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:
- Industrial Chemicals for Which Methemoglobin Formation is
the Principal Cause of Toxicity;
- 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
|
Revised May 30, 2018
 
|
