Paraphenylenediamine Toxicity

Etiology

Paraphenylenediamine is commonly used in its powdered form as an additive dyeing agent in various industries, including cosmetics, textiles, and film.[5][6] However, it is more commonly encountered by the general public as a dye in temporary body art called henna, a practice found in many parts of the world. The henna plant Lawsonia inermis is a flowering plant that has been used for centuries for its potent red-orange dyeing properties.[2] This plant is commonly found in Asia, the Middle East, Eastern Africa, and Australia, with its prevalence in customary and cultural practices following a similar distribution.

Henna is typically crushed into a paste and applied to skin, fingernails, and hair to create intricate patterns, often for festive or cultural events.[7] However, paraphenylenediamine has been increasingly added to henna paste to produce black henna. This practice decreases the amount of henna paste required, achieves a darker pigmentation, and speeds up the staining process.[2] Unfortunately, this is an unregulated adulteration of the henna paste in most locations.

In addition to henna body art, paraphenylenediamine is a dark pigmentation in hair dyes. Altering the paraphenylenediamine concentration with an oxidizing agent, such as hydrogen peroxide, can achieve a variety of shades. Shades can range from golden blonde in lower concentrations to jet black in higher concentrations.[3] Studies have shown the safety of paraphenylenediamine hair dye when used topically and in regulated formulations.[8] In developed countries, hair dye formulations have largely become standardized to contain a maximum of 2% paraphenylenediamine in 100 mL solution to decrease toxicity in case of accidental poisoning. Unfortunately, these concentrations may be as high as 90% in underdeveloped and developing countries due to a lack of standardized regulation.[4][5]

A growing trend, particularly in underdeveloped and developing countries, is the consumption of paraphenylenediamine-containing products, such as black henna or hair dye for intentional self-harm purposes. This issue has been documented through multiple case reports and reviews, particularly in Egypt, India, Morocco, Pakistan, Sudan, and Tunisia.[9][10][11][12][13] In the 1990s, paraphenylenediamine toxicity was reported as the leading cause of poisoning in Morocco.[9] This trend is likely due to the general affordability, ease of accessibility, and high potential for toxicity of paraphenylenediamine-containing products.[1][2]

Epidemiology

The worldwide demographic of paraphenylenediamine toxicity shows an average age of 21 to 30 years, with a significant predominance among females.[1][6][14] The most common route of exposure is oral ingestion.[1] Other risk factors include low socioeconomic background, living in rural areas, social and personal conflicts, and the lack of social support.[3]

Data published by the United States Environmental Protection Agency has listed the potential uses and sources of paraphenylenediamine in the United States (US Environmental Protective Agency. P-Phenylenediamine). Despite this, statistical data regarding the incidence of paraphenylenediamine toxicity in the Western world and, in particular, the United States have been limited in the literature.[15]

Furthermore, reporting of paraphenylenediamine toxicity in pediatric populations has also been scarce despite its prevalence, especially in areas where paraphenylenediamine is commonly used. Similar to the adult population, pediatric patients are noted to be predominantly female.[16] The main modality of toxicity in the pediatric population is accidental and suicidal ingestion, with the latter being the primary reason for ingestion in teenage patients.[17][16][18] The importance of considering non-accidental injuries in this vulnerable population should be noted, as cases involving the use of paraphenylenediamine as a homicidal agent have been reported.[17][16] A study found that the mean age of affected pediatric patients was 13.8 years, with ages ranging from 2 to 18 years.[16]

Pathophysiology

The transdermal route exposure to paraphenylenediamine primarily results in dermatologic manifestations, such as varying degrees of acute, subacute, or chronic contact dermatitis, although severe systemic manifestations, such as anaphylaxis, have been reported.[19][20] Delayed type IV hypersensitivity reactions are the most common mechanism; hence, the presentation may have a latent period of hours to days after exposure.[20] The pathophysiology of dermatitis associated with exposure is due to increased activity of multiple enzymes such as beta-glucuronidase, gamma-glutamyl transpeptidase, acid and base phosphatases, histidase, and tyrosinase, along with enhancing lipid peroxidation and histamine formation. Hyperkeratosis with dermal cell infiltration has been found.[20][21][22][23] Eczematoid contact dermatitis may result from chronic exposure.

