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ISOTHIAZOLONE COMPOUNDS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Isothiazolone compounds are broad spectrum antimicrobial agents used in cosmetics and personal care products (concentrations 0.000004% to 0.01% (100 ppm) of methylisothiazolinone). They are also used as sterilizers in humidifiers and air conditioners, preservatives in carpet cleaners, dishwashing liquids, fabric softeners, floor polishes, general cleaners, sprinkler liquids, slimicides in latex emulsions, cooling tower water, metalworking fluids, oil-field drilling muds, and in paper mills.

Specific Substances

    A) BENZOTHIAZOLINONE
    1) 8,2-Benzisothiazolin-3-one
    2) BIT
    CHLOROMETHYLISOTHIAZOLINON
    1) 5-chloro-2-methyl-4-isothiazolin-3-one
    2) CAS 26172-55-4
    3) Methylchloroisothiazolinone (CTFA adopted name)
    ISOTHIAZOLINONE
    1) CAS 1003-07-2
    METHYLISOTHIAZOLINON
    1) 2-METHYL-4-ISOTHIAZOLIN-3-ONE
    2) CAS 2682-20-4
    3) Methylisothiazolinone (CTFA adopted name)
    OCTYLISOTHIAZOLINONE
    1) CAS 26530-20-1

    1.2.1) MOLECULAR FORMULA
    1) METHYLISOTHIAZOLINONE: C4H5NOS (Burnett et al, 2010)

Available Forms Sources

    A) FORMS
    1) Kathon CG(R) is a mixture of chloromethylisothiazoline, methylisothiazoline, magnesium salts, and water (S Sweetman , 2002; Cronin et al, 1988).
    2) Approximately 57% of over-the-counter shampoos and conditioners in the United States contain Kathon CG (Fransway, 1988).
    B) USES
    1) Isothiazolone compounds are broad spectrum antimicrobial agents used in cosmetics and personal care products. They are also used as sterilizers in humidifiers and air conditioners, preservatives in carpet cleaners, dishwashing liquids, fabric softeners, floor polishes, general cleaners, sprinkler liquids, slimicides in latex emulsions, cooling tower water, metalworking fluids, oil-field drilling muds, and in paper mills. In the US, current cosmetics and personal care products contain from 0.000004% to 0.01% (100 ppm) of methylisothiazolinone (MIT) as a preservative (Burnett et al, 2010; Bourke et al, 1997). Commercial products for industrial use contain 1.5% to 14.3% before dilution.
    2) BABY WIPES: Some baby wipes contain methylisothiazolinone. Contact dermatitis has been reported in children and their parents who used disposable wipes during diaper changes (Cahill et al, 2014).
    3) FLOOR-CLEANING AGENT: Periorbital erythema and infiltration has been reported in a woman who was exposed to Indur Maxx (R) floor-cleaning agent, containing octylisothiazolinone (Recke et al, 2015).
    4) Kathon CG(R) is a mixture of chloromethylisothiazoline, methylisothiazoline, magnesium salts, and water. It is commonly used as a preservative for water-based cosmetic and toiletry products, both in "wash-off" products such as shampoos, hair conditioners, and liquid soaps, and in "leave-on" products, such as face, hand, and body creams, eye cosmetics, and topical medicaments (S Sweetman , 2002; Cronin et al, 1988).
    5) Isothiazolone compounds have sterilizing properties and are used in humidifier and air conditioning systems (Bourke et al, 1997).
    6) Euxyl 100 (methylchloroisothiazolinone/methylisothiozolinone; MCI/MI; Schylke and Mayr, Hamburg, Germany) is a mixture of 2 isothiazolinones (5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one), magnesium salts and water. Since MCI/MI is effective at very low concentrations against a wide spectrum of bacteria, yeasts, and fungi, it is used both in the industrial and cosmetic industries as a preservative (Mowad, 2000).

