PARAPHENYLENEDIAMINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) BASF URSOL D
2) BENZOFUR D
3) DEVELOPER 13
4) DEVELOPER PF
5) DURAFUR BLACK R
6) FENYLENODWUAMINA (POLISH)
7) FOURAMINE D
8) FOURRINE 1
9) FOURRINE D
10) FUR BLACK 41867
11) FUR BROWN 41866
12) FUR YELLOW
13) FURRO D
14) FUTRAMINE D
15) NAKO H
16) ORSIN
17) OXIDATION BASE 10
18) PARADIAMINOBENZENE
19) PELAGOL D
20) PELAGOL DR
21) PELAGOL GREY D
22) PELTOL D
23) PHENYLENEDIAMINES
24) RENAL PF
25) SANTOFLEX IC
26) TEPTRAL D
27) URSOL D
28) ZOBA BLACK D

1) p-Aminoaniline
2) 4-Aminoaniline
3) p-Benzenediamine
4) 1,4-Benzenediamine
5) black stone powder (folk medicine)
6) p-Diaminobenzene
7) 1,4-Diaminobenzene
8) "Para"
9) Paraphenylen-diamine
10) Phenylenediamine, para
11) 1,4-Phenylenediamine
12) PPD
13) C.I. 76060
14) C.I. Developer 13
15) C.I. Oxidation Base 10
16) CAS 106-50-3
17) NIOSH/RTECS SS 8050000
18) COLIPA n' A7

1) PARAPHENYLENEDIAMINE HYDROCHLORIDE
2) 1,4-Benzenediamine dihydrochloride
3) 4-Aminoaniline dihydrochloride
4) para-Aminoaniline dihydrochloride
5) para-Benzenediamine dihydrochloride
6) 1,4-Diaminobenzene dihydrochloride
7) para-Diaminobenzene dihydrochloride
8) 1,4-Phenylenediamine dihydrochloride
9) C.I. Oxidation Base 10A
10) C.I. 76061
11) CAS 624-18-0

Available Forms Sources

1) White to light purple crystals. Oxidizes to purple or black upon standing in air (ACGIH, 1991). This will result in black powder which then can be mixed with the hair dyes or henna.
2) Typical concentrations of paraphenylenediamine in hair dyes range from 0.2% in blond dyes to 4% in black dyes (IARC, 1978).

1) Paraphenylenediamine is used in hair dyes to obtain a brown or black shade. It is used in fur dyeing to produce black, grey, dull violet, and reddish-brown shades. It is also used in printing textiles (IARC, 1978).
2) Paraphenylenediamine and derivatives are used in photographic developers and in photochemical measurements (IARC, 1978; ACGIH, 1991).
3) Paraphenylenediamine is used as an intermediate in the manufacturing of dyes and other chemicals, including polyparaphenylene terephthalamide, which is used as tire cord (IARC, 1978). It is also a chemical intermediate in the manufacturing of dyes, antioxidants, and rubber accelerators (ACGIH, 1991; Lewis, 1997; Hathaway et al, 1996).
4) HAIR DYE - Paraphenylenediamine is known in the hairdressing trade as "para." In Africa and Asia it is frequently mixed with Henna and applied to color hands and feet and to dye hair a dark red shade (Filali & Soulaymani, 2001; Midha et al, 2000).

a) INTENTIONAL EXPOSURE - In developing countries, intentional ingestion of hair dyes containing paraphenylenediamine (PPD) has become a public health concern. PPD exposure is a major health concern in eastern Africa (particularly the Sudan), Morocco and the Indian subcontinent. In adults, 70% to 90% of PPD poisonings are due to intentional self-harm (Sampathkumar & Yesudas, 2009; Abdelraheem et al, 2009).

5) FOLK MEDICINE - Paraphenylenediamine has been used by a witch doctor as a homemade remedy for pain associated with a stable vertebral compression fracture (Averbukh et al, 1989). Paraphenylenediamine or "black stone" powder has been used as a home remedy for constipation (Shemesh et al, 1995).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Paraphenylenediamine (PPD) is an aniline derivative used as a hair and fur dye, photographic developer, in photochemical measurements, chemical intermediate in the manufacturing of dyes, antioxidants, rubber accelerators, and component of some temporary tattoos ("black henna"). PPD has been used as an ethnopharmaceutical treatment of pain and as a home remedy for constipation.
B) TOXICOLOGY: Allergic contact dermatitis is mediated by dendritic cell and T-cell activation. Human dendritic cells may be activated by PPD and its immediately formed derivatives. However, products of PPD acetylation do not participate in dendritic cell activation. Following the ingestion of PPD, calcium release and leakage of calcium ions from smooth endoplasmic reticulum along with irreversible changes in muscle structure results in rhabdomyolysis.
C) EPIDEMIOLOGY: The frequency of allergic reactions to PPD was found to be 5.5% by the North American Contact Dermatitis Group. One prospective study from India documented 1595 cases of PPD toxicity over 6.5 years from a single institution; 98% of cases were of suicidal intent.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Immediate hypersensitivity reactions (most common), delayed hypersensitivity reactions, and erythema multiforme have been reported following the application of PPD-containing products. Small quantities of the dust have caused inflammation of the pharynx and larynx, and asthmatic attacks in chronically exposed workers. Epigastric pain and recurrent vomiting are common shortly after ingestion, followed by painful progressive edema of the face, neck, and pharynx. Patients may also develop pain/rigidity of limb, respiratory distress, tachycardia, syncope, palpitations, chest pain, abnormal urine color, hypotension, hypertension, and nasal regurgitation.
2) SEVERE TOXICITY: Progression of airway swelling may lead to dyspnea, laryngeal edema, cyanosis, and respiratory failure or airway obstruction. Systemic toxicity can include tremors, rhabdomyolysis, hypocalcemia, metabolic acidosis, acute tubular necrosis, hepatotoxicity, and methemoglobinemia. In severe poisonings, anaphylaxis, seizures, hypotension, myocarditis, myocardial infarction, ventricular tachycardia/fibrillation, intravascular hemolysis, and/or flaccid paralysis may occur.

0.2.20)

A) Fetal loss has been reported in a pregnant woman (at 23 to 24 weeks gestation) who developed acute respiratory failure, acute renal failure, and rhabdomyolysis after ingesting an unknown amount of PPD. Examination of the fetal organs showed myocardial lysis, lung congestion, interstitial edema, and inflammatory infiltration of the lingua base, chorionic villus thrombosis, and abruptio placentae. Paraphenylenediamine was not teratogenic in rats.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta2-adrenergic agonists, corticosteroids or epinephrine. Consider bronchodilators and systemic corticosteroids in patients with significant bronchospasm. Consider aggressive fluid hydration and urine output monitoring for rhabdomyolysis. Manage mild hypotension with IV fluids.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treatment of severe anaphylaxis includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Methylprednisolone decreased mortality over hydrocortisone in a non-blinded, non-randomized, prospective study of severely intoxicated patients with PPD.

C) DECONTAMINATION

1) PREHOSPITAL: ORAL EXPOSURE: Do not induce emesis. Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration. INHALATIONAL EXPOSURE: Monitor for respiratory distress. If cough or difficulty breathing develops, administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists after washing. 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. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed.
2) HOSPITAL: ORAL EXPOSURE: Consider administration of activated charcoal after a potentially toxic ingestion, if the overdose is recent, the patient is not vomiting, and is able to maintain airway. Gastric lavage may be considered in large overdoses that present early to medical attention in conjunction with use of activated charcoal. INHALATIONAL EXPOSURE: Monitor for respiratory distress. If cough or difficulty breathing develops, administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists after washing. 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. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed.

D) AIRWAY MANAGEMENT

1) Death is most often due to acute respiratory distress. Endotracheal intubation may be exceedingly difficult because of upper airway edema; emergent tracheostomy or cricothyrotomy may be required.

E) ANTIDOTE

1) None.