Systemic toxic exposure to paraphenylenediamine affects multiple organ systems, including the integumentary, muscular, cardiorespiratory, and hepatorenal systems. The exact lethal dose has not yet been determined, but estimates range from 7 to 10 g.[24][25] The toxicity of paraphenylenediamine is mainly due to inhibition of cellular oxidation and subsequent corrosive properties.[1][4] 

Benzoquinone diamine, an oxidative product of paraphenylenediamine also known as Bandrowski base, is known to cause significant tissue necrosis due to its highly toxic, allergenic, and mutagenic properties.[2][3][21] However, the United States Environmental Protection Agency has not classified paraphenylenediamine as a carcinogenic compound (US Environmental Protective Agency. P-Phenylenediamine). The median lethal dose (LD50) for oral ingestion is approximately 100 mg/kg in most animals, and the lowest published dose associated with toxicity is 71 mg/kg in humans (National Institute for Occupational Health and Safety. P-Phenylenediamine). However, there is a case report of a 44-year-old male who consumed 3 g of paraphenylenediamine (63 mg/kg) and ultimately died as a result of rhabdomyolysis and renal failure 3 days later.[26]

Systemic manifestations of paraphenylenediamine toxicity can be categorized as early manifestations and late manifestations. Early-stage clinical findings (4 to 6 hours) include oropharyngeal, cervicofacial, and angioneurotic edema, which may rapidly progress to airway occlusion and cause asphyxia and respiratory failure.[4][9] The underlying mechanism is largely believed to be due to precipitous inflammatory edema of the cricopharyngeal and laryngeal structures.[9] 

Late-stage findings (>12 hours) include rhabdomyolysis and acute renal failure with associated clinical complications such as oliguria, anuria, renal tubular necrosis, arrhythmias, myocarditis, and acute hepatic injury.[4][19] Paraphenylenediamine is believed to induce rhabdomyolysis by triggering calcium ion leakage from the smooth endoplasmic reticulum, which causes rapid muscular contraction and muscle breakdown. The manifestation of acute renal failure in paraphenylenediamine toxicity is believed to be due to the combination of rhabdomyolysis, hypovolemia, and the direct toxin effect.[9] The pathogenesis of hepatic involvement is not well defined but is likely multifactorial. Cardiac manifestations have also been reported, including myocarditis, myocardial infarction, and arrhythmias, although the pathophysiology is poorly understood.[25][27][28]

Toxicokinetics

Literature evaluating the toxicokinetic properties of paraphenylenediamine in humans has mainly focused on transdermal exposure through the cosmetic hair dye industry. Although paraphenylenediamine is absorbed transdermally, its ability to cause a hypersensitivity reaction or dermatitis is not related to absorption but to its concentration, formulation, and exposure time. Studies have shown that dermal application of 1% and 2% paraphenylenediamine concentrations resulted in a peak serum concentration at 2 hours, but within 24 hours, paraphenylenediamine was undetectable in the serum.[29] This elimination is believed to be predominantly by renal excretion (90%).[30] An important clinical consideration for this is the potential for decreased elimination and prolonged toxicity in patients coming in with acute renal failure due to acute paraphenylenediamine toxicity, a well-documented complication. The metabolite identified in plasma and urine samples is predominantly N,N'-diacetylated-paraphenylenediamine. Fecal excretion was also minimally noted.[31] The half-life of elimination of paraphenylenediamine with dermal exposure is 7.8 hours (US Environmental Protective Agency. Provisional Peer-Reviewed Toxicity Values for p-Phenylenediamine). These studies are based on standardized commercial paraphenylenediamine concentrations no >2%, making it difficult to extrapolate to intoxications with higher concentrations.

The toxicokinetic effects of oral and intravenous dosing of paraphenylenediamine have only been studied in animal models. In studies with rats and mice, oral dosing showed almost complete absorption. Renal excretion was again noted as the predominant mode of elimination, with 90% of excretion occurring in the first 24 hours. The remainder of elimination was through feces with lower doses, which showed more feces excretion. This observation was theorized to be due to either the chemical being adsorbed to stomach contents or decreased enterohepatic recycling or alteration in the metabolite profile leading to increased excretion in bile. Biliary excretion was studied using intravenous exposure, which showed an inverse relation to the dose. This points to a hepatic metabolism route, suggesting that metabolism becomes saturated at higher doses. The distribution of paraphenylenediamine showed its presence in major tissues, including blood, kidneys, liver, muscles, skin, and adipose.[32] The half-life of elimination with oral absorption is unknown.

