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Journal of Occupational & Environmental Medicine:
doi: 10.1097/JOM.0b013e3182733909
Occupational Medicine Forum

Paranitroanaline Poisoning: A Failure in Basic Prevention?

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The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney.

Answered by Kathleen M. Fagan, MD, MPH, Rosemary K. Sokas, MD, MOH, George R. Grimes,MD, MPH, and Justin B. Sternes, BS. From the Occupational Safety and Health Administration (Drs Fagan and Sokas), Office of Occupational Medicine, Washington, DC; Department of Human Science (Dr Sokas), Georgetown University, Washington, DC; Occupational Health (Dr Grimes), Naval Branch Health Clinic, Indian Head, Md, Occupational Medicine Resident, Uniformed Services University of the Health Sciences, Bethesda, Md; and Occupational Safety and Health Administration, Peoria Area Office, Peoria, Il (Mr Sternes). E-mail:

Over Labor Day weekend in 2008, four hospitals in a small Midwestern city simultaneously received eight acutely ill men with complaints ranging from nausea and vomiting to seizures; all were cyanotic. Concerns about a terrorist attack prompted the involvement of the Federal Bureau of Investigation and the Environmental Protection Agency. The Federal Emergency Management Agency raised its threat level to yellow (risk level 3, with 5 being the highest). Once it became clear that all eight individuals worked at a local warehouse, a Hazardous Materials (HazMat) team was dispatched to evaluate the site. There they identified labeled barrels of paranitroaniline (p-nitroaniline or PNA; CAS 100-01-6; NO2C6H4NH2), and the incident was referred to the Occupational Safety and Health Administration (OSHA).

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The warehouse facility typically stored and handled a granular form of PNA, received in large 3000-lb supersacks imported from China. p-Nitroaniline was subsequently supplied to a US rubber manufacturer, and in 2004, the warehouse received a shipment of 284 fifty-five-gallon drums of finely ground PNA from India. The ground PNA could not be effectively utilized in the rubber-manufacturing process, and the drums remained in storage until 2008. At this time, the Beijing Summer Olympics led to a disruption in PNA shipments from China. The rubber manufacturer requested the finely ground PNA, requesting the warehouse to first transfer the PNA from the 55-gallon drums into supersacks.

Each drum was appropriately labeled, and material safety data sheets clearly noted that the chemical was potentially lethal by oral, inhalational, and dermal exposure routes. Nevertheless, the warehouse's director of operations, without utilizing the available hazard information, assembled an untrained team of eight workers to transfer the PNA powder. The workers were inadequately trained and erroneously informed that the powder was safe unless ingested. Although protective clothing and respirators were made available, workers were not required to wear them. Workers were provided with N-95 respirators but not instructed on their use, and only one employee was up-to-date with fit testing requirements. OSHA inspectors found yellow PNA powder on the inside of the respirators, indicating that they had been ineffective.

The makeshift transfer operation utilized three forklifts and was performed outside on a warehouse loading dock. The workers lifted the PNA drums with one forklift, using a drum tilter to empty the contents into a supersack held by a second forklift. Because the supersack opening was too small, an inverted supersack (with its bottom cut out) was held by a third forklift to act as a funnel for the PNA powder. Fine powder residue was caked on the inside of the drums and the workers used long-handled tools and mallets to scrape out the remaining PNA. At one point, a drum fell into the funnel sack, creating a large plume of PNA that covered the workers and loading dock.

Within 3 hours of the operation's onset, workers began experiencing fatigue and other nonspecific symptoms. Thought to have heat exhaustion, one worker was driven home, whereas another drove himself home. When the director of operations noted that multiple workers were symptomatic and had “blue lips,” he instructed them to stop working and shower. He drove two workers to a nearby hospital, where all three were admitted. The last three workers at the warehouse drove themselves to another hospital. The two workers who had gone home earlier sought care at two additional hospitals. Thus, four different area hospitals treated eight PNA-poisoned workers.