F) HYPERSENSITIVITY REACTION

1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

G) RHABDOMYOLYSIS

1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.

H) METHEMOGLOBINEMIA

1) Cyanosis following ingestion of PPD may be due to respiratory insufficiency and/or methemoglobinemia. Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

I) ENHANCED ELIMINATION

J) PATIENT DISPOSITION

1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. Mild allergic contact dermatitis may be managed as an outpatient.
2) OBSERVATION CRITERIA: All patients with deliberate ingestions, patients with respiratory distress, or any oral ingestion that is more than a sip, lick, or taste should be referred to healthcare facility for further management. Significant clinical manifestations typically present within the first 6 hours; however, rhabdomyolysis and renal failure may develop over days to weeks.
3) ADMISSION CRITERIA: Any patient with moderate to severe toxicity should be admitted to the hospital for further monitoring and supportive care.
4) CONSULT CRITERIA: Consult a nephrologist for dialysis in patients with evidence of oliguric or anuric renal failure. Patients with myocarditis should be evaluated by a cardiologist. Consult a regional Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.
5) TRANSFER CRITERIA: Patients requiring critical care management or hemodialysis should be transferred to facilities capable of higher levels of care.

K) PITFALLS

1) Oral ingestion can result in significant toxicity with doses as little as 3 g. Black powder form or a rock of PPD can be mistaken for other substances and lead to significant toxicity.

L) PHARMACOKINETICS

1) Absorption: Following application of 20 mg/kg to the scalp, 0.14% was absorbed. Metabolism: PPD undergoes acetylation by N-acetyltransferase 1 in keratinocytes to monoacetyl-PPD and diacetyl-PPD.

M) PREDISPOSING CONDITIONS

1) Patients with preexisting asthma, atopy, cardiac, or renal conditions may be at greater risk for severe toxicity. The slow-acetylation variant of N-acetyltransferase 1 may predispose an individual to sensitivity to PPD.

N) DIFFERENTIAL DIAGNOSIS

1) Allergic contact dermatitis crossreactivity was observed between PPD and other para-amino compounds, such as textile dyes (eg, Disperse Blue 106 or 124, orange #3), benzocaine, isopropyl-para-phenylenediamine, sulfa drugs, diaminotoluene, 2-nitro-4-phenylenediamine, aminophenol, and para-aminobenzoic acid, and aminoazobenzene.

0.4.3)

A) Monitor for respiratory distress. If cough or difficulty breathing develops, 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)

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)

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

Clinical Effects

Summary Of Exposure

Heent

3.4.2)

A) WITH POISONING/EXPOSURE

1) GUM DISCOLORATION: A purple color may be noted on the teeth or gums (Bowen, 1962; Nott, 1924).

3.4.3)

A) WITH THERAPEUTIC USE

1) HYPERSENSITIVITY: Immediate (usually) or delayed hypersensitivity reactions have been described following application of PPD-containing hair dyes to eyebrows or eyelashes. Typically pain and burning of the eye, blepharoconjunctivitis, and edema occur, which may progress to widespread facial edema and dermatitis (Harner, 1933; McCally et al, 1933; Moran, 1934; Greenbaum, 1933).

a) Lacrimation, photophobia, uveitis, and keratitis are also common. Most patients tested have had positive skin tests to paraphenylenediamine. Corneal necrosis, sometimes leading to permanent vision loss, has been reported (Brav, 1936; McCally et al, 1933; Grant & Schuman, 1993).

2) OPTIC NEURITIS: Bilateral optic neuritis has been reported in the absence of dermatitis (Keschner & Rosen, 1941).

a) A 24-year-old man developed severe facial swelling and exophthalmos after ingesting a paraphenylenediamine containing hair dye. He subsequently was noted to be blind and examination revealed optic neuritis that progressed to optic atrophy despite treatment with corticosteroids (Yagi et al, 1996).

3) ANIMAL STUDIES: DIRECT TOXICITY: In the absence of hypersensitivity, only mild conjunctivitis has been reported following instillation of PPD into rabbit eyes (Grant & Schuman, 1993).

3.4.5)

A) WITH POISONING/EXPOSURE

1) In one prospective study, 40 (2.5%) of 1595 patients developed nasal regurgitation after the ingestion of PPD-containing hair dye. Nasal twang of voice developed in 95% (6%) patients (Jain et al, 2013).

3.4.6)

A) WITH POISONING/EXPOSURE

1) LARYNGEAL EDEMA: A 60-year-old woman with a medical history of diabetes and hypertension, developed dyspnea, neck edema, blurred vision and weakness immediately after ingesting "black rock" containing henna and PPD (confirmed by toxicological analysis). After arrival to the ED, she developed severe dyspnea, agitation, and laryngeal angioedema. Otolaryngologic exam showed angioedema of tongue, pharynx and epiglottis with airway obstruction. Immediate airway support and intubation were required. She received IM epinephrine, steroids, and antihistamine after acute allergic reaction was suspected. Laboratory results revealed elevated serum creatinine, metabolic acidosis with normal anion gap, leukocytosis without eosinophilia, elevated hepatocellular enzymes, and elevated creatinine kinase concentrations (78,250 Units/L) and myoglobin (106,117 ng/mL). Following supportive care, including hemodialysis, her condition improved and she was extubated on day 3 and her renal function returned to normal a week later (Nevo-Shor et al, 2013).
2) In one prospective study, 95 (6%) of 1595 patients developed nasal twang of voice after the ingestion of PPD-containing hair dye (Jain et al, 2013).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension has been reported after severe poisoning (usually deliberate ingestion), secondary to anaphylactic shock (Sood et al, 1996; Ashraf et al, 1994; Hashim et al, 1992).
b) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Hypotension (range undefined) was reported in 149 (15%) cases (Jain et al, 2011).
c) In one prospective study, 239 (15%) of 1595 patients developed hypotension after the ingestion of PPD-containing hair dye (Jain et al, 2013).

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypertension has occasionally been reported in children (Hashim et al, 1992).
b) In one prospective study, 127 (8%) of 1595 patients developed hypertension after the ingestion of PPD-containing hair dye (Jain et al, 2013).

C) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia may develop, usually associated with hypotension or hypoxia (Sood et al, 1996; Lifshits et al, 1993; Squali et al, 1991).
b) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Tachycardia was reported in 214 (21%) cases. In 21 cases (9%), ventricular tachyarrhythmias occurred and among those 21 cases, 12 deaths were reported despite supportive treatment (Jain et al, 2011).
c) In one prospective study, 350 (22%) of 1595 patients developed sinus tachycardia after the ingestion of PPD-containing hair dye. Ventricular tachycardia/fibrillation developed in 22 (9%) patients (Jain et al, 2013).

D) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Ventricular dysrhythmias and cardiac arrest may develop, usually in the setting of intractable hypotension or hypoxia (Lifshits et al, 1993; Ashraf et al, 1994; Hashim et al, 1992; Bourquia et al, 1988).
b) CASE REPORT: Mild depression of the ST segment in ECG leads II and AVF was present in an adult patient who died 30 hours following ingestion of 3 grams of paraphenylenediamine (Saito et al, 1990).
c) CASE SERIES: A 27-year-old woman presented with dyspnea, difficulty in speaking, inability to walk, swollen face and neck, a black, swollen tongue, flaccid paraparesis, and pain and tenderness of the lower limbs after ingesting an unknown amount of PPD in a suicide attempt. Her vital signs included a respiratory rate of 40 breaths/min, a pulse rate of 120 beats/min and a blood pressure of 11/90 mmHg. About 500 mL of black colored urine was drained in her urinary catheter bag. Despite supportive care, her condition deteriorated and she developed ventricular dysrhythmias and died. Two of her 4 children presented several hours later with similar symptoms after ingesting a juice containing PPD. Her 5-year-old daughter died 37 hours after presentation despite supportive care. Her 7-year-old son developed renal failure, but recovered following 2 weeks of hemodialysis. Two younger children did not develop any symptoms (Abdelraheem et al, 2014).

E) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Two patients without any history of cardiovascular disease developed myocardial damage after paraphenylenediamine (PPD) poisoning. In the first case, ECG revealed the presence of localized ST segment elevation in precordial leads (V1-V4). Transthoracic echocardiography of this patient was consistent with diffuse myocarditis. In the second case, ECG revealed the presence of localized ST segment elevation in precordial leads (V3-V6). Transthoracic echocardiography of the second patient was consistent with localized myocarditis or septo-apical myocardial infarction. Troponin T levels were 23 ng/mL (case 1) and 29.7 ng/mL (case 2). In the second case, the angiography showed hypokinesia of the left ventricular septo-apical area due to the coronary spasm of the anterior interventricular artery (Brahmi et al, 2006).

F) MYOCARDITIS

1) WITH POISONING/EXPOSURE

a) In a series of 1020 patients with acute paraphenylenediamine poisoning, 238 were suspected of having myocarditis clinically. Manifestations included fatigue, chest pain, palpitations, dyspnea and syncope or presyncope. ECG changes included tachycardia, T wave inversion, ST segment elevation or depression, bundle branch blocks, intra ventricular conduction defects, atrial and ventricular premature complexes, and atrial fibrillation. Ventricular tachyarrhythmias developed in 21 patients. Troponin T was elevated in 136 patients with ECG changes. Transthoracic echocardiogram was performed in 238 of these patients and in 126 patients it revealed decreased left ventricular ejection fraction (less than 35%) and abnormalities in regional wall motion (Jain et al, 2011). It is unclear if some of the ECG changes might have been secondary to hyperkalemia.
b) In India, PPD poisoning occurs following the ingestion of either stone hair dye (containing 70% to 90% PPD; available in 20-gram packs) or branded hair dyes (containing 2% to 10% PPD; available in powder or liquid forms). In one prospective study, 240 (15%) of 1595 patients developed myocarditis after the ingestion of PPD-containing hair dye. Patients had fatigue, dyspnea, chest pain, palpitation, presyncope, syncope with positive ECG changes, including sinus tachycardia, T wave inversion, ST segment elevation or depression, bundle branch blocks, atrial and ventricular premature complexes, and atrial fibrillation. Ventricular tachyarrhythmias developed in 22 patients (9%); 138 patients (57.5%) had positive troponin T. Transthoracic echocardiographic studies revealed regional wall motion abnormalities and reduced left ventricular ejections fraction (LVEF of 35% or lower) in 130 patients (54%). Overall, 69 patients (29%) with myocarditis died. Hemodynamically unstable patients (decrease blood pressure or shock with systolic BP of less than 90 mm Hg) had a mortality rate of about 45% (Jain et al, 2013).

G) CHEST PAIN

1) WITH POISONING/EXPOSURE

a) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Chest pain was reported in 141 (14%) cases and palpitations in 139 (14%) (Jain et al, 2011).
b) In one prospective study, 265 (15.65%) of 1595 patients developed chest pain after the ingestion of PPD-containing hair dye (Jain et al, 2013).

H) SYNCOPE

1) WITH POISONING/EXPOSURE

a) In one prospective study, 287 (18%) of 1595 patients developed presyncope/syncope after the ingestion of PPD-containing hair dye (Jain et al, 2013).

I) PALPITATIONS

1) WITH POISONING/EXPOSURE

a) In one prospective study, 255 (16%) of 1595 patients developed palpitations after the ingestion of PPD-containing hair dye (Jain et al, 2013).

Respiratory

3.6.2)

A) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) Bronchospasm has been described in fur dyers exposed to paraphenylenediamine (Silberman & Sorrell, 1959). Small quantities of the dust have caused inflammation of the pharynx and larynx, and asthmatic attacks in chronically exposed workers (Hathaway et al, 1996).

B) DYSPNEA

1) WITH POISONING/EXPOSURE

a) Acute respiratory distress can occur rapidly due to angioneurotic edema, and is the most common cause of death following overdose (Abdelraheem et al, 2014; El-Ansary et al, 1983).
b) In one prospective study, 366 (23%) of 1595 patients developed respiratory distress after the ingestion of PPD-containing hair dye (Jain et al, 2013).

C) EDEMA

1) WITH POISONING/EXPOSURE

a) Common respiratory findings following ingestion of paraphenylenediamine includes asphyxia and respiratory failure associated with inflammatory edema of the cricopharynx and larynx. Characteristic symptoms associated with ingestion include severe edema of the face and neck, and a swollen dry, hard tongue. Emergent airway management may be necessary (Sampathkumar & Yesudas, 2009).
b) ANGIONEUROTIC EDEMA: Within hours of ingestion severe and painful swelling of the face, neck, and pharynx occurs, which may progress to the larynx and upper airway, producing acute respiratory difficulty or airway obstruction requiring emergent (often surgical) airway management (Suliman et al, 1995; Anuradha et al, 2004; El-Ansary et al, 1983; Chugh et al, 1982; Baud et al, 1984; Averbukh et al, 1989; Ashraf et al, 1994; Lifshits et al, 1993; Shemesh et al, 1995; Hashim et al, 1992; Bourquia et al, 1988; Squali et al, 1991; Filali & Soulaymani, 2001).
c) Endotracheal intubation may be exceedingly difficult because of upper airway edema; emergent tracheostomy or cricothyrotomy may be required (Hashim et al, 1992; Lifshits et al, 1993; Ashraf et al, 1994; Squali et al, 1991).
d) ONSET: Facial and upper airway edema generally develops within 6 hours of ingestion (Hashim et al, 1992) and resolves over 4 to 6 days (Yagi et al, 1996).
e) INCIDENCE

1) A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Severe edema of the face and neck was the most common effect and was reported in 745 (73%) cases, which caused dysphagia in 726 (71%) cases, and respiratory distress in 229 (22%) cases (Jain et al, 2011).
2) In a case series of 17 pediatric oral exposures to paraphenylenediamine, 8 (47%) patients developed angioneurotic edema (Abdelraheem et al, 2009).
3) In a 10 year review of poisoning with hair dye containing paraphenylenediamine, 150 cases were identified and all the patients presented with angioneurotic edema; emergent tracheostomy was done as needed in cases of severe edema. Several patients died due to severe edema before treatment could be initiated (Suliman et al, 1995).
4) In one prospective study, 1180 (74%) of 1595 patients developed severe edema of face and neck after the ingestion of PPD-containing hair dye (Jain et al, 2013).

f) CASE REPORTS

1) A 14-year-old girl presented to an ENT hospital with acute head and neck (cervical) angioedema requiring emergency tracheostomy 3 to 4 hours after intentionally ingesting an unknown quantity of paraphenylenediamine (PPD) contained in hair dye. At presentation her respiratory rate was 54 breaths/minute, heart rate was 98 beats/minute, blood pressure 110/70 mm/Hg, and her temperature was 37.9 degrees C. Examination revealed bilateral, nonpitting, nontender edema to the submandibular and submental areas. Her tongue was swollen against the palate and brown in color. She received supportive treatment and was transferred to a nephrology unit after oliguria persisted for 3 days. She was discharged home after 3 weeks on hemodialysis when her renal function was normal, laboratory values were near normal, and her breathing was spontaneous. A urine screen confirmed PPD toxicity. She was in good health at a follow-up visit 3 months later (Abdelraheem et al, 2011).
2) A tracheostomy was required in a 37-year-old woman following the intentional ingestion of hair dye containing an estimated 12 g paraphenylenediamine. The patient had significant laryngeal edema and required intubation for five days. No permanent sequelae was reported (Bhargava & Matthew, 2007).
3) A 14-year-old girl developed cervicofacial edema within 4 hours of ingesting about 50 mL of Super Vasamol 33 hair dye containing PPD. Following supportive care, including gastric lavage, hydrocortisone injection, and chlorpheniramine, her symptoms resolved 2 days later (Kumar & Patil, 2013).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CNS depression ranging from lethargy to coma may develop after severe poisoning (Lifshits et al, 1993).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Severe intoxications may uncommonly result in systemic complications of vertigo, tremors, seizures, and coma (Midha et al, 2000).
b) A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Seizures were reported in 23 (2%) cases (Jain et al, 2011).
c) In one prospective study, 47 (3%) of 1595 patients developed seizures after the ingestion of PPD-containing hair dye (Jain et al, 2013).