History and Physical

As the diagnosis of paraphenylenediamine toxicity requires a high index of suspicion due to its relatively rare occurrence in the Western community, thorough history-taking becomes crucial. As with other toxicologic histories, it is essential to determine the time, route, amount of product consumed, and potential for co-ingestion.[33] The specific product packaging can help identify the agent of concern and concentration used if available. In addition, psychiatric history, collateral history, and events leading up to clinical presentation are helpful details in cases due to intentional self-harm. Special care should be taken to identify the specific product of exposure due to varying concentrations of paraphenylenediamine used, although this may be difficult.[4]

As paraphenylenediamine toxicity does not have a specific pathognomonic physical examination finding, all systems should be carefully examined. Although nonspecific, the clinical findings commonly encountered were cervicofacial edema, upper airway edema, generalized muscle pain indicating rhabdomyolysis, and renal abnormalities such as oliguria, anuria, or chocolate-brown colored urine.[2][3][4] In patients with limited dermal toxicity, contact dermatitis at the site of use, typically the scalp or hairline, is present, and superinfection with cellulitis is possible.[20] 

During a comprehensive physical examination, major clinical manifestations should be considered in a system-based manner as follows:

• Neurologic: Coma and convulsions [3]                                                                                                                 
• Cardiac: Arrhythmias including sinus tachycardia and bradycardia, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, and myocarditis [2]                                                                                                        
• Respiratory: Dyspnea with underlying angioneurotic, cervicofacial, laryngeal, and oropharyngeal edema [34]  
• Gastrointestinal: Dysphagia, abdominal pain, and acute hepatic injury [1][6]                                                                           
• Renal: Chocolate brown urine, anuria, and oliguria [4][22]                                                                                               
• Musculoskeletal: Pain and rigidity of limbs, rhabdomyolysis [3]                                                                                
• Integumentary: Pruritis, erythema, vesicular, or bullous dermatitis in areas of topical exposure, often involving the scalp, face, hands, and legs [20]

Evaluation

Evaluation of paraphenylenediamine toxicity may be largely nonspecific, but understanding its clinical features and expected course can help curate a work-up to limit morbidity and mortality.[35] Initial assessment should systemically evaluate for any airway compromise, signs of respiratory distress, or impending circulatory collapse. This evaluation can be achieved by a primary cardiorespiratory status evaluation using continuous hemodynamic monitoring, electrocardiography, chest x-ray, and venous blood gas. In addition, care should be taken to look for signs of suspected anaphylaxis or anaphylactic shock, as cases have rarely been reported.[36][37] Given that these patients are often approached with a broad differential diagnosis initially, evaluation should aim to exclude other potential pathology.

Although there is no specific laboratory or radiologic test to investigate paraphenylenediamine toxicity, a laboratory work-up should coincide with the clinical features of the presenting system involved and screening for further expected toxicity. Elevated creatine phosphokinase, lactate dehydrogenase, and hepatic transaminitis were found in most patients after oral ingestion.[6] Despite its limitations, serum creatinine remained the most common indicator for assessing renal dysfunction.[10] Urinalysis often showed myoglobin casts, likely alluding to evolving acute tubular necrosis. Additional nonspecific laboratory findings included leukocytosis, metabolic acidosis, hypocalcemia, and hyperphosphatemia.[14]

In cases of limited dermal exposure with no signs of systemic involvement, the work-up focuses on confirming the presence of a paraphenylenediamine allergy. The gold standard to confirm contact allergy with paraphenylenediamine is by cutaneous patch test using 1% paraphenylenediamine in petrolatum. The process entails applying a commercially prepared allergen onto a small skin patch for 48 hours. This method is followed by observing for any allergic reaction on day 2 and day 4. Alternative testing for patients with a high risk for severe reactions includes using paraphenylenediamine 0.3% for 2 days or paraphenylenediamine 1% for 1 hour. An in vitro lymphocyte activation test has also been described, but its use in clinical practice is currently limited.[20] These tests are often performed in outpatient settings.

Treatment / Management

There is no antidote or specific treatment for paraphenylenediamine toxicity. As a result, the mainstay of treatment consists of early recognition, airway management, correcting electrolyte and acid-base derangements, and aggressive supportive measures, particularly for significant exposures and ill individuals.[2][3][17]

Decontamination

Immediate removal of visible toxin remnants upon hospital arrival is crucial. The effectiveness of activated charcoal in paraphenylenediamine toxicity has not been well documented. Theoretically, its low molecular weight and nonpolar state make it a plausible option; however, its hydrophilic nature does not (PubChem. p-Phenylenediamine).[38] The use of gastric lavage in the initial stage of detoxification is controversial due to its potential to increase the risk of airway obstruction, particularly in the setting of significant airway edema and respiratory distress. In addition, the corrosive and caustic nature of paraphenylenediamine increases the theoretical risk of further caustic injury and esophageal perforation.[4][39](A1)

Airway Management

As respiratory failure and asphyxia were the most typical causes of death in paraphenylenediamine toxicity, prompt and aggressive airway management is crucial. Endotracheal intubation or tracheostomy with or without mechanical ventilation were commonly listed interventions.[3] However, as the significant underlying pathology for airway collapse is severe angioneurotic edema with laryngeal edema, endotracheal intubation is often deemed difficult, if not impossible.[40] Thus, tracheostomy was noted to be more commonly used. A systematic review found that 48% of cases underwent emergency tracheostomy.[4] The role of other airway interventions, such as fiberoptic intubation or cricothyroidotomy, is yet to be explored in the literature, but it appears at face value to be valuable adjuncts or alternative means of securing the airway.(A1)

Anaphylaxis Management

In the event of hypersensitivity or anaphylactic complications, corticosteroids and antihistamines were commonly integrated into the initial treatment regimen.[17] For patients with anaphylaxis, intramuscular epinephrine should also be administered and managed according to local anaphylaxis protocols.