Symptoms experienced by the workers included dizziness, fatigue, dyspnea, “feeling drunk,” vomiting, convulsions, severe anxiety, and altered mental status. All were markedly cyanotic. The workers identified PNA as the exposure and initial blood methemoglobin levels ranged from 14.2% to 72.2% (normal < 3%) (Table 1). All eight workers were diagnosed with methemoglobinemia, decontaminated, and treated with oxygen and methylene blue. Their methemoglobin levels dropped to normal over one to two days.

Table 1
Table 1
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p-Nitroaniline is found in a variety of industries and is often the preferred intermediary for the manufacture of dyes. This chemical is used in the production of rubber, gasoline, pesticides, paints, and varnishes, and its toxicity has been recognized for many years.1–4 p-Nitroaniline is a fat-soluble compound and is readily absorbed across intact skin. Exposures most commonly occur via the skin and lungs, although ingestion has also been reported.5

p-Nitroaniline is acutely toxic to the hematopoietic system and, like other aniline derivatives, oxidizes hemoglobin from the ferrous (Fe2+) to the ferric (Fe3+) state, forming methemoglobin. Methemoglobin is unable to adequately transfer oxygen to tissues, thus shifting the oxyhemoglobin dissociation curve to the left. Cyanosis appears early on, causing the skin and mucous membranes to turn a deep shade of blue. Methemoglobin's dark brown pigment gives blood a “chocolate brown” appearance, and the urine is dark due to hemoglobinuria. In the presence of methemoglobinemia, pulse oximetry does not reliably measure oxygen saturation and may show falsely high or falsely low values.6

Patients with methemoglobinemia are generally less ill than they appear and their cyanosis does not clear with oxygen treatment alone. The severity of symptoms correlates with the percent of methemoglobin in the blood. Individuals may remain asymptomatic at levels up to 15% concentration of methemoglobin or experience only a grayish-blue skin color. Methemoglobin concentrations higher than 15% to 20% are associated with systemic symptoms, such as headaches, dyspnea, lightheadedness, fatigue, confusion, chest pain, and palpitations. Above 50%, patients experience more profound central nervous system effects, including central nervous system depression, altered mental status, and coma.6 A level of 30% methemoglobin (moderate to severe intoxication) is often used as the threshold for treatment with 100% oxygen and methylene blue. Methylene blue acts as an electron donor in the reduction of methemoglobin, allowing for the restoration of hemoglobin's oxygen-carrying capacity. Glucose-6-phosphate dehydrogenase deficiency is a relative contraindication for methylene blue treatment and can increase the risk of hemolytic anemia. Methemoglobin levels in excess of 70% are often fatal. Exchange transfusion may improve survival odds for these patients.6,7

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In the occupational setting, methemoglobinemia most commonly occurs from improper chemical usage or accidental spills.8 The opportunities for prevention in this case were many, and yet all were missed. At the most basic level, the information readily available on the PNA labels and material safety data sheet indicated that PNA is a potentially lethal chemical by all routes of exposure and should have triggered both hazard communication and preventive measures. Effective preventive measures include engineering and work practice controls, administrative controls, employee education, and the use of appropriate personal protective equipment (PPE). Appropriate PPE in this case would have included impervious coveralls, gloves, and full-face respirators (self-contained breathing apparatus) to completely prevent dermal and inhalational contact.

OSHA cited the company for violations of its Air Contaminants standard (29 CFR 1910.1000) because it exposed its employees to PNA above that standard's permissible exposure limit (1 ppm, 8-hour time-weighted average), as evidenced by the workers' illnesses. OSHA also cited the company for violations of other standards, including PPE (29 CFR 1910.132), Respiratory Protection (29 CFR 1910.134), Process Safety Management (PSM) (29 CFR 1910.119), and Hazard Communication (29 CFR 1910.1200). OSHA's PSM standard contains requirements related to processes or activities involving highly hazardous chemicals, such as PNA. These activities include using, storing, manufacturing, handling, or moving such chemicals at the site, or any combination of these activities. The PSM standard requires, among other things, chemical hazard evaluations, written operating plans for chemical processes and transfers, emergency action plans for spills and releases, and worker training, including training on emergency operations. Under the PSM standard, employers must conduct prestartup safety reviews of newly installed or modified equipment and changes in processes.9

