Methemoglobinemia

 

The following two web pages about "The Two Classes of Chemicals that Cause Methemoglobinemia" were written before 2006 and are based on documents published before 2006. The ACGIH document "Methemoglobin Inducers" was revised in 2006. In the revised document, some of the chemicals that were in Table 1 are now in Table 2. The following chemicals were moved from Table 1 to Table 2: Anisidine, MBOCA, Nitric oxide, Nitrogen trifluoride, Propylene glycol dinitrate, Toluidine (o, m, and p isomers), and Xylidines. The changes will be reflected in the web version of Haz-Map with the 2006 update. Also, other chemicals that can induce methemoglobinemia have been added to the web version of Haz-Map, but have not been added to these two web pages. 

The Two Classes of Chemicals that Cause Methemoglobinemia

ACGIH (American Conference of Governmental Industrial Hygienists) divides methemoglobin inducers into two classes:

  1. Industrial Chemicals for Which Methemoglobin Formation is the Principal Cause of Toxicity;
  2. Industrial Chemicals for Which Methemoglobin Formation is NOT the Principal Cause of Toxicity;

Tables 1 and 2 correspond with this classification system, with additional chemicals in each class based on information from ACGIH and HSDB.

T

Table 1--Industrial Chemicals: Methemoglobinemia Is the Primary Toxic Effect
Category Chemical Name CAS # Other Chemical Names
Aliphatic Nitrates Propylene glycol dinitrate 6423-43-4 PGDN
Aliphatic Nitros n-Propyl nitrate 627-13-4 Propyl ester of nitric acid
Aromatic Amines 2-Chloro-m-toluidine 95-81-8 2-Chloro-5-methylaniline; Methylbenzenamine; 6-Chloro-m-Toluidine
Aromatic Amines 3-Chloroaniline 108-42-9 m-Chloroaniline; Chlorobenzenamine; MCA; m-Aminochlorobenzene
Aromatic Amines 4,4’-Methylene bis(2-chloroaniline) 101-14-4 DACPM; MBOCA
Aromatic Amines Aniline 62-53-3 Includes aniline homologs
Aromatic Amines Dichloroaniline (mixed isomers) 27134-27-6 Dichloroaniline
Aromatic Amines Dimethylaniline 121-69-7 N,N-Dimethylaniline
Aromatic Amines Diphenylamine 122-39-4 Anilinobenzene, DPA, Phenylbenzenamine
Aromatic Amines m-Toluidine 108-44-1 3-Aminotoluene, 3-Toluidine
Aromatic Amines Monomethyl aniline 100-61-8 MA, (Methylamino)benzene, Methylphenylamine, N-Phenylmethylamine
Aromatic Amines N-Isopropylaniline 768-52-5 N-IPA, Isopropylaniline, Benzenamine, N-Phenylisopropylamine
Aromatic Amines o-Chloroaniline 95-51-2 2-Chloroaniline
Aromatic Amines o-Toluidine 95-53-4 o-Aminotoluene, 2-Aminotoluene, Methyl-2-aminobenzene, o-Methylaniline, 2-Methylaniline
Aromatic Amines p-Toluidine 106-49-0 para-Aminoanisole; 4-Anisidine; Methoxyaniline
Aromatic Amines Xylidene, mixed isomers 1300-73-8 Aminodimethylbenzene, Aminoxylene, Dimethylaminobenzene, Dimethylaniline, Xylidine isomers
Aromatic Nitros 2-Nitronaphthalene 581-89-5 beta-Nitronaphthalene
Aromatic Nitros Dinitrotoluene, all isomers 25321-14-6 Dinitrotoluol, DNT, Methyldinitrobenzene
Aromatic Nitros 2,4,6-Trinitrotoluene 118-96-7 1-Methyl-2,4,6-trinitrobenzene; TNT; Trinitrotoluene; 
Aromatic Nitros m-Dinitrobenzene 99-65-0 meta-Dinitrobenzene
Aromatic Nitros m-Nitroaniline 99-09-2 1-Amino-3-nitrobenzene; Nitroaniline; meta-Nitroaniline; 3-Nitrobenzenamine
Aromatic Nitros m-Nitrotoluene 99-08-1 m-Methylnitrobenzene, Methylnitrobenzene, meta-Nitrotoluene, 3-Nitrotoluene
Aromatic Nitros Nitrobenzene 98-95-3 Essence of mirbane, Nitrobenzol, Oil of mirbane
Aromatic Nitros o-Dinitrobenzene 528-29-0 ortho-Dinitrobenzene; Dinitrobenzene
Aromatic Nitros o-Nitrochlorobenzene 85-73-3 Chloro-o-nitrobenzene; Chloronitrobenzene; 2-Chloro-1-nitrobenzene; ; 2-Nitrochlorobenzene; 2-CNB
Aromatic Nitros o-Nitrotoluene 88-72-2 o-Methylnitrobenzene, Methylnitrobenzene, ortho-Nitrotoluene, 2-Nitrotoluene
Aromatic Nitros p-Dinitrobenzene 100-25-4 para-Dinitrobenzene
Aromatic Nitros p-Nitroaniline 100-01-6 para-Aminonitrobenzene, Nitroaniline, 4-Nitrobenzenamine, p-Nitrophenylamine, PNA
Aromatic Nitros p-Nitrochlorobenzene 100-00-5 p-Chloronitrobenzene; Chloronitrobenzene; 1-Chloro-4-nitrobenzene; 4-Nitrochlorobenzene; PCNB
Aromatic Nitros p-Nitrotoluene 99-99-0 p-Methylnitrobenzene, Methylnitrobenzene, para-Nitrotoluene, 4-Nitrotoluene
Fluorides, Inorganic Nitrogen trifluoride 7783-54-2 Nitrogen fluoride, Trifluoramine, Trifluorammonia
Irritant Gases Nitric oxide 10102-43-9 Mononitrogen monoxide
Nitrosobenzenes p-Dinitrosobenzene 105-12-4 Benzene, p-dinitroso-;  1,4-Dinitrosobenzene
Others Methyl Nitrite 624-91-9 Nitrous acid, methyl ester

