"Current Awareness"
Program
Vol. III.
August 1982
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NITROALKANES AND NITROALKENES
CARCINOGEN1CITY AND STRUCTURE-ACTIVITY
RELATIONSHIPS. OTHER BIOLOGICAL PROPERTIES,
METABOLISM. ENVIRONMENTAL SIGNIFICANCE.
David Y. Lai, Ph. D.
Yin-tak Woo, Ph. D.,
Joseph C. Arcos, D. Sc., and
Mary F. Argus, Ph. D.
Preparation for the Chemical Hazard
Identification Branch "Current
Awareness" Program
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Table of Contents;
5.2.2.6 - Nitroalkanes and Nitroalkenes
5.2.2.6.1 Introduction
5.2.2.6.2 Physical and Chemical Properties. Biological
Effects.
5.2.2.6.2.1 Physical and Chemical Properties
5.2.2.6.2.2 Biological Effects Other Than Carcinogenic
5.2.2.6.3 Carciongenicity
5.2.2.6.4 Metabolism and Mechanism of Action
5.2.2.6.5 Environmental Significance
References
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5.2.2.6 Nitroalkanes and Nitroalkenes.
5.2.2.6.1 Introduction.
Nitroalkanes (nitroparaffins) and nltroalkenes (nitro-olefins) have the
general formulas C Ho-. iNO- and-.C Ho^NO** resPect*vely* Several nitroalkanes,
including nitromethane (NM), nitroethane (NE), 1-nitropropane (1-NP), and
2-nitropropane (2-NP) have been commercially available since 1940. By virtue
of their unusual spectrum of industrially desirable properties, the demand for
them has rapidly increased for many diversified applications (see Section
5*2.2.6.5). These compounds are now produced in multi-million Ibs. quantities
annually in the United States (1). A brief discussion of potential occupa-
tional exposure and genotoxic effects of nitroalkanes has been included in a
recent review by Fishbein (2). .. . . .-.'....
»
Studies in the 1950's suggested that both NM and 2-NP were noncarcino-
genic in several animal species (3, 4). More recent investigations by Lewis
£t..al_. (5) also failed to show tumor induction in rats and rabbits exposed to
NM vapor; however, under very similar experimental conditions, 2-NP was found
by them to be a potent liver carcinogen in the rat.
Recently emerging evidence on the carcinogenicity in experimental
animals, along with various other toxic effects observed in workers exposed to
nitroalkanes, have attracted the attention of U.S. regulatory agencies to the
potential hazards of these chemicals to human health. The U.S. National
Institute for Occupational Safety and Health (NIOSH) issued guidelines for
handling 2-NP in the workplace as if it were a human carcinogen (1).
Interest in nitroalkenes stems largely from studies on air pollution in
metropolitan areas. It had been suspected for some time that conjugated
nitroalkenes may be components of "smog," since this type of chemicals could
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be formed by the reaction of unsaturated hydrocarbons with nitrogen oxides
originating from automobile exhausts. Subsequent analysis provided unequi-
vocal evidence that nitroalkenes were indeed present in the atmosphere (cited
in refs. 6, 7). Although several earlier attempts to demonstrate the presence
of nitroalkenes in automobile exhausts were unsuccessful due to the complexity
of the combustion mixture formed from commercial gasoline, Deichmann and his
associates (7, 8) identified several nitroalkenes in the exhaust of an experi-
mental internal combustion engine (one-cylinder, four cycle) using isobutylene
and 3-hexene (normal constituents of gasoline) as fuels. One of these nitro-
alkenes, 3-nitro-3-hexene, was found to induce primary carcinoma in the lungs
of mice and rats in a chronic inhalation study (7, 9). Based on the histolo-
glcal similarity between the tumors observed in animals and lung tumors in
man, the authors suggested that 3-nitro-3-hexene may be a potential human
carcinogen (7). . ,,., . , .