Injury and illness prevention programs can be used to reduce the number and severity of workplace injuries and illness in all businesses, including small businesses.10 These programs take a commonsense approach to identifying workplace hazards and developing a plan to prevent, reduce, or control the hazards. The components of effective injury and illness prevention programs include management commitment, worker participation, hazard identification and remediation, training, and program evaluation. Additional effort to include subcontra-cted workers is necessary to provide meaningful protection.

This incident highlights the roles of downsizing and globalization in worsening occupational safety and health risks. The incident also serves as a reminder that community disaster planning is often tested by such industrial disasters.

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All employers have a duty to maintain a work environment free from recognized hazards. Both PSM and injury and illness prevention programs provide employers with a blueprint to prevent incidents such as the one described. Occupational medicine physicians play an important role in educating workers and employers, particularly small business owners, about workplace health hazards and preventive measures. In this case, the basic elements of hazard identification, remediation, training, and appropriate selection of PPE could have been augmented by planning for emergency and first aid response procedures, including appropriate referral mechanisms, in the event of PNA exposure.

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1. Occupational Safety and Health Administration. Safety and Health Topics: Process Safety Management (PSM). Accessed February 8, 2012.

2. Occupational Safety and Health Administration. Safety and Health Topics: Hazard Communication. Accessed March 6, 2012.

3. Occupational Safety and Health Administration. Injury and Illness Prevention Program. Available at: Accessed November 27, 2011.

4. National Library of Medicine. TOXNET. Accessed February 8, 2012.

Disclaimer: This document is not a standard or regulation, and it neither creates new legal obligations nor alters existing obligations created by OSHA standards or the Occupational Safety and Health Act. It contains recommendations that are advisory in nature and informational in content and are intended to assist employers in providing a safe and healthful workplace.

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1. National Library of Medicine. TOXNET Hazardous Substance Database: 4-Nitroaniline. Bethesda, MD: US National Library of Medicine; last revision April 14, 2008.±hsdb:@term±@rn±@rel±100-01-6. Accessed March 3, 2012.

2. Anderson A. Acute paranitroaniline poisoning. Br J Ind Med. 1946;3:243–244.

3. Kulkarni BS, Acharya VN, Khanna RM, et al. Methemoglobinemia due to nitro-aniline intoxication. J Postgrad Med. 1969;15:192–200.

4. Sia HK, Huang PT, Wang SR, et al. Methemoglobinemia caused by p-nitroaniline intoxication: report of four cases. Changhua J Med. 2004;9:116–120.

5. Bradberry SM. Occupational methaemoglobinaemia. Toxicol Rev. 2003;22:13–27.

6. Curry SC. Hematologic consequences of poisoning. In: Shannon MW, Borron SW, Burns MJ, eds. Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose. 4th ed. Philadelphia, PA: Saunders Elsevier; 2007:291–295.

7. Navarro WH, Rugo HS. Occupational hematology. In: LaDou J, ed. Current Occupational & Environmental Medicine. 4th ed. New York: McGraw Hill Medical; 2007:208–211.

8. Bradberry SM. Occupational methaemoglobinaemia. Toxicol Rev. 2003;22:13–27.

9. Occupational Safety and Health Administration. Process Safety Management. Publication 3132, Washington, DC: US Department of Labor, Occupational Safety and Health Administration; 2000. Accessed March 3, 2012.

10. Occupational Safety and Health Administration. Injury and Illness Prevention Programs White Paper. Washington, DC: US Department of Labor, Occupational Safety and Health Administration; January 2012. Accessed March 3, 2012.

Copyright © 2014 by the American College of Occupational and Environmental Medicine


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