2-NITROPROPANE
1. EXPLANATION
This extraction solvent has been previously considered by the
Joint FAO/WHO Expert Committee on Food Additives at the twenty-third,
twenty-fifth, and twenty-eighth meetings (Annex 1, references 50, 56,
and 66). Toxicological monographs were published after the twenty-
fifth and twenty-eighth meetings (Annex 1, references 57 and 67). At
the twenty-eighth meeting, 2-nitropropane was considered to be
temporarily acceptable as a fractionating solvent in the production of
fats and oils, as long as its use continues to be limited to the
lowest technologically attainable. Since the last evaluation
additional data have become available, which are summarized below.
The previously published monograph has been expanded and reproduced in
its entirety.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
Ingestion of either 2-nitropropane or 1-nitropropane by rabbits
resulted in the formation of nitrite (Scott, 1943). Metabolism to
acetone and nitrite occurs in the liver (Ulrich et al., 1978).
Groups of 8-10 Wistar rats were administered 2-nitropropane by
intraperitoneal injection or inhalation. Injection of 1.7 g/kg bw
caused death in two hours and 89% blood methemoglobin. Quantities of
nitrite (1-2.5 mg/100 g tissue) were found in the heart, lungs,
kidney, spleen and liver. There was no trace in the other organs and
pulmonary excretion amounted to 76% of the injected dose. Injection
of 0.11 g/kg bw/day for 15 days followed by sacrifice 36 hours after
the last injection produced no methemoglobin, but nitrite was found in
all organs examined except the liver. 2-nitropropane was found in the
liver and lungs at concentrations of 18.7 and 360 mg/100 g tissue,
respectively. Urinary excretion of nitrite was also noted. When
groups of rats inhaled 2-nitropropane in air at 80 ppm for eight hours
per day and were killed the day after the fifth exposure,
methemoglobin was not detected, but nitrite was found in all organs
examined except the liver. No nitrite was detected in the urine
during the whole exposure period and no trace of 2-nitropropane was
found in the organs (Dequidt et al., 1972).
Male Sprague-Dawley rats (200-300 g) were administered 2-(14C)
nitropropane (2-(14C)NP) by inhalation for six hours at
concentrations of either 20 or 150 ppm, and the disposition of 14C in
these animals was followed for 48 hr. Over 40% of the amount inhaled
was absorbed. The absorbed 2-(14C) was rapidly metabolised and
eliminated. About 50% was excreted as 14CO2 at both exposure levels
after 48 hours. The fraction of unchanged 2-nitropropane excreted was
approximately 4% and 25% at the low and high exposure levels,
respectively. Urine and feces represented minor routes of excretion.
The distribution of 14C in the tissues of rats was inversely
proportional to the dose, and was primarily present in the excretory
organs (liver, kidneys, and lung). Only a small amount (less than 5%)
of the 14C was incorporated into liver macromolecules. The
concentration of 14C in the blood at 0 and 48 hours, and pulmonary
elimination of unchanged 2-(14C)-NP at the two exposure
concentrations, indicate that at the 150 ppm exposure concentration,
the kinetics of 2-(14C)-NP metabolism were non-linear (Nolan
et al., 1982).
In vitro studies with microsomal preparations from the induced
livers of rats show that in the presence of NADPH, nitropropane
degrades the heme moiety of hepatic microsomal P-450 (Ivantich
et al., 1978; Sakurai, 1980).
2.2 Toxicological studies
2.2.1 Acute toxicity
Animal Route Lethal dose Reference
Rat oral LD50 725 mg/kg bw IMC, 1977
inhl LC50 1513 ppm/4.5 hr Treon & Dutra, 1972
inhl LC50 3712 ppm/1 h IMC, 1979
(males) inhl LC50 400 ppm/6 h Lewis et al., 1979
Guinea-pig inhl LC50 4622 ppm/5.5 h Treon & Dutra, 1972
Rabbit oral LD50 500 mg/kg bw Machle et al., 1940
inhl LC50 2381 ppm/4.5 h Treon & Dutra, 1972
Cat inhl LC50 714 ppm Treon & Dutra, 1972
2.2.2 Short-term studies
2.2.2.1 Rats
Wistar rats were divided into 4 groups (5 males and 5 females per
group) and dosed by gavage with 2-nitropropane as an emulsion in 1%
methyl cellulose at 0, 20, 200 or 400 mg/kg bw/day for 28 days. In
the high dose group, all male rats died within 1 day and all female
rats within 10 days. At 200 mg/kg bw/day, all male rats died within
seven days while all females survived. Effects in the surviving
females of the high dose group included reduced body weight gain,
higher alanine aminotransferase, aspartate aminotransferase and total
bilirubin, and lower serum total protein and albumin levels. In
addition, there was an increase in liver weights and multiple hepatic
changes including multifocal single cell necrosis and Kupffer cell
pigmentation. In the lowest dose group multifocal centrilobular
hepatocellular hypertrophy was observed. There were no changes in
blood biochemistry values. The authors concluded that the changes in
the low dose group were metabolic adaptations (Berryman & Wilson,
1989).