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: Isothiazolone compounds are broad spectrum antimicrobial agents used in cosmetics and personal care products. They are also used as sterilizers in humidifiers and air conditioners, preservatives in carpet cleaners, dishwashing liquids, fabric softeners, floor polishes, general cleaners, sprinkler liquids, slimicides in latex emulsions, cooling tower water, metalworking fluids, oil-field drilling muds, and in paper mills. In the US, current cosmetics and personal care products contain from 0.000004% to 0.01% (100 ppm) of methylisothiazolinone (MIT) as a preservative. Commercial products for industrial use contain 1.5% to 14.3% before dilution.
    B) PHARMACOLOGY: Isothiazolones demonstrate antimicrobial activity against gram-positive and gram-negative bacteria, fungi, yeast, and algae.
    C) TOXICOLOGY: Concentrations of 0.06% or less are non-irritant and solutions of 1.5% or more are corrosive. Cosmetics containing as low as 5 to 7 ppm may produce dermatitis in sensitized individuals. Reactions are more likely to occur in patients with pre-existing damaged skin who use "leave-on" cosmetic preparations.
    D) EPIDEMIOLOGY: Exposure is common as these compounds are used in a variety of cosmetics and toiletries; toxicity is very rare. Low concentrations can cause dermatitis in sensitized individuals.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: These products can cause gastrointestinal mucosa, respiratory, or eye irritations. Dermal contact also cause irritation and delayed contact dermatitis can develop in sensitized individuals.
    2) SEVERE TOXICITY: In theory, ingestion of undiluted formulations (1.5% or more) could cause caustic injury (marked burns to gastrointestinal mucosa, abdominal pain, gastrointestinal bleeding, and gut perforation). Inhalation or aspiration of undiluted solutions could theoretically cause upper airway edema, stridor, hoarseness, and dyspnea. However, these effects have never been reported. Dermal contact with high concentrations can cause burns.
    0.2.20) REPRODUCTIVE
    A) Maternal and fetal deaths but no teratogenicity were observed in rabbits and rats.

Laboratory Monitoring

    A) The vast majority of patients do not require laboratory evaluation.
    B) Hematocrit, or complete blood count should be evaluated in gastrointestinal bleeding cases.
    C) Patch test material for Kathon CG is available for diagnosis of delayed contact dermatitis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment for mild and moderate symptoms consists of symptomatic and supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients who ingest undiluted industrial products may sustain caustic gastrointestinal injury. Perform endoscopy early (within 12 hours) in patients with stridor, drooling, vomiting, significant oral burns, difficulty swallowing or abdominal pain, and in all patients with deliberate ingestion. If burns are absent or grade I severity, patient may be discharged when they are able to tolerate liquids and soft foods by mouth. If mild grade II burns, admit the patient for intravenous fluids, and slowly advance diet as tolerated. Perform barium swallow or repeat endoscopy several weeks after ingestion (sooner if difficulty swallowing) to evaluate for stricture formation. Early surgical consultation is recommended for patients with severe grade II or grade III burns, large deliberate ingestions, or signs, symptoms or laboratory findings concerning for tissue necrosis or perforation. Early endotracheal intubation and bronchoscopy in patients with respiratory distress or upper airway edema.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; toxicity is from irritant/caustic effects, not systemic absorption. Dilution with a small amount of milk or water may be useful if it can be done shortly after ingestion. Remove contaminated clothing and wash exposed area thoroughly with soap and water. Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    D) AIRWAY MANAGEMENT
    1) Unlikely to be necessary. Patients with stridor or respiratory distress after ingestion of high concentration product, and patients with severe bronchospasm may need intubation for respiratory support.
    E) ANTIDOTE
    1) None
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients and those with mild irritation can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with more than mild irritation and those with deliberate exposure to high concentration products should be referred to a healthcare facility for evaluation and treatment.
    3) ADMISSION CRITERIA: The very rare patient with severe gastrointestinal or respiratory symptoms or extensive dermal burns or ocular injury should be admitted.
    4) CONSULT CRITERIA: Contact your local poison center or consult a medical toxicologist for any patient with severe toxicity. Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated. Consult an ophthalmologist for patients with evidence of corneal injury.
    G) PITFALLS
    1) Significant toxicity is rare; do not overtreat.
    H) DIFFERENTIAL DIAGNOSIS
    1) Exposure to other irritants or caustics. Other causes of contact dermatitis.
    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) Treat burns with topical antibiotics and analgesics as needed. Treat contact dermatitis with topical or systemic corticosteroids as needed.

Range Of Toxicity

    A) TOXICITY: Concentrations of 0.06% or less are non-irritant and 1.5% or more solutions are corrosive. No acute dermal irritation was seen in humans after contact with 100 ppm. Dermal sensitization has occurred with 25 to 56 ppm, and rarely with 5 to 7 ppm.