5.2.2.6.2 Physical and Chemical Properties. Biological Effects.
5.2.2.6.2.1 PHYSICAL AND CHEMICAL PROPERTIES.
Nitroalkanes. The physical constants of nitroalkanes that have been
tested for carcinogenicity are listed in Table I. These compounds are color-
less, oily liquids with somewhat pleasant odors. Their boiling points are
higher than those of the corresponding hydrocarbons. They have limited water
solubility, but are miscible with aromatic hydrocarbons, alcohols, esters,
ketones, ethers, and higher aliphatic carboxylic acids. Nitromethane is
classified as an explosive since, under appropriate conditions of temperature,
confinement, chemical reaction, and shock, explosion can occur. Other nitro-
alkanes are also explosive, although they are less hazardous than nitro-
methane.
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Table I. Chemical Structures and Physical Properties of
Nitroalkanes and 3-Nitro-3-hexenea
Density Vapor
Mol. B.P. at 25°C Pressure
Compound Formula . Wt. (°C) (g/ml) at 20°C, torr
Nitromethane CH3N02 ' . 61.04 101 1.131 27.3
Nitroethane CH3CH2N02 75.07 114 1.045 15.8
1-Nitropropane CH3CH2CH2N02 89.10 > 131 0.996 7.6
2-Nitropropane CH3CH(N02)CH3 89.10 120 0.983 13.0
N02 .
3-Nitro-3-hexene CH3CH2-C=CHCH2CH3 129.18 71 0.978
Solubility ifl RyO
at 25°C
(% by wt.)
11.1
4.7
1.5
1.7
a Data summarized from Kirk-Othmer: Encyclopedia of Chemical Technology [2nd Ed., fy>l. 13, John Wiley, New
York, 1976, p. 864-883] and from Lampe, K.F., Mende, T.J., and Mills, A.P. [J. Chem. Eng. Data _7, 85-90,
1962]. . .
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The chemistry of nitroalkanes has been extensively reviewed in a number
of publications (10-14) and was the subject of two symposia (15, 16a). Nitro-
alkanes C, to C_ dre synthesized industrially by reaction in the vapor-phase
between propane and nitric acid at elevated temperature and pressure. The
nitromethane, nitroethane, and nitropropane formed are then separated by
fractional distillation. Nitroalkanes exist in tautomeric equilibria with
their nitronic acid isomers (aci forms), which are much more acidic than their
nitro forms:
H H H
© I
R-C-:*' * - - ' ~ H
H
Nitro form Aci form
The ratio of the two forms in equilibrium is governed by the stability of the
anion which depends in part on the nature of the R group. The aci form is
amphoterically reactive, with the protonated aci form being electrophilic and
the anionic aci form being nucleophilic (16b). It has been found that the
proportion of the aci form present in water at 25 C increases with the size of
the R group in the order: C-Hy > C-Hc > CH3 (17).
Nitroalkanes are oxidized only slowly by strong oxidizing agents but are
reduced quite readily by a number of reducing agents to yield oximes,
hydroxylamines, or alkylamines. In the presence of strong alkali, HM reacts
rapidly to fora methazonic acid, whereas higher primary nitroalkanes decompose
to give nitrites. Under alkaline conditions, chlorination of nitroalkanes may
also occur, resulting in substitution by chlorine of one or more hydrogen
atoms on the carbon linked to the nitro group. Chloronitroalkanes in which
the chloro and nitro groups are linked to different carbons can be formed by
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chlorinating the nitroalkanes under anhydrous conditions and irradiating with
visible light. Interaction of nitroalkanes with aldehydes in the presence of
alkali yields nitrphydroxy compounds, which can be further reduced to produce
aminohydroxy derivatives. When molar equivalents of nitroalkanes, formalde-
hyde, and amines are reacted, Mannich bases are formed.
Nitroalkenes. Because of their importance as air pollutants, 21 nitro-
alkenes from C, to Cg were synthesized by Deichmann's group for toxicological
evaluation (6). The physical properties of these nitroalkenes have been
described (18 ). They range from colorless to pale yellow liquids with
boiling points in the same order of magnitude as those of nitroalkanes. Some
physical constants of 3-nitro-3-hexene, the nitroalkene found to be carcino-
genic in mice and rats (7, 9), are shown in Table I. The chemical properties
of nitroalkenes, including reduction, hydration, halogenation, and reaction
with alcohol, thiols, amines, and ammonia by double bond addition have been
extensively described by Levy and Rose (10).