In a drinking water study, Fischer 344 rats (10 males and 10
females per group) were dosed with 1000, 100, 10, 1.0 or 0.1 or 0 mg/l
of 2-nitropropane for four weeks (equivalent to 128 and 99 mg/kg
bw/day for female and male rats in the 1000 mg/l groups, respectively,
and 17 and 14 mg/kg bw/day for male and female rats in the 100 mg/l
groups, respectively, based on daily fluid consumption). Reduced food
and fluid consumption and reduced body weight gain were observed in
the highest dose group, as well as elevated organ weights. In the 100
mg/l group there was a slight elevation in liver weights in males. The
authors concluded that there were no treatment-related effects at 10
mg/l (estimated to be 1 to 2 mg/kg bw/day) (Griffin & Coulston, 1986).
2.2.2.2 Guinea-pigs and rabbits
Rabbits and guinea-pigs were administered 2-nitropropane by the
oral (stomach tube) and inhalation routes. Progressive weakness,
ataxia, and collapse were noted as well as twitching and convulsions.
General visceral and cerebral congestion as well as some degree of
liver damage were present in all dying animals. Edema, cloudy
swelling, fatty infiltration, and necrosis were seen in the liver.
Changes in the kidney, myocardium and other organs and tissues were
marked by edema, pallor and cloudy swelling (Machle et al., 1940).
2.2.2.3 Rats, guinea-pigs, rabbits, cats and monkeys
Five species of laboratory animals were exposed by inhalation to
2-nitropropane at concentrations ranging from 83 to several thousand
ppm for up to seven hours per day until toxic effects were observed.
Severity of toxic effects decreased in the following order: cat, rat,
rabbit, and guinea-pig. Signs of toxicity included: weakness,
dyspnea, cyanosis, prostration, convulsions and coma. Pathologic
changes included general vascular endothelial damage/pulmonary edema
and hemorrhage, selective disintegration of brain neurons, and
hepatocellular damage. Formation of methemoglobin and Heinz bodies
was related to the severity of the exposure. No pathologic changes
occurred after exposure to air concentrations of 328 ppm or 83 ppm in
the tissues of rats, rabbits, guinea-pigs or monkeys. In the cat, 328
ppm caused severe liver damage and slight to moderate toxic
degeneration of the heart and kidneys (Treon & Dutra, 1972).
Subsequent examination of tissue sections from this study has revealed
the presence of clear cell foci in the livers of rats exposed to air
containing 328 ppm of 2-nitropropane for 17 exposure periods of seven
hours each (NIOSH, 1977). These cell foci are commonly believed to be
"cytologically similar to the cellular elements of neoplastic
nodules". The proliferative nodules are known to be induced by
carcinogens and "at the least, they indicate an increased probability
for the development of hepatocellular carcinoma" (Squire & Levitt,
1975).
2.2.2.4 Rats and rabbits
Groups of 50 male rats and 15 male rabbits were exposed to either
27 or 207 ppm of 2-nitropropane seven hours per day, five days per
week, for periods up to 24 weeks. Groups of equal size were exposed
to filtered air and served as controls. Ten rats from each group were
killed after 2 days, 10 days, 1 month, 3 months, and 6 months. Five
rabbits from each group were killed after 1, 3 and 6 months. Body
weight gains for both rats and rabbits at either exposure
concentration were similar to the control groups. No exposure-related
effect was seen in hematological evaluations. The liver weights were
significantly elevated in the rats exposed to 207 ppm 2-nitropropane
for 2, 3 and 6 months. No gross or microscopic changes were apparent
in either rats or rabbits from the low dose group and for rabbits in
the high dose group. However, multiple hepatocellular carcinomas and
neoplastic nodules were present in the livers from all 10 rats in the
high exposure groups after six months. Numerous focal areas of
hepatocellular hypertrophy, hyperplasia, and necrosis were seen in the
livers of the high exposure group of rats after three months. There
was also some incidence of hemorrhagic lesions in the lungs of the
high exposure group of rats. The lungs of three of five rabbits in
the high exposure group showed microscopic alterations (Lewis
et al., 1979).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
A group of 60 male and 60 female TEX:(ICR)AM mice were exposed to
2-nitropropane by inhalation at a concentration of 100 ppm for seven
hours per day, five days per week, for 18 months. The control group
consisted of 60 male and 60 female mice of the same strain. The
2-nitropropane used in this study was 95.6% pure. The mice were
observed daily and weighed weekly during the first 13 weeks and then
at two-week intervals for the remainder of the study. No
hematological or clinical chemistry effects were noted. The treated
male mice showed a slight but significant decrease in weight during
the first 37 weeks of the study. There was no effect on absolute
organ weights. The incidence of nodular hyperplasia in the livers of
the control and treated males were 10 and 15, respectively, and in the
females, 4 and 13, respectively. This increase of nodular hyperplasia
in female mice was statistically significant. The incidences of
hepatocellular carcinoma in the control and treated males were 1 and
4, respectively, and in the females 1 and 1, respectively, (Griffin
et al., 1987).