 

Chemicals which May Cause Methemoglobinemia as a Secondary Effect

Chemicals listed in Table 2 have been reported to induce methemoglobinemia in experimental animals or in humans after ingestion, intravenous administration or exposure following a chemical accident.

Definition of Methemoglobinemia

"Methemoglobin is the oxidized form of hemoglobin in which the iron in the heme component has been oxidized from the ferrous (+2) to the ferric (+3) state. This renders the hemoglobin molecule incapable of effectively transporting and releasing oxygen to the tissues. Normally, there is about 1% of total hemoglobin in the methemoglobin form. A small amount of methemoglobin exists in red cells as a result of normal oxidative functions." (ACGIH Documentation of TLVs)

It is not the presence of methemoglobin but the amount that is important. There are no signs or symptoms when 0 to 15% methemoglobin levels are present. A concentration of 15 to 20 % results in "chocolate brown" blood and clinical cyanosis. Symptoms of hypoxia such as dyspnea, fatigue and headache appear when the concentration reaches 20 to 45%. "Administration of methylene blue is indicated in symptomatic patients with methemoglobin levels greater than 30%." (See Chapter 72, "Methemoglobin-Forming Chemicals" by Donna L. Seger, in Sullivan)

Exposures that Caused Methemoglobinemia in the Past

"In the United Kingdom between 1961 and 1980, chloroaniline, p-toluidine, nitrobenzene, and nitrochlorobenzene were the most common industrial causes of methemoglobinemia. Dermal exposure was a more frequent route of toxicity than inhalation with these compounds." (Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988.)

"Historically, most work-related episodes of methemoglobinemia and hemolytic anemia have been due to exposure to aromatic nitro and amino compounds. These compounds have been used most extensively as intermediates in the synthesis of aniline dyes; they are used also as accelerators and antioxidants in the rubber industry and in the production of pesticides, plastics, paints, and varnishes." (Rugo HS, Damon LE, "Occupational Hematology," p. 206, LaDou)

Non-Occupational Causes of Methemoglobinemia

As for non-occupational exposures, this is the subject of a ATSDR Case Studies monograph, "Nitrate/Nitrite Toxicity." See Table 3 from that monograph. "Infants less than 4 months of age are at particular risk of nitrate toxicity from contaminated water. . . . The widespread use of nitrate fertilizers increases the risk of well-water contamination in rural areas."

 

Table 3--Reported Inducers of Methemoglobinemia 

Agent

Source/Use

Inorganic nitrates/nitrites
Contaminated well water
Meat preservatives
Vegetables—carrot juice, spinach
Silver nitrate burn therapy
Industrial salts
Contaminants of nitrous oxide canisters for anesthesia
Butyl/isobutyl nitrite
Amyl nitrite
Nitroglycerin
Room deodorizer propellants
Inhalant in cyanide antidote kit
Pharmaceuticals for treatment of angina
Aniline/aminophenols
Nitrobenzene
Sulfonamides
Phenazopyridine
Antimalarials
Sulfones
p-Aminosalicylic acid
Naphthalene
Copper sulfate
Resorcinol
Chlorates
Combustion products
Local anesthetics
Laundry ink
Industrial solvents; gun-cleaning products
Antibacterial drugs
Pyridium
Chloroquine; Primaquine
Dapsone
Bactericide (tuberculostatic)
Mothballs
Fungicide for plants, seed treatment
Antiseborrheic, antipruritic, antiseptic
Matches, explosives, pyrotechnics
Fires
Benzocaine; lidocaine; Propitocaine; Prilocaine

 

MetHgb:Secondary

Revised April 11, 2011

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