Clinical Effects

Summary Of Exposure

    A) USES: Isothiazolone compounds are broad spectrum antimicrobial agents used in cosmetics and personal care products. They are also used as sterilizers in humidifiers and air conditioners, preservatives in carpet cleaners, dishwashing liquids, fabric softeners, floor polishes, general cleaners, sprinkler liquids, slimicides in latex emulsions, cooling tower water, metalworking fluids, oil-field drilling muds, and in paper mills. In the US, current cosmetics and personal care products contain from 0.000004% to 0.01% (100 ppm) of methylisothiazolinone (MIT) as a preservative. Commercial products for industrial use contain 1.5% to 14.3% before dilution.
    B) PHARMACOLOGY: Isothiazolones demonstrate antimicrobial activity against gram-positive and gram-negative bacteria, fungi, yeast, and algae.
    C) TOXICOLOGY: Concentrations of 0.06% or less are non-irritant and solutions of 1.5% or more are corrosive. Cosmetics containing as low as 5 to 7 ppm may produce dermatitis in sensitized individuals. Reactions are more likely to occur in patients with pre-existing damaged skin who use "leave-on" cosmetic preparations.
    D) EPIDEMIOLOGY: Exposure is common as these compounds are used in a variety of cosmetics and toiletries; toxicity is very rare. Low concentrations can cause dermatitis in sensitized individuals.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: These products can cause gastrointestinal mucosa, respiratory, or eye irritations. Dermal contact also cause irritation and delayed contact dermatitis can develop in sensitized individuals.
    2) SEVERE TOXICITY: In theory, ingestion of undiluted formulations (1.5% or more) could cause caustic injury (marked burns to gastrointestinal mucosa, abdominal pain, gastrointestinal bleeding, and gut perforation). Inhalation or aspiration of undiluted solutions could theoretically cause upper airway edema, stridor, hoarseness, and dyspnea. However, these effects have never been reported. Dermal contact with high concentrations can cause burns.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) CASE REPORT: A 47-year-old woman developed malaise, mild conjunctival, nasal symptoms, slight pyrexia and eosinophilia (10% of WBC count of 7.0x10(9)/L) after exposure to paint and cleaning products containing methylchloro- and methyl-isothiazolinone (MCI/MI) (Fernandez De Corres et al, 1995).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) CORROSIVE to eyes in concentrations of 1.5% or greater. Corrosive effects may be delayed.
    2) IRRITANT at concentrations of 0.3% or greater. Non-irritating at 0.06%. Irritant effects may be delayed.
    3) CASE REPORT: A 47-year-old woman developed systemic systems (malaise, mild conjunctival, nasal symptoms, slight pyrexia and 10% of WBC count of 7.0x10(9)/L were eosinophils) after exposure to paint and cleaning products containing methylchloro- and methyl-isothiazolinone (MCI/MI) (Fernandez De Corres et al, 1995).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) RHINORRHEA: Inhalation of 2.64 mg/m(3) produced rhinorrhea and eosinophilic droplets in nasal turbinate mucosa in rats (Hagan JV & Baldwin RC, 1983). The minimum amount to produce rhinitis was 1.15 mg/m(3).
    2) CASE REPORT: A 47-year-old woman developed systemic systems (malaise, mild conjunctival, nasal symptoms, slight pyrexia and 10% of WBC count of 7.0x10(9)/L were eosinophils) after exposure to paint and cleaning products containing methylchloro- and methyl-isothiazolinone (MCI/MI) (Fernandez De Corres et al, 1995).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ASTHMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Occupational asthma was reported in a 53-year-old man 5 months after starting work in an isothiazolinone manufacturing plant (Bourke et al, 1997).
    B) HYPERSENSITIVITY REACTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 53-year-old woman with no previous history of eczema or other allergies presented with severe respiratory symptoms, erythema in the face, and edema around the eyes after moving to a newly painted apartment. Prior to presentation, she received prednisolone (25 mg twice daily) prescribed by general practitioner. Four days after patch testing, she developed positive reactions to methylisothiazolinone (MI) 2000 ppm and farnesol 5%. Her symptoms resolved after moving out of her apartment, but she suffered recurrence of symptoms on 3 occasions after she visited her apartment to remove her belongings (Lundov et al, 2011).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) Dyspnea and bradypnea were observed in rats exposed to 2.64 mg/m(3).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRIC ULCER
    1) WITH POISONING/EXPOSURE
    a) Full strength (1.5 to 14%) solutions are corrosive to gastric mucosa.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Severe skin irritation occurs with 0.6% or greater concentrations. Moderate skin irritation occurs with 0.3% solutions. 0.06% solution is not a primary irritant (pp CS-472). In one study, methylisothiazolinone (MIT)-containing shampoos, sunscreens, and lotions (concentrations 100 ppm or 0.01%) were not irritating to volunteers (Burnett et al, 2010). However, Irritant reactions to 1000 ppm were described in a study of occupational dermatitis (Bjorkner et al, 1986).