2.2.3.2 Rats
A group of 125 male and 125 female Sprague-Dawley rats were
exposed to 2-nitropropane by inhalation at a concentration of 25 ppm
for seven hours per day, five days per week for 22 months. The
control group also consisted of 125 males and 125 females. The
technical grade 2-nitropropane used in the study was 95.6% pure; the
remainder being other lower nitroparaffins. Representative groups of
animals were killed after 2, 3, 6 or 12 months of exposure. All rats
remaining alive after 22 months were killed for necropsy. No
exposure-related effects were found upon periodic examination of serum
and blood chemistry. At necropsy, final brain, liver, kidney and body
weights were compared. There was a significant increase in relative
liver weights for the 6- and 22-month exposure groups. Detailed
microscopic examination was performed only on liver tissue. Liver
congestion was present in 1 of 125 control males versus 8 of 125
exposed males. In females, the corresponding incidence was 0 versus
7. Focal areas of hepatocellular nodules were present in 2 of 125
control versus 10 of 125 exposed males, and 1 of 125 control versus 3
of 124 exposed females. Focal vacuolization of hepatocyte cytoplasm
was observed in 46% of exposed males versus 18% in controls. The
authors concluded that no significant pathological changes or
malignancies were attributable to exposure of rats to 25 ppm
2-nitropropane, seven hours per day five days per week, for 22 months
(Griffin et al., 1981).
A group of male and female rats were exposed to 2-nitropropane at
a concentration of 200 ppm, seven hours a day five days per week for
up to six months. Groups were killed after 10 days, 1 month, 3 months
and 6 months. One group was held for an additional 6-month post-
exposure period. Morphological changes occurred more extensively in
males that included hepatocellular nodules, hyperplasia, necrosis and
multivacuolated fatty metamorphosis. The livers of six of ten rats
had pre-neoplastic foci and metastasizing tumours were apparent in
nine out of ten rats that were held six months post-exposure. Similar
findings were observed after exposing rats to 2-nitropropane at a
concentration of 100 ppm for 18 months. Hepatocellular carcinoma
occurred in males after 12 months of exposure and in females after 18
months (Griffin et al., 1978, 1980).
Twenty-six male Sprague-Dawley rats were dosed by gavage three
times per week with 1 mmol/kg bw of 2-nitropropane (equivalent to 89
mg/kg bw) for 16 weeks. Twenty-nine animals served as vehicle
controls. Several rats died in this group and there was an
unspecified decrease in body weight. Twenty-two rats surviving 16
weeks or longer developed hepatocarcinomas, and four also developed
metastasis to the lungs (Fiala et al., 1987).
2.2.4 Reproduction studies
A group of adult female Sprague-Dawley rats (number unspecified)
were injected i.p. with 170 mg/kg bw of 2-nitropropane on days 1-15 of
gestation. Litters were examined one day prior to parturition. A 1-2
day retardation of heart development (type of assessment unspecified)
was observed in pups from nine out of ten litters (Harris et al.,
1979).
2.2.5 Special studies on genotoxicity
The mutagenic activity of 2-nitropropane was studied in the
Salmonella typhimurium (Ames) test with and without microsomal
activation. A dose-related increase in revertants was found in all
four tester strains. The increase in revertants was significant in
all four strains tested and was enhanced in the presence of microsomal
preparations. Negative results were obtained in the mouse
micronucleus test (Hite and Skeggs, 1979).
Mutagenic activity with microsomal activation of 2-nitropropane
was shown in S.typhimurium strains TS-98 and TA-100. Repeat tests
in TA-98 using higher concentrations (10-20 µl/plate) confirmed the
mutagenic effect (Brusick, 1977).