5.2.2.6.2.2 BIOLOGICAL EFFECTS OTHER THAN CARCINOGENIC
Toxic Effects. In marked contrast to the highly toxic aromatic nitro
compounds, nitroalkanes have generally low toxicity (3, 4, 19-22). There
appears to be no evidence for skin irritation or absorption through the skin
sufficient to cause systemic injury. High concentrations of nitroalkanes are,
however, lethal to animals eioher by oral administration or by inhalation.
The toxicity of nitroalkanes generally increases with an increase in molecular
weight. The oral LD5Q (expressed in g/kg) of MM, NE, 2-NP, and 1-NP in the
rat was 1.21, 1.1, 0.725, and 0.455, respectively (cited in refs. 14, 21).
Studies of the structure-toxicity relationships (20) indicate that introduc-
tion of additional nitro groups to carbon-1 in methane, ethane, and propane
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derivatives leads to an increase in toxicity; replacement of one nitro group
by a methyl group in the methane and ethane derivatives lowers the toxicity.
Unsaturation of the hydrocarbon chain as in nitroalkenes results in great
augmentation of toxicity (6, 7). Bromine-substituted nitroalkanes are
generally more toxic than their chlorinated analogs (20.)
Acute inhalation studies using cats, rats, rabbits, and guinea pigs
showed considerable species differences in their tolerance to 2-NP, with cats
being the most sensitive to 2-NP and guinea pigs the least sensitive (3).
Inhalation of lethal doses of nitroalkanes brings about in the animals rest-
lessness, irritation of the eyes and the respiratory tract, salivation, and
central nervous system symptoms, (convulsions, anesthesia, and coma) (19).
Similar symptoms, as well as gastrointestinal tract irritation, are produced
by oral administration. Animals that inhaled high doses of 2-NP showed
general vascular endothelial damage, in addition to specific damage to the
liver and brain, and pulmonary edema and hemorrhage (3). Methemoglobinemia
and decrease in prothrombin content of the blood were also observed in animals
exposed to 2-NP vapors (3, 23). There is evidence that low levels of both
saturated and unsaturated aliphatic nitro compounds inhibit the oxygen
consumption of polymorphonuclear leucocytes (24).
The acute toxic effects of nitroalkenes in several species have been
extensively studied by Deichmann _e£_al_« (6). The nitroalkenes are highly
toxic agents which produce, in* addition to severe local irritation, nany signs
of systemic intoxication (hyperexcitability, tremor, clonic convulsions,
tachycardia, increase in the rate and magnitude of respiration, etc.). All
rats exposed to atmosphere containing 557 ppm 3-nitro-3-hexene died within
3070 minutes. Regardless of the mode of administration, the damage was most
severe to the lung; lethality was caused by respiratory failure and asphyxial
convulsion.
5
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Although epidemiological surveys on the consequences of exposure to
nitroalkanes and nitroalkenes are scanty, a number of cases of occupation-
related human intoxication by 2-NP have been recorded. In 1947, Skinner (25)
reported that workers exposed to 20 to 45 ppm of 2-NP during an industrial
coating-dipping process complained of anorexia, nausea, severe occipital
headache, vomiting, and diarrhea. Similar symptoms were experienced by
workers exposed to mixtures of 1- and 2-NP (cited in ref. 1). More recently,
Gaultier et_ al. (26) described the development of fatal- toxic hepatitis in
workers exposed to high concentrations of 2-NP. Hine ^£ jil^ (27) suspected
that the fatalities of four men working with solvent mixtures containing
11-28% 2-NP might be attributed to chronic intoxication by 2-NP. In 1979, a
retrospective mortality study of 1,481 workers employed between 1955 and 1977
at a 2-NP producing plant in the United States was reported (cited in ref.
28). The authors concluded that "analysis of these data does not suggest any
unusual cancer or other disease mortality pattern among this group of
workers." However, they added that "both because the cohort is small and
.because the period of latency is, for most, relatively short, one cannot con-
clude from these data that 2-NP is non-carcinogenic in humans."
No specific health effects of nitroalkenes have been documented. How-
ever, they are believed to be one of the classes of atmospheric pollutants
responsible for eye and respiratory tract irritation commonly experienced by
individuals residing in smogg^ cities (29).
