
    B) Gastrointestinal decontamination is generally not necessary. Consider activated charcoal if large amounts of a high concentration product are ingested.
    C) 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.
    D) Observe patients and treat symptomatically.
    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) Data are not available for potential toxic dose and symptoms when ingested in pure form. Toxic/lethal doses in animals are around 600 mg/kg. If extrapolated to an adult man, this would be around 42 grams.
    B) Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) In tests done with rats and monkeys using doses up to 16 mg/kg/day, no changes were seen in either general behavior or appearance. No microscopic lesions attributable to denatonium were seen.

Heent

    3.4.1) SUMMARY
    A) Rabbit tests have shown low ocular irritancy.
    3.4.3) EYES
    A) Denatonium was tested in rabbits and shown not to be irritating to ocular mucosa in concentrations of 0.005 to 0.05% (Klein-Swartz, 1991).

Respiratory

    3.6.1) SUMMARY
    A) Animal tests have shown very low respiratory irritancy.
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Inhalation toxicity was not reported when ten rats were tested with a concentration of 0.1% w/v (Anon, 1989).

Neurologic

    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) In tests done with rats and monkeys using doses up to 16 mg/kg/day, no changes were seen in either general behavior or appearance. No microscopic lesions that could be attributed to denatonium were seen (Anon, 1981) b, c).

Gastrointestinal

    3.8.1) SUMMARY
    A) Vomiting may be seen as a side effect of the intense bitter taste.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) Vomiting may be seen after ingestion of products containing denatonium (Sibert & Frude, 1988), presumably due to the bitter taste.
    2) Facial grimacing, pronounced mouth movements, crying, and a shocked expression have been seen after ingestion of orange juice containing 10 ppm of denatonium benzoate by toddlers (Sibert & Frude, 1988).

Hematologic

    3.13.1) SUMMARY
    A) Increased coagulation times were noted in one series of tests done on rats.
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) COAGULATION TIME INCREASED
    a) Coagulation times were slightly higher in one animal study conducted over 18 months (Klein-Schwartz, 1991).

Dermatologic

    3.14.1) SUMMARY
    A) In animal tests, low contact sensitivity has been noted. In humans, low acute irritancy has been noted with concentrations of under 0.05%.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Human adults tested with concentration of 0.05% and 0.005% did not experience significant skin irritation (Anon, 1989).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ALLERGIC REACTION
    a) GUINEA PIGS - Denatonium was tested in guinea pigs at concentrations of 10% w/v, and was found to have a very low sensitizing potential (Klein-Schwartz, 1991).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) CASE REPORT - Urticaria and asthma have been reported in a 30-year-old who was exposed to an insecticide spray containing denatonium. He had a similar reaction to other denatonium containing products (Bjorkner, 1980).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) In vitro testing by the manufacturer found denatonium not to be mutagenic.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No routine laboratory test are needed unless otherwise clinically indicated.

Methods

    A) CHROMATOGRAPHY
    1) Can be determined by HPLC (Budavari, 1996).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) No routine laboratory test are needed unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY -
    1) Gastrointestinal decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastrointestinal decontamination is generally not necessary. Consider activated charcoal if large amounts of a high concentration product are ingested, or if significant coingestants are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    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).
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) No treatment is necessary when ingested as part of a product where it is used as a bittering agent. Treatment would be as for the ingested agent without denatonium.
    2) Since toxicity data for acute ingestion of pure substance is unknown, amount greater than 1 gram (arbitrarily assigned) should have emesis induced assuming there are no contraindications. Once more data are available this number will probably increase. Activated charcoal may also be given.
    B) OBSERVATION REGIMES
    1) Since symptomatology caused by ingestions of high concentrations in unknown, patients should be observed for at least four hours for any untoward effects.

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).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Data are not available for potential toxic dose and symptoms when ingested in pure form. Toxic/lethal doses in animals are around 600 mg/kg. If extrapolated to an adult man, this would be around 42 grams.
    B) Minimum lethal human exposure is unknown.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Data are not available for potential toxic dose and symptoms when ingested in pure form. Toxic/lethal doses in animals are around 600 milligrams/kilogram. If extrapolated to an adult human, this would be around 42 grams.
    2) DOSES CAUSING EFFECTS - In a HUMAN study, >500 parts per million caused skin irritation (Payne et al, 1993).
    B) ANIMAL DATA
    1) Eye irritation in RABBITS was observed when they were exposed to >500 parts per million (Payne et al, 1993).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 584 mg/kg (RTECS, 2001)
    2) Neonatal, 23 mg/kg (Anon, 1981d)
    B) LD50- (SKIN)RAT:
    1) >2000 mg/kg (Payne et al, 1993)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Based on studies in rats, it is thought that recognition and transmission of a "bitter" taste by specific taste cells is due, at least in part, to a rise in the intracellular calcium concentration, and a receptor-second messenger mechanism leading to neurotransmitter release (Akabas et al, 1988).

Physicochemical

Physical Characteristics

    A) white crystalline powder, or white granules; odorless (Technical Information, 1989).
    B) crystals when isolated from a mixture of isopropanol and ethyl acetate (Technical Information, 1989)

Ph

    A) 6.5-7.5 (Technical Information, 1989)

Molecular Weight

    A) Denatonium benzoate: 446.57

References

General Bibliography

    1) Akabas MH, Dodd J, & Al-Awqati Q: A bitter substance induces a rise in intracellular calcium in a subpopulation of rat taste cells. Science 1988; 242:1047-1050.
    2) Anon: Contract for testing the acute and chronic toxicity of denatonium benzoate, an acerbic ingredient proposed for use in bad-tasting paint to prevent paint pica: two year oral toxicity study in rats, Government Reports Announcements and Index, Issue 07. Department of Housing and Urban Development, report 2F; National Technical Information Service, 1981.
    3) Bjorkner B: Contact urticaria and asthma from denatonium benzoate (Bitrex(R)). Contact Dermatitis 1980; 6:466-471.
    4) Budavari S: The Merck Index, 11th ed, Merck & Company, Inc, Whitehouse Station, New Jersey, 1996.
    5) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    6) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    12) Klein-Schwartz W: Denatonium benzoate: review of efficacy and safety. Vet Hum Toxicol 1991; 33:545-547.
    13) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    14) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    15) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    16) Payne HAS, Smalley HM, & Tracy MJ: Denatonium benzoate as a bitter aversive additive in ethylene glycol and methanol-based automotive products, SAE International Congress and Exposition, Detroit, MI, 1993.
    17) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    18) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    19) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    20) Rogers GC: The role of aversive bittering agents in the prevention of pediatric poisonings. Pediatrics 1994; 93:68-69.
    21) Sibert J & Frude N: Poison prevention is more than child-resistant closures: bittering agents in the prevention of accidental poisoning; reaction of children to denatonium benzoate (Bitrex(R)), Presented at the National Safety Council Congress, Orlando, FL, 1988.