    1) CASE REPORT: A 37-year-old industrial chemist developed an immediate local blister after spilling Kathon WT, containing 10% chloromethylisothiazolone and 3.8% methylisothiazolone. Re-exposure resulted in a delayed severe erythematous blistering rash that persisted for 3 weeks (O'Driscoll & Beck, 1988).
    2) CASE REPORT: A worker developed erythema and minor blistering 2 hours after carrying on his shoulder containers which contained the isothiazolinone biocide 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one in a 3:1 ratio (MCI/MI). Severe pain and a 3% mid-dermal burn developed 9 hours later (Tay & Ng, 1994).
    3) CASE REPORT: Periorbital erythema and infiltration has been reported in a woman who was exposed to Indur Maxx (R) floor-cleaning agent, containing octylisothiazolinone (Recke et al, 2015).
    B) HYPERSENSITIVITY REACTION
    1) WITH POISONING/EXPOSURE
    a) Allergic delayed contact dermatitis is the most common dermal manifestation of isothiazolone exposure. Kathon CG is being used increasingly in leave-on cosmetics, such as face and hand creams and lotions, and is an increasing cause of cosmetic dermatitis (Burnett et al, 2010; Mowad, 2000; de Groot & Weyland, 1988).
    b) Although contact allergy from industrial use has been reported, most problems are due to personal care products (Mowad, 2000).
    c) In animal studies, methylchloroisothiazolinone was a strong sensitizer and methylisothiazolinone was a weak sensitizer (Burnett et al, 2010).
    d) One study reported that isothiazolinones do not always cross-react, therefore, allergy to one isothiazolinone did not mean sensitivity to the entire group (Mowad, 2000). However, another retrospective study reported an increase in primary sensitization to methylisothiazolinone resulting in a rise in methylchloroisothiazolinone/methylisothiazolinone reactions caused by immunological cross-reactions (Geier et al, 2012). In a study of 80 volunteers, the sensitization threshold was at or around 1000 ppm. It was suggested that some subjects with known sensitivity to methylchloroisothiazolinone/methylisothiazolinone may also react to methylisothiazolinone following exposures to high concentrations of methylisothiazolinone (500 to 1000 ppm) (Burnett et al, 2010).
    e) Concentration-dependent delayed contact dermatitis has been demonstrated in both humans and animals. In guinea pigs, dermatitis was seen after sensitization with 1000 ppm 3 times weekly for 3 weeks. At induction concentrations of 25 ppm, delayed sensitivity could only be produced by challenge doses of 2000 ppm (Chan et al, 1983).
    f) Paper hanging, water painting, the use of certain hair gels or cosmetics, and work in metallurgical, pottery or paper manufacturing industries may increase exposure to Kathon, Kathon CG or to the Kathon CG analogue, 1,2-benzisothiazolin-3-one (1,2-BIT; Proxel(R)), which has also been associated with allergic contact dermatitis (Damstra et al, 1992) Valsecchi et al, 1993).
    1) The isothiazolinone mixture, Grotan TK 2 has also been associated with allergic contact dermatitis among workers in a nylon producing textile industry (Valsecchi et al, 1993).
    g) TYPE OF RASH: The rash consists of a sharply demarcated erythematous vesicular lesion, usually on the hands and face. Dermatitis can be elicited from use of preparations containing as little as 5 to 7 ppm (Hannuksela, 1986). The primary sensitizer is 5-chloro-2-methyl-4-isothiazolin-3-one.
    h) INCIDENCE: Although the frequency of positive patch tests is high, the occurrence of dermatitis after exposure to cosmetics and toiletries is low in individuals with healthy skin. Most reactions to healthy skin occur on the face and around the eyes (de Groot & Herxheimer, 1989).
    i) RISK FACTORS: Most reactions have been reported in patients with previously damaged skin or dermatitis, with leave-on products usually implicated (de Groot & Weyland, 1988). Patients most at risk are older and have a history of long-standing dermatitis (Fransway, 1989).
    j) PATCH TESTS: Patch tests with 56 ppm in creams or lotions to humans resulted in moderate to severe skin sensitization in 2 of 10 and 4 of 50, respectively. Exposure to 25 ppm in water sensitized 1 of 18 volunteers. Photosensitivity has not been demonstrated in animals or humans (pp CS-472).
    1) In a retrospective analysis, eczema patients were patch tested with methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) 4 mcg/cm(2), MCI/MI 0.02%, MI 0.2%, or MI 0.02%. Between 2011 to 2013, patch testings with methylisothiazolinone (MI) 0.02% and MI 0.2% were performed in 1511 and 1655 patients, respectively. At least 1 of the 4 agents produced a positive reaction in 96 patients. Overall, 61% of positive patch test reactions were to both MCI/MI and MI with 23% positive reactions to MCI/MI alone, and 13% to MI alone. Sources of exposure to these agents were cosmetics (45%), cleaning agents (7%), paint (15%), airborne (14%), and baby wipes (1%). Hand eczema and face eczema were observed in 49 (51%) and 37 patients (39%), respectively (Madsen & Andersen, 2014). In another retrospective study from Europe, it was shown that sensitization incidence to isothiazolinone has increased from less than 1% in 2005 to 10.9% in the first half of 2013. Approximately 64% of methylisothiazolinone (MI)-sensitized patients reacted to products containing 50 ppm and 18% reacted to products containing 5 ppm. Higher reaction intensity was observed for MI than for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) (Gameiro et al, 2014).