C) SECONDARY PERIPHERAL NEUROPATHY

1) A 16-year-old boy developed a motor peripheral neuropathy with weakness that progressed proximally, culminating in areflexic paralysis with complete absence of motor nerve conduction in all limbs after ingesting a hair dye containing paraphenylenediamine He gradually recovered motor function (Sood et al, 1996).
2) Other authors have reported a syndrome of weakness with increased muscle tone and increased reflexes (Hashim et al, 1992).

D) FLACCID PARALYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Following an intentional ingestion of 100 mL of a hair dye containing paraphenylenediamine, a 14-year-old boy developed severe retrosternal and epigastric burning and vomiting within 2 hours. Angioedema was evident on hospital admission. Within 12 hours he had severe cramping pain in all extremities followed by weakness in lower and upper limbs. Hypotonic areflexia was reported, with normal sensory system. Complete absence of conduction in all 4 limbs was noted on motor nerve conduction velocity testing. Concurrent toxin-induced renal failure was reported. Recovery was gradual and uneventful. The patient was discharged after 35 days (Midha et al, 2000).
b) CASE SERIES/PEDIATRIC: In a three year review of hospitalized Sudanese children exposed to hair dye containing paraphenylenediamine, 17 cases of poisoning were found. Of these cases, 5 (29.4%) developed flaccid paraplegia. Most exposures were intentional and occurred in females with a mean age of 13.8 years. Fifteen patients completely recovered and two patients died (11.8%; one due to acute renal failure with multi-organ involvement and one died suddenly of cardiotoxicity) (Abdelraheem et al, 2009).

Gastrointestinal

3.8.2)

A) GASTRITIS

1) WITH POISONING/EXPOSURE

a) Epigastric pain and recurrent vomiting are common shortly after ingestion (Baud et al, 1984; Chugh et al, 1982; Hashim et al, 1992).

B) DYSPHAGIA

1) WITH POISONING/EXPOSURE

a) In one prospective study, 1148 (72%) of 1595 patients developed dysphagia after the ingestion of PPD-containing hair dye (Jain et al, 2013).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Elevated serum concentrations of hepatic enzymes have been noted following ingestion (Ryoo et al, 2014; Nevo-Shor et al, 2013; Ashraf et al, 1994; Midha et al, 2000).
b) INCIDENCE: Serum AST and ALT levels were increased in 685 cases out of 1020 (67%) in a study that analyzed clinical and treatment outcomes involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. The AST levels were higher compared with ALT levels, suggesting muscle injury rather than liver necrosis. AST levels were greater than 1000 international units/L in 206 cases (Jain et al, 2011).
c) CASE REPORT: Laboratory analysis showed an AST of 1544 units/L, ALT of 286 units/L, and LDH of 596 units/L in a 14-year-old girl after she presented to an ENT hospital 4 hours after intentionally ingesting an unknown quantity of paraphenylenediamine (PPD) contained in hair dye. She was discharged home after 3 weeks on hemodialysis when her renal function was normal, laboratory values were near normal, and her breathing was spontaneous. She was in good health at a follow-up visit 3 months later (Abdelraheem et al, 2011).

B) HEPATIC NECROSIS

1) WITH POISONING/EXPOSURE

a) Elevated aminotransferase levels and evidence of hepatic necrosis on autopsy have been observed following ingestion (Baud et al, 1984; Chugh et al, 1982).
b) CASE REPORT: A hairdresser exposed for five years developed fatal liver atrophy, but a cause-effect relationship was not proven (Israels & Susman, 1934).

Genitourinary

3.10.2)

A) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Serum creatinine levels were 1.5 to 3 mg/dL in 102 cases with 21 (21%) deaths; 3.1 to 4.5 mg/dL in 39 cases with 7 (23%) deaths; 4.6 to 6 mg/dL in 37 cases with 11 (30%) deaths; 6.1 to 7.5 mg/dL in 48 cases with 20 (42%) deaths; greater than 7.5 mg/dL in 35 cases with 21 (60%) deaths (Jain et al, 2011).

B) ACUTE TUBULAR NECROSIS

1) WITH POISONING/EXPOSURE

a) Renal tubular necrosis has been reported after ingestion and may occur secondary to intravascular hemolysis or rhabdomyolysis (Chugh et al, 1982; Suliman et al, 1983; Ashraf et al, 1994; Filali & Soulaymani, 2001).

C) GLOMERULONEPHRITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Allergic vasculitis and crescentic glomerulonephritis were described in two women who chronically used PPD-based hair dyes (Brown et al, 1987).

D) ABNORMAL URINE

1) WITH POISONING/EXPOSURE

a) Proteinuria, hematuria, and myoglobinuria have been reported after ingestion (Ashraf et al, 1994; Shemesh et al, 1995; Hashim et al, 1992).
b) Urine is often described as dark brown or black in color (Abdelraheem et al, 2014; Abdelraheem et al, 2009; Sood et al, 1996; Shemesh et al, 1995; Hashim et al, 1992; Saito et al, 1990; Squali et al, 1991; Midha et al, 2000), and is usually observed with the first void following exposure, and becomes less noticeable which each subsequent void (Bhargava & Matthew, 2007; Suliman et al, 1995).
c) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Chocolate brown colored urine and myoglobinuria were detected in 549 (54%) cases (Jain et al, 2011).
d) INCIDENCE: In a case series of 17 pediatric exposures to paraphenylenediamine, dark-colored urine was the most common finding observed and occurred in 14 (82.3%) patients (Abdelraheem et al, 2009).
e) In one prospective study, 861 (54%) of 1595 patients developed chocolate brown color urine after the ingestion of PPD-containing hair dye (Jain et al, 2013).

E) ALBUMINURIA

1) WITH POISONING/EXPOSURE

F) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Oliguria occurred in 84 (8%) cases and anuria in 46 (5%) cases. A higher mortality rate (63%) was associated with anuria compared with decreased urine output or oliguria. Dialysis was required in 88 (9%) cases (Jain et al, 2011).
b) CASE SERIES

1) PEDIATRIC: In a three year review of hospitalized Sudanese children exposed to hair dye containing paraphenylenediamine, 17 cases of poisoning were found. Of these cases, 12 (70.5%) developed acute renal failure (ARF). Most exposures were intentional and occurred in females with a mean age of 13.8 years. Renal biopsy was obtained in 4 children that developed prolonged ARF; 2 cases showed evidence of typical acute tubular necrosis, one had mild mesangial proliferation and one had normal findings. Dialysis (hemodialysis (7); peritoneal dialysis (2)) was required in nine patients, while three patients received conservative therapy. Fifteen patients completely recovered and two patients died (11.8%; one due to acute renal failure with multi-organ involvement and one died suddenly of cardiotoxicity) (Abdelraheem et al, 2009). The authors noted that PPD had been available in its pure form (90-99%) in local markets in Sudan.
2) In a 10 year review of poisoning with hair dye containing paraphenylenediamine, 150 cases were identified with 90 (60%) patients developing acute renal failure requiring dialysis. The mean serum creatinine was 707 micromol/L (range 265 to 2033 micromol/L) which peaked in approximately five days after ingestion. Most patients received peritoneal dialysis for a mean of 2.4 sessions per patient until recovery. Of the remaining patients without ARF, 48 patients had mild renal impairment which improved with supportive care and the remaining 12 patients had no signs or symptoms of renal failure (Suliman et al, 1995).
3) In one prospective study, 143 (9%) of 1595 patients developed oliguria after the ingestion of PPD-containing hair dye. Anuria developed in 80 (5%) patients (Jain et al, 2013).