Mutagenicity. Limited information is available on the mutagenicity of
nitroaliphatic compounds. Chiu et_ai. (30) tested the mutagenic activity of
53 commercially available nitro compounds (mostly aromatic) in Salmonella
typhicmrium. The majority of these compounds displayed mutagenic activity.
However, nitromethane, the only aliphatic compound tested, was found to be
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non-mutagenic to both TA100 and TA98 strains. 1-Nitropropane (1-NP), 1-nitro-
butane, and 1-nitrohexane were selected for rautagenicity testing by the U.S.
National Toxicology Program. Preliminary results indicate that neither of the
three chemicals are mutagenic (31). Studies by Kite and Skeggs (32) also
indicate that 1-NP and NE are inactive in several Salmonella tester-strains,
with or without microsonal activation. 2-Nitropropane, however, was shown to
produce a significant increase in revertants in all of the tester strains
(particularly in strain TA100 in the presence of S-9 mix). The mutagenic
effects of NE and 2-NP were also studied in the micronucleus test; the results
were negative for both compounds (32, 33a). From these studies, the authors
(32) concluded that 2-NP has the potential for causing point mutations but
probably will not cause a chromosome mutation of the clastogenic type. Recent
results from Speck ji£ jil_. (33b) lend further support to the mutagenicity of
, 2-NP in strains TA100 and TA98 of S. typhimurium. Again, S-9 mix was not
required, but it did enhance the mutagenic action of 2-NP. Moreover, muta-
genicity was fully expressed in tester strains (TA100NR3 and TA98NR101), which
are deficient in nitroreductase. These findings led the authors to suggest
that 2-NP was an ultimate mutagen which did not require metabolic activation
or enzymic reduction of the nitro group to the corresponding hydroxylamine;
however, further biotransformation of 2-NP by microsonial enzymes probably
produces additional mutagenic species.
Lo'f roth _e£jal/ (34a) conducted mutagenicity tests on several primary (Cl
to C5) and secondary (C3 to C5) mono-nitroalkanes in strains TA100, TA98 and
TA1535 of Salmonella typhimurium. They found that none of the primary nitro-
alkanes, except nitroethane (NE), exhibited detectable autagenicity. The
secondary nltroalkanes, on the other hand, are all mutagenic and their
activity decreases in order: nitroporpane > nitrobutane > nitropentane. The
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mutagenicity response is the highest in strain TA100 and is not significantly
affected by S-9 mix.
Teratogenicity. The teratogenic effects of 2-NP on the fetal development
of the rat.have been studied by Harris £t__al_. (34b). Adult female Sprague-
Dawley rats were injected intraperitoneally with 170 mg/kg body weight of 2-NP
on day 1 to 15 of gestation. Retarded heart development was observed in pups
from 9 out of 10 litters from mothers treated with 2-NP. Thirty to 86% of the
pups examined within a litter were affected.
There are no direct studies on the teratogenicity of other nitroaliphatic
.'' *-
compounds. A teratogenesis study (35) and a three-generation reproduction
study (36) in mice exposed to a mixture of NE, diethylhydroxylamine and
diethylamine hydrogen sulfite has been reported. The data indicate no evi-
dence of compound-induced terata, embryotoxicity, or inhibition of fetal
growth and development. f. . v ''.>..
5.2.2.6.3 Carcinogenicity.
While several nitroaromatic compounds have been shown to be potent car-
cinogens (see Section 5.1.2.4.1.3 in Vol. II B), there is a scarcity of infor-
mation on the carcinogenic potential of nitroalkanes and nitroalkenes.
Because of the increasing interest in nitroalkanes for industrial applica-
tions, several carcinogenicity bioassays have been conducted to supplement the
information on the potential health hazard of these chemicals. A synoptic
tabulation of the data on nitroalkanes up to CL, as well as the results of the
carcinogenicity studies on 3-nitro-3-hexene, are given in Table II.