    2) Patch testing with Kathon CG, 100 ppm, resulted in positive reactions in 13/1511 contact dermatitis patients. Use of a lotion containing 8.6 ppm of Kathon CG did not produce a reaction in any of 11 positive-patch test patients who were tested (Hjorth & Roed-Petersen, 1986).
    3) Patch testing with a 300 ppm concentration in 976 patients yielded positive reactions in 43 (4.4%) and identified twice as many patients who were sensitized than testing with 100 ppm. Use tests have shown that patients reacting to 300 ppm may develop clinical dermatitis on intact skin whereas patients reacting to 100 ppm may develop dermatitis only after contact to abraded skin (Bjorkner et al, 1986).
    4) Positive patch test reactions were observed in 50 of 3744 (1.3%) dermatitis patients tested with Kathon CG in water. Reactions consisted of sharply demarcated erythemato-vesicular lesions. Twenty of these patients were subsequently tested with a preparation containing 15 ppm; 8 developed dermatitis (Meneghini et al, 1987).
    5) Lower rates of sensitization (0.8 to 1.1%) were found in one study, and the rate did not increase significantly when the original cohort of patients were retested 12 months later (Cox & Shuster, 1988).
    k) BABY WIPES: Some baby wipes contain methylisothiazolinone. Contact dermatitis has been reported in children and their parents who used disposable wipes during diaper changes (Boyapati et al, 2013; Cahill et al, 2014).
    l) CASE REPORT: A man with a 1-year history of contact dermatitis caused by methylisothiazolinone in a hair gel, presented with symptoms mimicking folliculitis decalvans. He had follicular crust, tufting, and cicatrization on his scalp, as well as red, infiltrated lesions on his face (Aerts et al, 2014).
    m) CASE REPORT: A 53-year-old woman with no previous history of eczema or other allergies presented with severe respiratory symptoms, erythema in the face, and edema around the eyes after moving to a newly painted apartment. Prior to presentation, she received prednisolone (25 mg twice daily) prescribed by general practitioner. Four days after patch testing, she developed positive reactions to methylisothiazolinone (MI) 2000 ppm and farnesol 5%. Her symptoms resolved after moving out of her apartment, but she suffered recurrence of symptoms on 3 occasions after she visited her apartment to remove her belongings (Lundov et al, 2011).
    n) CASE REPORT: A 47-year-old psychologist developed widespread dermatitis of the axillae, breasts and face while using cosmetics, shampoo and fabric softeners containing methylchloro- and methyl-isothiazolinone (MCI/MI) for approximately one year. In addition, she developed systemic systems (malaise, mild conjunctival, nasal symptoms, slight pyrexia and 10% of her WBC count of 7.0x10(9)/L were eosinophils) after exposure to paint and cleaning products containing MCI/MI (Fernandez De Corres et al, 1995).
    o) CASE REPORT: A 29-year-old man presented with erythema, dermatitis with vesiculation, and large blisters on his upper thigh and left arm, forehead, and fifth digit of his right foot 15 days after cleaning a cooling tower, using Calcolith-Z(R) (containing less than 23% hydrochloric acid and less than 2% aryl ammonium chloride; pH less than 1) and Biocil-I(R) (containing less than 3% of isothiazolinone and a ratio of methylchloroisothiazolinone to methylisothiazolinone of 3:1; pH less than 3). Initially, he developed transient erythema on his left upper thigh and arm the day after exposure. On day 10, he developed pruritic erythematous dermatitis on the same areas. Vesicles and bullae were observed during physical examination. Laboratory results revealed elevated total serum IgE (135 kUnits/L) 20 days postexposure. Patch testing revealed a positive reaction to methylchloroisothiazolinone/methylisothiazolinone (100 ppm) (Willi et al, 2011).
    C) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 49-year old man developed well-demarcated, red, urticarial plaques containing tense bullae on the anterior trunk, both upper extremities, and left thigh along with a burning sensation 10 to 20 minutes following a spill of 15% glutaraldehyde and isothiazoline to the skin. Treatment included: triamcinolone 0.1% cream and oral prednisone which provided initial improvement; dexamethasone was added for ongoing blisters. Resolution occurred over a 5-month period (Chen & Fairley, 1988).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DERMATITIS CONTACT
    a) In guinea pigs, dermatitis was seen after sensitization with 1000 ppm 3 times weekly for 3 weeks. At induction concentrations of 25 ppm, delayed sensitivity could only be produced by challenge doses of 2000 ppm (Chan et al, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Maternal and fetal deaths but no teratogenicity were observed in rabbits and rats.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Maternal and fetal deaths but no teratogenicity were observed in rabbits and rats given 1.5 to 15 mg/kg.
    3.20.3) EFFECTS IN PREGNANCY
    A) DEATH
    1) Maternal and fetal deaths but no teratogenicity were observed in rabbits and rats given 1.5 to 15 mg/kg.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS26172-55-4 (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