Rhabdomyolysis and Acute Renal Injury Management

As a general consideration in these patients, it is critical to avoid dehydration and hypoxia as the presence of these conditions leads to worsening tissue breakdown, consequently leading to further renal injury.[40] Early administration of isotonic fluids (8 to 10 L/d) has been shown to limit the progression of acute renal injury due to rhabdomyolysis.[9][17][40] Although it remains unclear if paraphenylenediamine is amenable to dialysis, hemodialysis has been reported to aid renal recovery in cases of severe kidney failure.[10](B3)

Differential Diagnosis

The differential diagnoses of a patient presenting with paraphenylenediamine toxicity can be extensive due to its nonspecific clinical manifestations. Regardless, other causes with similar manifestations can be considered based on the hallmarks of the disease, which are rhabdomyolysis, cervicofacial angioedema, and acute kidney injury.[1] This list is not all-inclusive but may serve as a good starting point.[41][42] Differential diagnoses include the following:

• Substance abuse, such as synthetic cannabinoids, amphetamines, cocaine, and heroin
• Medication-induced nephrotoxicity, such as cyclosporine, vancomycin, and aminoglycosides
• Alcohol toxicity
• Occupational toxins, such as agrichemicals
• Heavy metal toxicity, such as calcium, lead, mercury, and uranium
• Snake bites, such as Viperidae and Elapidae
• Viral hepatitis
• Vascular ischemia
• Hypersensitivity and anaphylaxis
• Trauma and crush syndrome
• Malignant hyperthermia
• Metabolic myopathies
• Extreme physical activity-induced rhabdomyolysis
• Heat disorders, such as heat stroke and heat exhaustion
• Severe dehydration

Prognosis

The prognosis of paraphenylenediamine toxicity largely depends on the severity of exposure, timeliness of medical intervention, and the patient's overall health. Early recognition and prompt treatment significantly improve outcomes, with many patients recovering fully with appropriate care. Mild cases, characterized by localized skin reactions, generally resolve with symptomatic treatment and avoidance of further exposure.

However, severe cases involving systemic toxicity, such as rhabdomyolysis, renal failure, or anaphylaxis, can have a more guarded prognosis and may require intensive care. Renal recovery and improved clinical outcomes were observed with early clinical detection; prompt airway interventions; supportive medical management, such as fluids, steroids, antihistamines, and dialysis; and timely referral.[1][6][10][17][43] 

Long-term complications, such as chronic kidney disease or persistent allergic sensitization, may impact the quality of life. Comprehensive follow-up care is crucial to monitor and manage any ongoing health issues, ultimately influencing the long-term prognosis.

The mortality rate of paraphenylenediamine toxicity has considerable variation in the current literature, with rates ranging from 0.03% to rates as high as 60%.[2][10][44] The most common causes of death were due to angioneurotic edema, respiratory failure, and fatal arrhythmias.[6][22] Several risk factors were linked to poor outcomes, which were late hospital presentation, no gastric lavage performed, tracheostomy or intubation requirement, neurologic involvement such as convulsions or low Glasgow Coma Scale score, established baseline renal failure, dialysis requirement, and intensive care unit admission.[14] 

Complications

Paraphenylenediamine poisoning can cause life-threatening adverse effects affecting multiple organ systems, including neurologic, cardiac, respiratory, renal, and hepatic systems.[1] Although rare, cases of seizures and coma were reported.[4] Angioneurotic edema with subsequent airway compromise necessitating tracheostomy and hepatic and renal failure requiring hemodialysis were commonly documented.[22] Cardiac complications such as myocarditis, myocardial infarction, and fatal arrhythmias, including atrial fibrillation, ventricular tachycardia, and ventricular fibrillation, have been observed.[25][27][28] Severe allergic reactions, including anaphylaxis, can occur, posing immediate life-threatening risks. Chronic exposure may lead to sensitization and long-term dermatologic conditions.

Similar complications were noted in pediatric populations, such as the development of respiratory failure requiring tracheostomy and acute renal and hepatic failure requiring dialysis.[16][35] Prompt recognition and management of these complications are essential to mitigate adverse outcomes and ensure patient safety.