c) CASE REPORTS

1) A 24-year-old woman developed angioedema (swelling of lips, tongue, neck, and eyelids), severe metabolic acidosis, hypokalemia, rhabdomyolysis, and acute renal failure (serum creatinine 4.3 mg/dL; urea 120 mg/dL) after ingesting about 80 mL of a hair dye solution containing paraphenylenediamine. Despite supportive care, she died 24 hours after ingestion (Patra et al, 2015).
2) CASE SERIES: A 27-year-old woman presented with dyspnea, difficulty in speaking, inability to walk, swollen face and neck, a black, swollen tongue, flaccid paraparesis, and pain and tenderness of the lower limbs after ingesting an unknown amount of PPD in a suicide attempt. Her vital signs included a respiratory rate of 40 breaths/min, a pulse rate of 120 beats/min and a blood pressure of 11/90 mmHg. About 500 mL of black colored urine was drained in her urinary catheter bag. Despite supportive care, her condition deteriorated and she developed ventricular dysrhythmias and died. Two of her 4 children presented several hours later with similar symptoms after ingesting a juice containing PPD. Her 5-year-old daughter died 37 hours after presentation despite supportive care. Her 7-year-old son developed renal failure, but recovered following 2 weeks of hemodialysis. Two younger children did not develop any symptoms (Abdelraheem et al, 2014).
3) A 32-year-old man presented with a 3-day history of feeling unwell, anorexia, fatigue, and abdominal bloating after ingesting a large amount of boiled henna containing PPD. He also had yellowish discoloration of the sclera and dark-colored urine. Laboratory analysis revealed a reduced hemoglobin (8.8 g/dL), and elevated serum creatinine (more than double). Initially, his renal function and hemolysis deteriorated despite supportive care. However, his condition improved following transfusion with packed red blood cells and hemodialysis. He was discharged on day 13 (Qurashi et al, 2013).
4) A 14-year-old girl developed acute renal failure after presenting to an ENT hospital with acute head and neck angioedema requiring emergency tracheostomy 3 to 4 hours after intentionally ingesting an unknown quantity of paraphenylenediamine (PPD) contained in hair dye. At presentation she was catheterized and 150 mL of brown colored urine was obtained. Laboratory analysis showed creatinine 254 mcmol/L (2.87 mg/dL) and BUN 9.8 mmol/L (27.5 mg/dL). She was treated with antihistamines, hydrocortisone, and antibiotics without much improvement. Oliguria persisted over 3 days and hemodialysis was initiated after hydration, diuretics, and forced alkaline diuresis failed. She was transferred to a nephrology unit. A urine screen confirmed PPD toxicity and renal biopsy results were consistent with acute tubular necrosis. She was discharged home after 3 weeks on hemodialysis when her renal function was normal, laboratory values were near normal, and her breathing was spontaneous. She was in good health at a follow-up visit 3 months later (Abdelraheem et al, 2011).
5) A 60-year-old woman with a medical history of diabetes and hypertension, developed dyspnea, neck edema, blurred vision and weakness immediately after ingesting "black rock" containing henna and PPD (confirmed by toxicological analysis). After arrival to the ED, she developed severe dyspnea, agitation, and laryngeal angioedema. Otolaryngologic exam showed angioedema of tongue, pharynx and epiglottis with airway obstruction. Immediate airway support and intubation were required. She received IM epinephrine, steroids, and antihistamine after acute allergic reaction was suspected. Laboratory results revealed elevated serum creatinine, metabolic acidosis with normal anion gap, leukocytosis without eosinophilia, elevated hepatocellular enzymes, and elevated creatinine kinase concentrations (78,250 Units/L) and myoglobin (106,117 ng/mL). Following supportive care, including hemodialysis, her condition improved and she was extubated on day 3 and her renal function returned to normal a week later (Nevo-Shor et al, 2013).
6) After ingesting 20 g of PPD, a 22-year-old man developed severe angioneurotic edema, rhabdomyolysis, intravascular hemolysis with hemoglobinuria and oliguric acute renal failure (serum creatinine 3.8 mg/dL; BUN 120 mg/dL). Despite supportive therapy, the patient had a cardiac arrest and died on second day of admission (Anuradha et al, 2004).
7) Following the ingestion of 100 mL of hair dye containing paraphenylenediamine, a 14-year-old boy developed rapid onset hypotonic areflexic motor paralysis with acute renal failure. The patient passed 15 mL of dark black colored urine after 24 hours. Anuria developed. BUN and serum creatinine levels were 224 and 10 mg/dL, respectively. Hemolysis was not present; CPK was not elevated; urine myoglobin was negative. The patient gradually recovered following hemodialysis and supportive measures (Midha et al, 2000).

d) RISK FACTORS: The presence of rhabdomyolysis and hypovolemia can significantly increase the risk of developing acute renal failure, which significantly contributes to overall morbidity and mortality (Sampathkumar & Yesudas, 2009).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis has been reported (Ashraf et al, 1994; Nevo-Shor et al, 2013).
b) CASE REPORT: A 24-year-old woman developed angioedema (swelling of lips, tongue, neck, and eyelids), severe metabolic acidosis (pH 6.9, bicarbonate 6.7 mEq/L, pCO2 14.8 mmHg, pO2 140.5 mmHg), hypokalemia, rhabdomyolysis, and acute renal failure after ingesting about 80 mL of a hair dye solution containing paraphenylenediamine. Despite supportive care, she died 24 hours after ingestion (Patra et al, 2015).

Hematologic

3.13.2)

A) APLASTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) Anecdotal cases of aplastic anemia are generally not well documented and are unsubstantiated by extensive experimental animal data (Burnett et al, 1977). Severe aplastic anemia was reported in two women who had used a PPD-based hair dye 2 to 4 weeks prior to presentation, but a cause-effect relationship could not be proven (Hopkins & Manoharan, 1985).

B) ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 14-year-old girl developed anemia after presenting to an ENT hospital with acute head and neck angioedema requiring emergency tracheostomy 3 to 4 hours after intentionally ingesting an unknown quantity of paraphenylenediamine (PPD) contained in hair dye. Laboratory analysis at presentation showed a hemoglobin of 11.8 g/dL. She was discharged home after 3 weeks on hemodialysis. She was in good health at a follow-up visit 3 months later (Abdelraheem et al, 2011).

C) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Methemoglobinemia has been reported following ingestion (Chugh et al, 1982).
b) CASE REPORT: A 30-year-old man presented with cyanosis and drowsiness after inadvertently using hair dye containing paraphenylenediamine instead of a toothpaste. Laboratory results revealed a serum methemoglobin (MetHb) concentration of 59.5% and elevated liver enzymes. Following treatment with methylene blue 2 mg/kg (1 mg/kg twice), his MetHb concentration decreased to 49.4% (oxygen saturation: 80%). At this time, he received methylene blue again (total dose: 6 mg/kg) which resulted in his complete recovery (Ryoo et al, 2014).

D) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Leukocytosis is common after ingestion (Nevo-Shor et al, 2013; Lifshits et al, 1993; Sood et al, 1996; Ashraf et al, 1994).

E) INTRAVASCULAR HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) Renal tubular necrosis has been reported after ingestion and may occur secondary to intravascular hemolysis or rhabdomyolysis (Anuradha et al, 2004; Chugh et al, 1982; Suliman et al, 1983; Ashraf et al, 1994; Filali & Soulaymani, 2001).
b) CASE REPORT: A 32-year-old man presented with a 3-day history of feeling unwell, anorexia, fatigue, and abdominal bloating after ingesting a large amount of boiled henna containing PPD. He also had yellowish discoloration of the sclera and dark-colored urine. Laboratory analysis revealed a reduced hemoglobin (8.8 g/dL), and elevated serum creatinine (more than double). Initially, his renal function and hemolysis deteriorated despite supportive care. However, his condition improved following transfusion with packed red blood cells and hemodialysis. He was discharged on day 13 (Qurashi et al, 2013).