Ueatherby (4) reported first in 1955 the results of a chronic study on NM
in the rat. Although definite pathological changes were observed in the
liver, there was no evidence of carcinogenic activity of NM when it was
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Table II. Carcinogenicity of Nitroalkanes and 3-Nitro-3-hexene
Compound
Nitromethane
Nitroethane3
1-Nitropropane
2-Nitropropane
3-Nitro-3-hexene
Species and Strain
rat, albino
rat , Sprague-Dawley
rabbit, white
rat, Long-Evans
rat, Fischer
rat, rabbit, cat,
monkey and guinea pig
rabbit, white
rat, Sprague-Dawley .
rat, Sprague-Dawley
rat,
mouse, Swiss
rat, CFN
dog, beagle
goat,
Route
p.o.
inhalation
inhalation
inhalation
i.g.
inhalation
inhalation
inhalation
inhalation
inhalation
'. inhalation
inhalation
inhalation
inhalation
Principal Organs Affected
None
None
None
Testes
Esophagus
None
None
Noneb
Liver
Liver
Lung «
Lung
None
None
References
(4)
(5)
(5)
(37)
(38)
(3)
(5)
(39, 40)
(5)
(Cited. in 28)
(7, 9)
(7)
(7)
(7)
'in a mixture also containing diethylhydroxylamine and diethylamine hydrogen sulfite,
'Preneoplastic liver nodules were observed.
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administered to young male rats at dose levels of 0.1% and 0.257, in the
drinking water for a period of 15 weeks. However, since the test was con-
ducted for notably less than the lifetime of the animals, it is difficult to
assess the carcinogenic potential of' the compound. An early study of Treon
and Dutra (3) found also 2-NP to be noncarcinogenic in rats, rabbits, cats,
guinea pigs and monkeys which survived 130 7-hour periods of exposure (5
days/week) to 83 or 328 ppm 2-Nf vapor. Again, the negative results of this
study are difficult to interpret since only 1 or 2 animals of each species
were used and the experiment was not carried out for the lifetime of the
animals. More recently, NIOSH sponsored a comprehensive inhalation study of
NM and 2-NP to appraise the adequacy of exposure standards in the workplace
(5). Fifty male rats and 15 male rabbits.were exposed to either 98 or 745 ppm
of NM, or 27 or 207 ppm of 2-NP over a period of 6 months. To simulate condi-
tions likely to be experienced by workers, the exposures were for 7 hours/day,
5 days/week. No exposure-related gross or microscopic alterations were
observed in tissues of rats and rabbits exposed to the low dose of 2-NP and
both doses of NM, nor in tissues of rabbits exposed to 207 ppm of 2-NP.
However, hepatocellular carcinomas and neoplastic nodules were found in all 10
rats killed 6 months after exposure to 207 ppm of 2-NP. Control animals
exposed to filtered air did not develop neoplasms. Although certain short-
comings existed in the conduct of this study, it was concluded that 2-NP was a
potent carcinogen in the rat. t. In accord with the results of the above study,
Griff in ^££l^. (39) found preneoplastic liver nodules in rats exposed to 200
ppm for 6 months, but no malignancies or significant pathological lesions in
the livers of male or female rats exposed to a low dose of 2-NP (25 ppm, 7
hours/day, 5 days/week) over a period of 22 months (40). Preliminary results
of a report also indicate that rats exposed to 2-NP at 100 ppn 7 hours/day, 5
days/week, for 9 months also developed liver tumors (cited in ref. 28).
9
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In 1968, Hadidian _et__al.« (38) mass screened the carcinogenic potential of
38 structurally diverse compounds, including 1-NP, by feeding the compounds at
various doses to male and female rats, 5 times/week for 52 weeks. At the
termination of the experiments, they found that 1 of the 15 male rats which
received 1-NP at the dose of 3 mg/day by gavage developed an esophageal papil-
loma not seen in the controls. There has been no follow-up studies on the
carcinogenicity of 1-HP; confirmation of the marginal activity of 1-NP is
needed.