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) The vast majority of patients do not require laboratory evaluation.
    B) Hematocrit, or complete blood count should be evaluated in gastrointestinal bleeding cases.
    C) Patch test material for Kathon CG is available for diagnosis of delayed contact dermatitis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) No specific lab work (CBC, electrolytes) is needed unless otherwise clinically indicated.
    2) Hematocrit, or complete blood count should be evaluated in gastrointestinal bleeding cases.
    4.1.4) OTHER
    A) OTHER
    1) DERMAL
    a) The patch test material for Kathon CG, from the North American Contact Dermatitis Group or the Rohm and Haas company contains 100 ppm (0.67%) of active ingredient in an aqueous vehicle. This concentration has been found to be non-irritating and unlikely to induce sensitization (de Groot & Weyland, 1988).
    b) A concentration of 2000 ppm (0.2% aqueous) has been recommended for patch testing for methylisothiazolinone to maximize sensitivity of the test (Latheef & Wilkinson, 2015).

Methods

    A) CHROMATOGRAPHY
    1) High pressure liquid chromatography is the preferred method for determining low levels of isothiazolones in aqueous solutions.

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) The very rare patient with severe gastrointestinal or respiratory symptoms or extensive dermal burns or ocular injury should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients and those with mild irritation can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact your local poison center or consult a medical toxicologist for any patient with severe toxicity. Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated. Consult an ophthalmologist for patients with evidence of corneal injury.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with more than mild irritation and those with deliberate exposure to high concentration products should be referred to a healthcare facility for evaluation and treatment.