Reproductive

3.20.1)

3.20.2)

A) LACK OF EFFECT

1) Paraphenylenediamine was not teratogenic in rats given up to 30 mg/kg/day, although maternal toxicity was evident at this dose (Re et al, 1981).

3.20.3)

A) MYOCARDIAL INJURY

1) CASE REPORT: A 22-year-old pregnant woman (at 23 to 24 weeks gestation) presented with acute respiratory failure about 9 hours after ingesting an unknown amount of PPD. On presentation, she had macroglossia, cervicofacial and oropharyngeal edema, black urine, and a hypogastric mass above the navel. Laboratory results revealed elevated liver enzymes, acute renal failure (urea, 32 mmol/L, serum creatinine, 200 mcmol/L), and rhabdomyolysis (serum creatinine phosphokinase, 10,880 International Units [IU]/L; normal, less than 180 IU/L). Four days after admission, a pelvic ultrasound revealed a normally progressing pregnancy; however, 5 days later, the pregnancy appeared non-progressing and the patient expelled a non-viable fetus. Examination of the fetal organs showed myocardial lysis, lung congestion, interstitial edema, and inflammatory infiltration of the lingua base, chorionic villus thrombosis, and abruptio placentae. Following supportive care, the patient's condition gradually improved and she was discharged 19 days after admission (Abidi et al, 2008).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS106-50-3 (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) IARC Classification

a) Listed as: para-Phenylenediamine
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

B) IARC Carcinogenicity Ratings for CAS624-18-0 (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

3.21.3)

A) CARCINOMA

1) No excess risk of carcinoma was observed in a study of 120,557 women during the first 20 years following use of permanent hair dyes (Hennekens et al, 1979).

Genotoxicity

Dermatologic

3.14.2)

A) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Contact dermatitis is a common manifestation of hypersensitivity to PPD (Warshaw et al, 2013; Mayer, 1954; Dobkevitch & Baer, 1947; Modee & Skog, 1962; Wakelin et al, 1998).
b) Contact dermatitis has also been reported with many paraphenylenediamine derivatives (Hansson et al, 1997; Rustemeyer & Frosch, 1995; Hemmer et al, 1997; Marliere et al, 1998; Weller & Ormerod, 1996). The frequency of allergic reactions to PPD was found to be 5.5% by the North American Contact Dermatitis Group (Warshaw et al, 2013).
c) Contact dermatitis may be seen on the feet of people wearing shoes dyed with PPD (Romaguera et al, 1988). Hair dyed 24 hours previously with a PPD solution did not elicit dermatitic reactions on patch tests in any of 20 PPD-sensitive individuals tested. Oxidized PPD is probably non-allergenic (Reiss & Fisher, 1974).
d) In one study, the most common sites of allergic contact dermatitis with PPD exposure were the face and/or neck (72.4%), trunk (46.3%), hands (42.5%), legs (41.8%), and arms (38.8%). Crossreactivity was observed between PPD and other para-amino compounds, such as textile dyes (eg, Disperse Blue 106 or 124, orange #3), benzocaine, isopropyl-para-phenylenediamine, sulfa drugs, diaminotoluene, 2-nitro-4-phenylenediamine, aminophenol, and para-aminobenzoic acid, and aminoazobenzene (LaBerge et al, 2011).
e) Allergic contact dermatitis is mediated by dendritic cell and T-cell activation. Human dendritic cells may be activated by PPD and its immediately formed derivatives (Coulter et al, 2007). However, products of PPD acetylation do not participate in dendritic cell activation (Aeby et al, 2009).

B) EDEMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 14-year-old girl developed cervicofacial edema within 4 hours of ingesting about 50 mL of Super Vasamol 33 hair dye containing PPD. Following supportive care, including gastric lavage, hydrocortisone injection, and chlorpheniramine, her symptoms resolved 2 days later (Kumar & Patil, 2013).
b) In one prospective study, 1180 (74%) of 1595 patients developed severe edema of face and neck after the ingestion of PPD-containing hair dye (Jain et al, 2013).

C) ERYTHEMA MULTIFORME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Erythema multiforme was described in a 70-year-old woman with contact dermatitis following use of a PPD-containing hair dye (Tosti et al, 1988).
b) CASE REPORT: A severe generalized vesicular erythema multiforme-like reaction was observed in a 6-year-old boy after receiving a temporary henna tattoo containing PPD. An eczematous rash at the tattoo site was observed 11 days after exposure, with generalized erythematous macules 12 days later. The patient recovered completely with supportive care, with no other sources found for the reaction. Patch testing was not performed (Sidwell et al, 2008).

D) LICHENOID DERMATITIS

1) WITH POISONING/EXPOSURE

a) Lichen planus has resulted from contact with photographic color developing agents containing PPD (Liden & Brehmer-Andersson, 1988).

E) ABNORMAL COLOR

1) WITH THERAPEUTIC USE

a) Contact leukoderma and discoloration of the scalp and hair have been reported with topical use (Brancaccio & Cohen, 1995; Bajaj et al, 1996).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis has been reported with and without associated acute renal failure (Qurashi et al, 2013; Sampathkumar & Yesudas, 2009; Bhargava & Matthew, 2007; Anuradha et al, 2004; Baud et al, 1984; Averbukh et al, 1989; El-Ansary et al, 1983; Ashraf et al, 1994; Shemesh et al, 1995; Bourquia et al, 1988; Saito et al, 1990; Squali et al, 1991; Filali & Soulaymani, 2001).
b) PATHOLOGY: Following the ingestion of paraphenylenediamine, calcium release and leakage of calcium ions from smooth endoplasmic reticulum along with irreversible changes in muscle structure results in rhabdomyolysis. It has been suggested that rhabdomyolysis is the primary cause of acute renal failure, which can significantly increase overall morbidity and mortality (Sampathkumar & Yesudas, 2009).
c) INCIDENCE: Serum CPK levels were increased in 521 out of 1020 (51%) cases in a study that analyzed clinical and treatment outcomes involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. The highest CPK value recorded was 2,81,000 international units/L (Jain et al, 2011).
d) CASE REPORT: A 14-year-old girl developed rhabdomyolysis after presenting to an ENT hospital with acute head and neck angioedema requiring emergency tracheostomy 3 to 4 hours after intentionally ingesting an unknown quantity of paraphenylenediamine (PPD) contained in hair dye. Laboratory analysis showed a creatine kinase (CK) level of 6180 units/L. She was discharged home after 3 weeks on hemodialysis when her renal function was normal, laboratory values were near normal, and her breathing was spontaneous. She was in good health at a follow-up visit 3 months later (Abdelraheem et al, 2011).
e) CASE REPORT: A 37-year-old woman intentionally ingested a hair dye containing an estimated 12 g of paraphenylenediamine, and had an initial CPK of 20,610. She was treated with aggressive fluid therapy and the patient had no evidence of acute renal failure. Within 48 hours, her CPK was 3610 and creatinine was normal. The patient made a complete recovery following supportive care (Bhargava & Matthew, 2007).
f) CASE REPORT: A 60-year-old woman with a medical history of diabetes and hypertension, developed dyspnea, neck edema, blurred vision and weakness immediately after ingesting "black rock" containing henna and PPD (confirmed by toxicological analysis). After arrival to the ED, she developed severe dyspnea, agitation, and laryngeal angioedema. Otolaryngologic exam showed angioedema of tongue, pharynx and epiglottis with airway obstruction. Immediate airway support and intubation were required. She received IM epinephrine, steroids, and antihistamine after acute allergic reaction was suspected. Laboratory results revealed elevated serum creatinine, metabolic acidosis with normal anion gap, leukocytosis without eosinophilia, elevated hepatocellular enzymes, and elevated creatinine kinase concentrations (78,250 Units/L) and myoglobin (106,117 ng/mL). Following supportive care, including hemodialysis, her condition improved and she was extubated on day 3 and her renal function returned to normal a week later (Nevo-Shor et al, 2013).
g) CASE REPORT: A 24-year-old woman developed angioedema (swelling of lips, tongue, neck, and eyelids), severe metabolic acidosis, hypokalemia, rhabdomyolysis, and acute renal failure after ingesting about 80 mL of a hair dye solution containing paraphenylenediamine. Despite supportive care, she died 24 hours after ingestion (Patra et al, 2015).

