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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.
TTable 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-Chlorom-Toluidine

Aromatic Amines

3-Chloroaniline

108-42-9

m-Chloroaniline;
Chlorobenzenamine; MCA; mAminochlorobenzene

Aromatic Amines

4,4-Methylene
chloroaniline)

101-14-4

DACPM; MBOCA

bis(2-

Aromatic Amines

Aniline

62-53-3

Includes aniline homologs

Aromatic Amines

Dichloroaniline
isomers)

27134-276

Dichloroaniline

Aromatic Amines

Dimethylaniline

121-69-7

N,N-Dimethylaniline

Aromatic Amines

Diphenylamine

122-39-4

Anilinobenzene,
Phenylbenzenamine

Aromatic Amines

m-Toluidine

108-44-1

3-Aminotoluene, 3-Toluidine

Aromatic Amines

Monomethyl aniline

100-61-8

MA,
(Methylamino)benzene,
Methylphenylamine,
NPhenylmethylamine

Aromatic Amines

N-Isopropylaniline

768-52-5

N-IPA,
Isopropylaniline,
Benzenamine,
NPhenylisopropylamine

Aromatic Amines

o-Chloroaniline

95-51-2

2-Chloroaniline

(mixed

DPA,

Aromatic Amines

o-Toluidine

95-53-4

o-Aminotoluene,
2Aminotoluene,
Methyl-2aminobenzene, 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

25321-146

Dinitrotoluol,
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,
metaNitrotoluene, 3-Nitrotoluene

DNT,

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-Chloro1-nitrobenzene;
;
2Nitrochlorobenzene; 2-CNB

Aromatic Nitros

o-Nitrotoluene

88-72-2

o-Methylnitrobenzene,
Methylnitrobenzene,
orthoNitrotoluene, 2-Nitrotoluene

Aromatic Nitros

p-Dinitrobenzene

100-25-4

para-Dinitrobenzene

100-01-6

para-Aminonitrobenzene,
Nitroaniline,
Nitrobenzenamine,
Nitrophenylamine, PNA

Aromatic Nitros

p-Nitroaniline

4p-

Aromatic Nitros

p-Nitrochlorobenzene

100-00-5

p-Chloronitrobenzene;
Chloronitrobenzene; 1-Chloro4-nitrobenzene;
4Nitrochlorobenzene; PCNB

Aromatic Nitros

p-Nitrotoluene

99-99-0

p-Methylnitrobenzene,
Methylnitrobenzene,
paraNitrotoluene, 4-Nitrotoluene

Fluorides,
Inorganic

Nitrogen trifluoride

7783-54-2

Nitrogen fluoride, Trifluoramine,


Trifluorammonia

Irritant Gases

Nitric oxide

10102-439

Mononitrogen monoxide

Nitrosobenzenes

p-Dinitrosobenzene

105-12-4

Benzene,
p-dinitroso-; 1,4Dinitrosobenzene

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
Vegetablescarrot 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

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