Heicklen et al. (37) have conducted a series of long-term toxicological
tests on a mixture of diethylhydroxylamine, NE, and diethylamine hydrogen
sulfite in rats to ascertain the safety of these compounds. This mixture was
tested because diethylhydroxylamine is used as an inhibitor of the photochemi-
cal formation of smog from NE and diethylamine hydrogen sulfite. Of the 27
male rats exposed 7 hours/day, 5 days/week to the mixture of the compounds
containing about 10 ppm NE, two developed interstitial cell tumors in the
testes after about 2 years. One male rat also developed a hemangioendo-
thelioma 3 months after the exposure. None of the 25 control males showed any
tumor. However, whether this low incidence of carcinogenicity was actually
due to NE or to the other two compounds in the mixture remains to be inves-
tigated.
Two studies of the carcinogenicity of 3-nitro-3-hexene, identified in
automobile exhausts, were carried out by Deichnann and his associates (7,
9). In the first study (9), 20 Swiss mice of each sex were exposed to 0.2 ppra
3-nitro-3-hexene vapor 6 hours/day, 5 days/week. Forty mice served as
untreated controls. Among the 27 animals which survived 128-302 exposures
(over 439 days), 5 developed adenocarcinoraas of the lung. Of the 23 controls
.which survived the same length of time, one developed a pulnonary adenoma.
10
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The low survival rate of the animals in both the test and control groups was
attributed to bacterial infection which may have played some role in the
promotion of tumorigenesis. In the second bioassay (7), goats, dogs, and rats
were used. After 18 months of inhalatory exposure, there was no evidence of
carcinogenic activity in 2 goats at 0.2 ppm level of exposure, nor in 4 dogs
at either 0.2, 1, or 2 ppm level of exposure. However, 6 of 100 rats exposed
to 1 ppm and 11 of 100 rats exposed to 2 ppm 3-nitro-3-hexene developed
primary malignant lung tumors with histopathological characteristics similar
to lung cancers in nan. No primary malignant lesions were seen in the lung of
100 control rats. Based on these data, it was concluded that 3-nitro-3-hexene
might be a potential human carcinogen.
5.2.2.6.4 Metabolism and Mechanism of Action.
Studies with rats and rabbits have demonstrated that nitroalkanes are
rapidly absorbed arid metabolized after inhalation or oral administration
(41-43). Nitrite is the major metabolite found in the blood, urine, and
various organs after administration of NE, 1-NP, or 2-NP but not NM. A por-
tion of the unchanged compounds is excreted in the expired air. There is also
evidence suggesting the formation of small amounts of mercapturic acid deriva-
tives from NE and 1-NP (44). In in vitro studies in which NM was incubated
aerobically with rat liver microsomes and NADPH, the compound was found to
undergo denitrification, althcyjgh to a lesser extent than 2-NP (45). Rat
liver microsomes also catalyze the formation besides nitrite of formal-
dehyde, acetaldehyde and acetone, from NM, NE, and 2-NP, respectively (45,
46). Denitrification is decreased by inhibitors of raicrosomal mixed-function
oxidases and increased in microsomes originating from animals treated with the
enzyme inducers, phenobarbital and 3-methylcholanthrene, suggesting the
involvement of cytochrorae P-450 type nixed-function oxidases (46).
11
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The oxidative metabolic degradation of nitroalkanes is assumed to proceed
^following the reaction:
v
[0] -HNO
R-CH -NO, ^> [R-CH-NO ] > R-CHO
<£.£.. \ £
OH
The metabolism of nitroalkenes does not appear to have been studied.
The nechanism(s) of the biological action of nitroaliphatic compounds is
not known. It is possible that denitrification may be a molecular mechanism
involved in carcinogenesis by nitroalkanes. This appears to be supported by
the observation that 2-NP is a more potent carcinogen than the lower nitro-
alkanes; this is consistent with the relative rates of "oxidative denitrifica-
tion" of nitroalkanes, since their affinity toward the microsomal mixed-
function oxidase system decreases with decrease of the chain length (46).
Thus, the absence of carcinogenicity and mutagenicity of NM may be attributed
to the low rate of denitrification of this compound.
Speck £t_jil_. (33b) hypothesized, however, that 2-NP exerts its mutagenic,
and probably, carcinogenic action via a direct, non-enzynic reaction between
the compound and DNA. This was based on two findings. Firstly, that the
mutagenicity of 2-NP does not require metabolic activation and is fully
expressed in tester strains of _S_. typhimurium deficient in nitroreductase.