B) MUSCLE PAIN

1) WITH POISONING/EXPOSURE

a) Muscle swelling, pain, and tenderness have been reported after ingestion (Shemesh et al, 1995; Ashraf et al, 1994; Bourquia et al, 1988; Saito et al, 1990; Squali et al, 1991).
b) INCIDENCE: A study analyzed the clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009. Muscle pain and/or limb rigidity was documented in 480 (47%) cases (Jain et al, 2011).
c) CASE REPORT: TRISMUS: Spasm of the masseter muscles strong enough to prevent opening the mouth occurred in one reported case (Squali et al, 1991). Trismus was reported in another adult following the ingestion of 12 g of paraphenylenediamine (Bhargava & Matthew, 2007).
d) In one study, 765 (48%) of 1595 patients developed pain/rigidity of limb after the ingestion of PPD-containing hair dye (Jain et al, 2013).

Immunologic

3.19.2)

A) HYPERSENSITIVITY REACTION

1) WITH POISONING/EXPOSURE

a) Immediate (usually) or delayed hypersensitivity reactions have been described following application of PPD-containing hair dyes to eyebrows or eyelashes. Typically pain and burning of the eye, blepharoconjunctivitis, and edema occur, which may progress to widespread facial edema and dermatitis (Harner, 1933; McCally et al, 1933; Moran, 1934; Greenbaum, 1933).

1) Lacrimation, photophobia, uveitis, and keratitis are also common. Most patients tested have had positive skin tests to paraphenylenediamine. Corneal necrosis, sometimes leading to permanent vision loss, has been reported (Brav, 1936; McCally et al, 1933).

B) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Generalized anaphylaxis was described after application of a commercial hair dye containing paraphenylenediamine after 3 previous immediate hypersensitivity reactions. Skin testing with the dye and components revealed reaction to an oxidation product of PPD, N',N'-bis-(4-aminophenyl)-2,5- diamino-1,4-quinonediimine (Bandrowski's base). The reaction presumably occurred after mixing hydrogen peroxide with the hair dye solution (Goldberg et al, 1987).
b) Fatal and non-fatal anaphylaxis have been reported after use of paraphenylenediamine containing hair dyes (Belton & Chira, 1997; Fukunaga et al, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Obtain a CBC, renal function tests, serum electrolytes, methemoglobin concentration, CK, and liver enzymes concentrations in symptomatic patients.
C) Obtain a urinalysis, specifically for evidence of discoloration, proteinuria, hematuria, hemoglobinuria, or myoglobinuria.
D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
E) Obtain an ECG, and institute continuous cardiac monitoring.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Obtain a CBC, renal function tests, serum electrolytes, methemoglobin concentration, CK, and liver enzymes concentrations in symptomatic patients.

4.1.3)

A) URINALYSIS

1) Obtain a urinalysis, specifically for evidence of discoloration, proteinuria, hematuria, hemoglobinuria, or myoglobinuria.
2) The first voided urine after ingestion may be black or dark in color and gradually becomes less noticeable with each subsequent void (Bhargava & Matthew, 2007; Suliman et al, 1995).

4.1.4)

A) OTHER

1) MONITORING

a) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
b) Obtain an ECG, and institute continuous cardiac monitoring.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patient with moderate to severe toxicity should be admitted to the hospital for further monitoring and supportive care.

6.3.1.2) HOME CRITERIA/ORAL

A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. Mild allergic contact dermatitis may be managed as an outpatient.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a nephrologist for dialysis in patients with evidence of oliguric or anuric renal failure. Patients with myocarditis should be evaluated by a cardiologist. Consult a regional Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.

6.3.1.4) PATIENT TRANSFER/ORAL

A) Patients requiring critical care management or hemodialysis should be transferred to facilities capable of higher levels of care.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) All patients with deliberate ingestions, patients with respiratory distress, or any oral ingestion that is more than a sip, lick, or taste should be referred to healthcare facility for further management. Significant clinical manifestations typically present within the first 6 hours; however, rhabdomyolysis and renal failure may develop over days to weeks.

Monitoring

Oral Exposure

6.5.1)

A) ORAL EXPOSURE: Do not induce emesis. Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
B) INHALATIONAL EXPOSURE: Monitor for respiratory distress. If cough or difficulty breathing develops, administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
C) DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists after washing.
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. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed.

6.5.2)

A) SUMMARY: ORAL EXPOSURE: Consider administration of activated charcoal after a potentially toxic ingestion, if the overdose is recent, the patient is not vomiting, and is able to maintain airway. Gastric lavage may be considered in large overdoses that present early to medical attention in conjunction with use of activated charcoal.
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).

C) GASTRIC LAVAGE

1) Gastric lavage may be preferable to emesis due to the rapid development of upper respiratory swelling and respiratory distress. Intubation should be performed before initiating lavage.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta2-adrenergic agonists, corticosteroids or epinephrine. Consider bronchodilators and systemic corticosteroids in patients with significant bronchospasm. Consider aggressive fluid hydration and urine output monitoring for rhabdomyolysis. Manage mild hypotension with IV fluids.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treatment of severe anaphylaxis includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Methylprednisolone decreased mortality over hydrocortisone in a non-blinded, non-randomized, prospective study of severely intoxicated patients with PPD.

3) DIFFERENTIAL DIAGNOSIS

a) Allergic contact dermatitis crossreactivity was observed between PPD and other para-amino compounds, such as textile dyes (eg, Disperse Blue 106 or 124, orange #3), benzocaine, isopropyl-para-phenylenediamine, sulfa drugs, diaminotoluene, 2-nitro-4-phenylenediamine, aminophenol, and para-aminobenzoic acid, and aminoazobenzene (LaBerge et al, 2011).

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Obtain a CBC, renal function tests, serum electrolytes, methemoglobin concentration, CK, and liver enzymes concentrations in symptomatic patients.
3) Obtain a urinalysis, specifically for evidence of discoloration, proteinuria, hematuria, hemoglobinuria, or myoglobinuria.
4) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
5) Obtain an ECG, and institute continuous cardiac monitoring.

C) AIRWAY MANAGEMENT

1) Death is most often due to acute respiratory distress. Endotracheal intubation may be exceedingly difficult because of upper airway edema; emergent tracheostomy or cricothyrotomy may be required (Sampathkumar & Yesudas, 2009; Hashim et al, 1992; Lifshits et al, 1993; Ashraf et al, 1994; Squali et al, 1991).
2) Emergency tracheostomy was required in 10 of 24 overdose cases in one series (El-Ansary et al, 1983).

D) ANGIOEDEMA

1) There is no specific therapy and most cases resolve slowly. Antihistamines and corticosteroids have been recommended, but their efficacy is not proven (Suliman et al, 1983; Yagi et al, 1996).

E) HYPERSENSITIVITY REACTION

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).

F) METHEMOGLOBINEMIA

1) Cyanosis following ingestion of PPD may be due to respiratory insufficiency and/or methemoglobinemia. Ensure a patent airway before administration of treatment for presumed methemoglobinemia.
2) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

3) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

4) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

G) HEMODIALYSIS

1) Hemodialysis may be required if oliguric or anuric renal failure develop. Several large retrospective studies have reported the effective use of hemodialysis following PPD toxicity. In most patients, renal function recovers and long term hemodialysis is not required (Abdelraheem et al, 2009).
2) In a prospective study that analyzed clinical and treatment outcomes of 1020 cases involving ingestion of paraphenylenediamine (PPD) contained in hair dye from July 2004 to March 2009, dialysis was required in 88 (9%) cases. Hemodialysis was administered in 50 cases and had a 24% (n=12) mortality rate. Peritoneal dialysis was administered in 38 cases and had a 66% (n=25) mortality rate (Jain et al, 2011).