Monitoring

    A) The vast majority of patients do not require laboratory evaluation.
    B) Hematocrit, or complete blood count should be evaluated in gastrointestinal bleeding cases.
    C) Patch test material for Kathon CG is available for diagnosis of delayed contact dermatitis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ORAL EXPOSURE: Prehospital gastrointestinal decontamination is not recommended; toxicity is from irritant/caustic effects, not systemic absorption. Dilution with a small amount of milk or water may be useful if it can be done shortly after ingestion.
    B) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    2) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    C) DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area thoroughly with soap and water.
    D) EYE EXPOSURE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastrointestinal decontamination is not recommended; toxicity is from irritant/caustic effects, not systemic absorption. Dilution with a small amount of milk or water may be useful if it can be done shortly after ingestion.
    B) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    2) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment for mild and moderate symptoms consists of symptomatic and supportive care.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Patients who ingest undiluted industrial products may sustain caustic gastrointestinal injury. Perform endoscopy early (within 12 hours) in patients with stridor, drooling, vomiting, significant oral burns, difficulty swallowing or abdominal pain, and in all patients with deliberate ingestion. If burns are absent or grade I severity, patient may be discharged when they are able to tolerate liquids and soft foods by mouth. If mild grade II burns, admit the patient for intravenous fluids, and slowly advance diet as tolerated. Perform barium swallow or repeat endoscopy several weeks after ingestion (sooner if difficulty swallowing) to evaluate for stricture formation. Early surgical consultation is recommended for patients with severe grade II or grade III burns, large deliberate ingestions, or signs, symptoms or laboratory findings concerning for tissue necrosis or perforation. Early endotracheal intubation and bronchoscopy in patients with respiratory distress or upper airway edema.
    B) MONITORING OF PATIENT
    1) The vast majority of patients do not require laboratory evaluation.
    2) Hematocrit, or complete blood count should be evaluated in gastrointestinal bleeding cases.
    3) Patch test material for Kathon CG is available for diagnosis of delayed contact dermatitis.
    C) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    2) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    D) ENDOSCOPIC PROCEDURE
    1) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
    2) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
    3) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.
    a) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992)
    4) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):
    a) Advancing across the cricopharynx under direct vision
    b) Gently advancing with minimal air insufflation
    c) Never retroverting or retroflexing the endoscope
    d) Using a pediatric flexible endoscope
    e) Using extreme caution in advancing beyond burn lesion areas
    f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).
    5) GRADING
    a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding, and perforation is related to the severity of the initial burn (Zargar et al, 1991):
    b) Grade 0 - Normal examination
    c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
    d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
    e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
    f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
    g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.
    6) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
    7) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
    8) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).
    E) CORTICOSTEROID
    1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
    2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
    3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
    4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
    5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
    6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
    7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
    8) STUDIES
    a) ANIMAL
    1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
    2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
    3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).
    b) HUMAN
    1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
    2) META ANALYSIS
    a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
    b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
    c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).
    3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
    4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
    5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).
    a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
    b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
    c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
    d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
    e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).
    6) ADVERSE EFFECTS
    a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).
    F) SURGICAL PROCEDURE
    1) SUMMARY: Initially if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed. If dilation is unsuccessful colonic intraposition or gastric tube placement may be needed. Early laparotomy should be considered in patients with evidence of severe esophageal or gastric burns on endoscopy.
    2) STRING - If a second degree or circumferential burn of the esophagus is found a string may be placed in the stomach to avoid false channel and to provide a guide for later dilation procedures (Gandhi et al, 1989).
    3) STENT - The insertion of a specialized nasogastric tube or stent immediately after endoscopically proven deep circumferential burns is preferred by some surgeons to prevent stricture formation (Mills et al, 1978; (Wijburg et al, 1985; Coln & Chang, 1986).
    a) STUDY - In a study of 11 children with deep circumferential esophageal burns after caustic ingestion, insertion of a silicone rubber nasogastric tube for 5 to 6 weeks without steroids or antibiotics was associated with stricture formation in only one case (Wijburg et al, 1989).
    4) DILATION - Dilation should be performed at 1 to 4 week intervals when stricture is present(Gundogdu et al, 1992). Repeated dilation may be required over many months to years in some patients. Successful dilation of gastric antral strictures has also been reported (Hogan & Polter, 1986; Treem et al, 1987).
    5) COLONIC REPLACEMENT - Intraposition of colon may be necessary if dilation fails to provide an adequate sized esophagus (Chiene et al, 1974; Little et al, 1988; Huy & Celerier, 1988).
    6) LAPAROTOMY/LAPAROSCOPY - Several authors advocate laparotomy or laparoscopy in patients with endoscopic evidence of severe esophageal or gastric burns to evaluate for the presence of transmural gastric or esophageal necrosis (Cattan et al, 2000; Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993).
    a) STUDY - In a retrospective study of patients with extensive transmural esophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (esophagoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient to fresh air. Monitor the patient for respiratory distress; if a cough or difficulty in breathing develops, evaluate for respiratory tract irritation, bronchitis, pulmonary edema and pneumonia.
    6.7.2) TREATMENT
    A) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) 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).
    2) Early (1 to 2 minutes postexposure) and thorough rinsing with tap water removed 90% of applied isothiazolinone from cadaver skin. A 20 minute exposure, followed by tap water rinsing, resulted in only 60% removed (Cardin et al, 1986).
    6.9.2) TREATMENT
    A) DERMATITIS
    1) Contact dermatitis is usually alleviated with topical corticosteroid therapy. Severe or extensive dermatitis may benefit from a brief course of systemic corticosteroids.
    B) BURN
    1) Treat burns with topical antibiotics and analgesics as needed.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) A 37-year-old industrial chemist developed an immediate local blister after spilling Kathon WT, containing 10% chloromethylisothiazolone and 3.8% methylisothiazolone. Re-exposure resulted in a delayed severe erythematous blistering rash that persisted for 3 weeks (O'Driscoll & Beck, 1988).
    2) A worker developed erythema and minor blistering 2 hours after carrying on his shoulder containers which contained the isothiazolinone biocide 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one in a 3:1 ratio (MCI/MI). Severe pain and a 3% mid-dermal burn developed 9 hours later. A burns specialist was consulted and daily tulle gras dressings applied. The patient was discharged after 5 days. A leaking container which contained the biocide was found at the employee's worksite (Tay & Ng, 1994).
    B) ADVERSE EFFECTS
    1) A 48-year-old man developed contact dermatitis on the hands and forearms, and demonstrated a positive patch test response to Kathon(R) CG and Algezid II during the course of his employment as a telecommunications engineer. His occupation required him to periodically immerse his hands and forearms into a photographic developing chemical bath. The chemical bath contained the biocide Algezid II and Kathon 886, according to the Algezid II manufacturers. No allergic skin reactions to the other chemicals contained in the photographic developing bath were identified through patch testing. The desquamative eczema cleared after the patient changed employment (Brown, 1990).
    2) Allergic contact dermatitis associated with the Kathon(R) CG analogue, 1,2-benzisothiazolin-3-one (1,2-BIT; Proxel(R)) has been reported (Damstra et al, 1992).
    a) A 45 year old male paper-hanger presented with hand dermatitis which was not responsive to standard therapies. Patch testing with a European standard series of agents was negative. Patch tests to 1,2-BIT (0.04%) were positive. The dermatitis resolved with cessation of exposure.
    b) Hand dermatitis and positive reactions to patch testing with 1,2-BIT (0.4%) and/or Kathon(R) CG were detected among other individuals who were exposed to one or both of these agents as a result of occupation or hobbies. The dermatitis improved or completely resolved in most cases with the use of impervious gloves or with cessation of exposure.
    c) Paper hanging, water painting, the use of certain hair gels or cosmetics, work in metallurgical or paper manufacturing industries were considered to increase risk of exposure to these chemicals. The authors report that cross-sensitivity between 1,2-BIT and Kathon(R) CG is unlikely. Ten percent of a random sample demonstrated a positive patch test to 1,2-BIT.
    3) Valsecchi et al (1993) report six cases of allergic contact dermatitis associated with isothiazolinone exposure during work in the nylon producing textile industry. The source of exposure was handling of yarn which had been treated with a lubricating oil emulsion which contained Grotan TK 2 (0.10 to 0.15%) as a bacterial static agent. Gloves were not worn (Valsecchi et al, 1993).
    a) Erythematous, vesicular and desquamating lesions occurred on the hands and/or forearms. Patch tests were positive to Kathon CG (100 ppm in water) or Kathon CG and Grotan TK 2. The dermatitis cleared upon worker reassignment to positions which did not involve exposure to isothiazolinones. No relapses occurred during the 2 year follow up period.
    b) Kathon is a mixture of two isothiazolinones (5-chloro-2-methyl-4- isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one) in a ratio of 3:1, respectively, with MgCl2 and Mg(NO3)2 added as stabilizers. Grotan TK 2 is a brand name for an isothiazolinone mixture.