Secondly, that the sedimentation of purified single-stranded DNA on sucrose
gradient was altered after in vitro reaction with 2-NP, suggesting the alkyla-
tion of purine noieties of DNA by 2-NP (33b). As indicated in Section
5.2.2.6.2.1, the protonated aci form of nitroalkanes can act as an electro-
phile.
The reactivity of nitroalkenes towards simple nucleophiles (see Section
5.2.2.6.2.1 on Physical and Chemical Properties) is likely to be the basis of
12
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their toxic effects. Also, nitroalkenes may be represented by the ionic
resonant limit structures exemplified below:
0 0 0» ' J°
\ J \ 71
. N N
H5C2-C=^H-C2H5 -<^ > H5C2-C-CH-C2H5
further suggesting that they may act as alkylating agents under biological
conditions. The reaction of nitroalkenes with cellular nucleophiles does not
appear to have been studied.
5.2.2.6.5 Environmental Significance.
Nitroaliphatic compounds are not known to occur naturally, but arise
during the combustion of organic materials. Several nitroalkanes have been
detected in tobacco smoke (47, 48). A filterless 85 mm U.S. blend cigarette
was found to contain 0.53 ug NM, 1.1 ug NE, 0.13 ug 1-NP, 1.1 ug 2-NP, and
0.71 ug nitrobutane in the smoke (47). Moreover, in the exhaust from various
combustion systems, nitroalkenes and low levels of NM and NE have been
detected (49).
Nitroalkanes are widely used as specialty solvents in industry. Their
unique properties make them excellent solvents for a wide variety of organic
compounds, resins, cellulose esters, fats, oils, gums, waxes, and dyes.
Solvent blends containing nitroalkanes offer vast improvements over conven-
tional solvent systems, especially for polyvinyl films in coating and
paintings. Nitroalkanes also find important uses in industry as intermediates
in the synthesis of a wide variety of products ranging from dyes and textile
chemicals to Pharmaceuticals and insecticides. In addition, the combustion
properties of many nitroalkanes render them useful as gasoline and diesel fuel
13
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additives, and as rocket propellants. Accordingly, occupational exposure to
nitroalkanes occurs in various industries. It is estimated that about 30
million Ibs. of 2-NP are produced annually, and approximately 185,000 workers
are exposed to 2-NP during its production and use in the United States (28).
The National Institute of Occupational Safety and Health has suggested that
"it would be prudent to handle 2-NP in the workplace as if it were a human
carcinogen" (1). The current Occupational Safety and Health Administration
(OSHA) standards for occupational exposure to 1-NP and,2-NP are 25 ppm and the
threshold limit values for NM and NE are 100 ppm (50). However, OSHA recom-
mends that worker exposure to 2-NP be reduced to the lowest feasible levels
,(28).
The persistence of nitroalkanes in the environment is low and they are
not considered to pose serious environmental hazards, except in the work-
place. In both terrestrial and aquatic environments nitroalkanes are degraded
rapidly under most conditions. In aerobic environments biodegradation of
various nitroalkanes by bacteria in the soil and activated sludge has been
described (51-53). Under anaerobic conditions nitroalkanes are easily reduced
to products, which presumably serve as nitrogen source for many bacterial
species (54). In aquatic environments, nitroalkanes evaporate at roughly the
same rate as water. Nitroalkanes released from water or generated from
cigarette smoke and combustion systems are degraded rapidly by direct
photolysis. %
During the chlorination of water, as during sanitary water treatment,
there is the possibility that nitroalkanes nay form trichloronitroraethane
(chloropicrin), a compound much more toxic than the original nitroalkanes (21)
and used as a chemical warfare agent during World War I. Chloropicrin, formed
by the reaction of NM (50 ug/1) and chlorine (1.12 mg/1) has actually been
14
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detected in the finished drinking water in Seattle, Washington (55). Recent
epidemiological studies have strengthened the evidence for a link between
chlorinated organic contaminants in drinking water and increased incidence of
human cancer (cited in ref. 56).
REFERENCES TO SECTION 5.2.2.6
<
1. Finklea, J.F.: "Current Intelligence Bulletin: 2-Nitropropane."
National Institute for Occupational Safety and Health (NIOSH). April
25, 1977.
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