H) CORTICOSTEROID

1) Methylprednisolone (1 g/day for 5 days) decreased mortality over hydrocortisone in the non-blinded, non-randomized, prospective study of severely intoxicated patients with PPD (Jain et al, 2013).

a) In this study, 1020 patients who developed oro-facial edema, swallowing difficulty, and change in color of urine after the ingestion of PPD-containing hair dyes, were treated with corticosteroids. About 28% (n=83) of 300 patients who were treated with IV hydrocortisone 300 mg/day for 7 days died. In contrast, 14% (n=101) of 720 patients who were treated with IV methylprednisolone 1 g/day for 5 days died (Jain et al, 2013).

Inhalation Exposure

6.7.1)

Eye Exposure

6.8.1)

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

Dermal Exposure

6.9.1)

A) 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).

Abstracts

Case Reports

1) FATALITY: A 40-year-old woman ingested an unknown amount of PPD and developed recurrent vomiting, facial and neck swelling, and oliguria within two hours. Upon admission 24 hours postingestion, dyspnea, cyanosis, angioneurotic edema, and respiratory stridor were noted. Tracheostomy was performed. Intravascular hemolysis, hyperkalemia, and bronchopneumonia subsequently developed. Death occurred after 11 days due to septicemia. Acute renal tubular necrosis and hepatocellular necrosis were found at autopsy (Chugh et al, 1982).
2) FATALITY: A 60-year-old man ingested an unknown amount of PPD. He was admitted with significant edema of the face, neck, lips, tongue, and pharynx. Vital signs and neurological status appeared normal. Creatinine, CPK, AST, gamma GT, and LDH values were elevated. Gastric lavage was refused. Intravenous hydrocortisone and chlorpheniramine were administered. Metabolic acidosis, hematuria, labored breathing, and increased facial and laryngeal edema developed. A tracheostomy was performed following unsuccessful endotracheal intubation. Lower limb rigidity and pain occurred, with hypotension and decreased alertness. Anuria and progression of hypotension occurred. Hemodialysis was initiated. Cardiac arrest and death occurred within 4 hours of hospital admission. Autopsy revealed acute tubular necrosis and rhabdomyolysis (Ashraf et al, 1994).
3) FATALITY: A 44-year-man died 30 hours after ingesting 3 g (63 mg/kg) of paraphenylenediamine in hair dye. Autopsy revealed the cause of death to be rhabdomyolysis and renal failure (Saito et al, 1990).
4) A 20-year-old woman ingested 40 mL of a 4 percent solution of PPD (1600 mg). Recurrent vomiting, abdominal pain, and facial and neck swelling developed shortly after ingestion. Acute renal failure was noted on admission. On the third day cyanosis, drowsiness, angioneurotic edema, and hemolysis were noted, with a methemoglobin level of 3.5 g (37% of total hemoglobin). LDH was elevated (471 IU/L) and hyperkalemia was present. Hemodialysis was performed for 13 days and was followed by a period of diuresis. Renal biopsy showed acute tubular necrosis, which resolved within a week (Chugh et al, 1982).

1) INFANT FATALITY: A 22-month-old child ingested an unknown amount of PPD crystals. Initial signs soon after ingestion included vomiting, which progressed within a few hours to include a swollen tongue and dyspnea, and finally fatal cardiac arrest (Bowen, 1962).
2) A 15-year-old girl ingested a solution of PPD-containing hair dye. One hour postingestion progressive lip, tongue, and neck swelling was noted which was maximal after 4 hours. Slight drowsiness and dyspnea were present. Twelve hours after admission, oliguria with dark urine was noted which progressed to anuria for 4 days. Hyperkalemia was present. Peritoneal dialysis was done for 5 weeks. A renal biopsy revealed acute tubular necrosis. Full recovery occurred (Suliman et al, 1983).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) A 44-year-old man died of renal failure and rhabdomyolysis 30 hours after ingestion of 3 g (63 mg/kg) of paraphenylenediamine (Saito et al, 1990).
2) CASE REPORT: A 24-year-old woman developed angioedema (swelling of lips, tongue, neck, and eyelids), severe metabolic acidosis, hypokalemia (serum potassium, 2.9 mEq/L), rhabdomyolysis, and acute renal failure after ingesting about 80 mL of a hair dye solution containing paraphenylenediamine. Despite supportive care, she died 24 hours after ingestion (Patra et al, 2015).

Maximum Tolerated Exposure

1) ADULT

a) A 37-year-old woman ingested a hair dye containing an estimated 12 g PPD and developed dyspnea and angioneurotic edema requiring a tracheostomy, along with rhabdomyolysis and trismus. There was no evidence of acute renal failure. The patient recovered with supportive care (Bhargava & Matthew, 2007).
b) Ingestion of 1800 mg by an adult resulted in methemoglobinemia, angioneurotic edema, and acute renal failure, with recovery (Chugh et al, 1982). This amount is contained in 40 mL of a black hair dye containing 4% PPD.

2) PEDIATRIC

a) A 14-year-old girl developed cervicofacial edema within 4 hours of ingesting about 50 mL of Super Vasamol 33 hair dye containing PPD. Following supportive care, including gastric lavage, hydrocortisone injection, and chlorpheniramine, her symptoms resolved 2 days later (Kumar & Patil, 2013).
b) A 6-year-old boy developed generalized vesicular erythema multiforme-like reaction about 3 weeks after receiving a temporary ("black henna") tattoo containing PPD (Sidwell et al, 2008).

3) TDLo Oral Man: 71 mg/kg (Lewis, 1996).

Workplace Standards

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

a) Adopted Value

1) p-Phenylenediamine

a) TLV:

1) TLV-TWA: 0.1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

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

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

c) TLV Basis - Critical Effect(s): URT irr; skin sens
d) Molecular Weight: 108.05

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

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

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

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

e) Additional information:

B) ACGIH TLV Values for CAS624-18-0 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

C) NIOSH REL and IDLH Values for CAS106-50-3 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: p-Phenylene diamine
2) REL:

a) TWA: 0.1 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 25 mg/m3
b) Note(s): Not Listed

D) NIOSH REL and IDLH Values for CAS624-18-0 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

E) Carcinogenicity Ratings for CAS106-50-3 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: p-Phenylenediamine

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): 3 ; Listed as: para-Phenylenediamine

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: p-Phenylene diamine
5) MAK (DFG, 2002): Category 3B ; Listed as: p-Phenylenediamine

a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

F) Carcinogenicity Ratings for CAS624-18-0 :

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

G) OSHA PEL Values for CAS106-50-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: p-Phenylene diamine
2) Table Z-1 for p-Phenylene diamine:

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: 0.1

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: Yes
5) Notation(s): Not Listed

H) OSHA PEL Values for CAS624-18-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)RAT:

1) 37 mg/kg (RTECS , 2002)

B) LD50- (ORAL)RAT:

1) 80 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) Symptoms of rapid respirations, wheezing, and increased mouth, nose, and eye secretions were noted in dogs given 170 mg/kg IV. Swelling of nose, lips, conjuctivae, and neck was pronounced within 1.5 to 4 hours (Hanzlik, 1923).

Range Of Toxicity

11.3.2)

A) DOG

1) Definite symptoms began at 170 mg/kg IV (Hanzlik, 1923).

B) CAT

1) The minimum lethal dose was 100 mg/kg orally (Hanzlik, 1923).

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

FeedBack

PARAPHENYLENEDIAMINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Reproductive

Carcinogenicity

Genotoxicity

Dermatologic

Musculoskeletal

Immunologic

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Physical Characteristics

Molecular Weight

Clinical Effects

Range Of Toxicity

General Bibliography