Range Of Toxicity

Summary

    A) TOXICITY: Concentrations of 0.06% or less are non-irritant and 1.5% or more solutions are corrosive. No acute dermal irritation was seen in humans after contact with 100 ppm. Dermal sensitization has occurred with 25 to 56 ppm, and rarely with 5 to 7 ppm.

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) In the US and Europe, the maximum permitted concentration of methylisothiazolinone (MIT) in cosmetics (or as preservative) is 100 ppm (0.01%). Overall, current cosmetics products contain from 0.000004% to 0.01% (100 ppm) of MIT as a preservative (Lundov et al, 2011; Burnett et al, 2010). In one study, many patients allergic to MIT reacted to 50 ppm (Lundov et al, 2011).
    2) MARGIN OF SAFETY: In one study, a margin of safety (MOS) of MIT was determined in a worst case scenario: 100% dermal absorption in a 60-kg individual, the maximum permitted concentration of 100 ppm or 0.1 mg/g, and global daily exposure of 17.79 g/day from all products including multiple cosmetics and personal care products. Using this assumption, a 60-kg individuals will be exposed to 0.0296 mg/kg per day of MIT from all products (0.1 mg/g x 17.79 g/day x 1/60 kg = 0.0296 mg/kg/day) (Burnett et al, 2010).
    3) DERMAL: No acute irritation was seen in humans with 100 ppm (0.67%) dermally, but sensitization has occurred with 25 to 56 ppm, and rarely with 5 to 7 ppm (Hannuksela, 1986). Solutions of 1.5% or greater are corrosive (de Groot & Weyland, 1988).
    4) In 1992, allowable levels of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was 15 ppm and 7.5 ppm in rinse-off and leave-on products, respectively (Mowad, 2000).

Workplace Standards

    A) ACGIH TLV Values for CAS26172-55-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS26172-55-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS26172-55-4 :
    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

    D) OSHA PEL Values for CAS26172-55-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 53 mg/kg (RTECS , 2002)
    2) 60 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Isothiazolones demonstrate antimicrobial activity against gram-positive and gram-negative bacteria, fungi, yeast, and algae (Burnett et al, 2010).

Physicochemical

Physical Characteristics

    A) METHYLISOTHIAZOLINONE: Colorless, clear with a mild odor, liquid at 20 degrees C; completely soluble in water; mostly soluble in acetonitrile, methanol, hexane; slightly soluble in xylene (Burnett et al, 2010).

Ph

    A) METHYLISOTHIAZOLINONE: 3.87 at 25 degrees C (Burnett et al, 2010)

Molecular Weight

    A) METHYLISOTHIAZOLINONE: 115.2 (Burnett et al, 2010)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
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