An unscheduled DNA synthesis (UDS) assay was carried out in human
diploid fibroblasts with exposures of 3 hours duration and
concentrations up to 5,000 µg/ml of culture medium. There was no
increase in UDS in cells treated with 2-nitropropane.
A dominant lethal test was carried out in male rats with exposure
to atmospheres containing 25 ppm or 200 ppm 2-nitropropane for 7
hr/day for five consecutive days. There were no effects attributable
to 2-nitropropane on pregnancy frequency, numbers of corpora lutea or
implantations, or the frequency of early deaths. Reductions to 75%
were seen, however, in pregnancy frequencies in weeks 1 and 5 of the
200 ppm atmosphere group and in the frequencies of live implantations
and late deaths in week 2 of the 200 ppm atmosphere group.
A sperm abnormality test was carried out in male mice with
exposure to atmospheres containing 25 ppm or 200 ppm 2-nitropropane
for 7 hr/day for 5 consecutive days. Sperm abnormality frequency was
not increased by 2-nitropropane treatment neither was the frequency
increased by EMS treatment. These results were therefore considered
to be inconclusive.
A cytogenetic test was carried out in male and female rat bone
marrow cells from rats exposed to atmospheres containing 25 ppm or 200
ppm 2-nitropropane for 7 hr/day for 5 consecutive days. A single
exposure of 7 hr duration was followed by sampling after 6 hr, 24 hr
and 48 hr. There were no increases in the frequencies of chromosomal
aberrations in male or female rats.
A sex-linked recessive lethal test was carried out in Drosophila
melanogaster with exposure to atmospheres of 700 ppm 2-nitropropane
for 4.5 hours. Sex-linked recessive lethal mutation frequency was
increased except in mature spermatozoa in one stock of flies. These
results could not be replicated (McGregor, 1981).
2.2.6 Special studies on the effect of glutathione and diethylmaleate
on the hepatoxicity of 2-nitropropane.
This study was carried out on groups of 25 male Sprague-Dawley
rats. An untreated group was administered 100 mg/day glutathione by
gavage, another group was administered diethyl maleate (0.6 ml/kg)
i.p., and a third group served as a control. The test groups were
exposed to 200 ppm 2-nitropropane by inhalation, 7 hr/day, 5
days/week. The glutathione-treated animals in the test group were
treated 5 days/week prior to exposure to 2-nitropropane, and the
diethyl maleate group were exposed 5 days/week and later 3 days/week
to 2-nitropropane. Interim sacrifices (5 rats/group) were carried out
at 3 months and 6 months, and the remaining animals were sacrificed at
7 months. Glutathione did not have any effect on the progressive
development of nodular hyperplasia and hepatocellular carcinoma.
Diethyl maleate, which causes a marked reduction in blood glutathione
levels, delayed the appearance of hepatic cell injury and no
hepatocellular carcinomas were observed at terminal sacrifice in this
group (Coulston, 1982).
2.3 Observations in man
Five of the six people exposed daily in an industrial setting to
2-nitropropane at concentrations ranging from 20-45 ppm complained of
daily episodes of anorexia, nausea, diarrhea, vomiting and occipital
headaches. Two workers in another plant, where the concentration of
2-nitropropane in their breathing zone varied between 10 and 15 ppm,
were apparently symptom-free (Skinner, 1947).
An epidemiological study on 1481 employees of a Sterlington,
Louisiana (USA) production facility was completed in 1979. The study
covered the years between January 1955 and July 1977. Depending on
which department the employees worked in, classification was made into
three cohorts (direct, indirect, or no exposure). Prior to 1977,
there was no formalized monitoring system. Between 1955 and 1962
corrective action was taken to reduce exposure based upon an informal
subjective odour threshold evaluation. Between 1962 and 1977 measured
concentrations were made above 25 ppm. Excursions above 25 ppm were
at times accompanied by symptoms of headache and nausea. For a six-
month period in 1977, 98% of 144 air samples were below 10 ppm (time-
weighted average). Causes of death were coded from death certificates
and compared with those expected using age-time-cause specific
mortality rates. It was concluded that the data did not suggest any
unusual cancer or disease mortality. It was further noted: "However,
both because the cohort is small and because the period of latency
(the time between first exposure and observation) is for most part
relatively short, one cannot conclude from these data that
2-nitropropane is non-carcinogenic in humans". Three unusual findings
were also pointed out: (1) there were 4 lymphatic cancers, where 0.9
was expected in the "no exposure" male population, and (2) there were
4 deaths from "sarcomatous" cancer in the "no exposure" population
(Miller & Temple, 1979).
An occupational health examination programme was carried out in
workers exposed to 2-nitropropane, generally at levels less than 25
ppm, during an 8-hour workday. The period of exposure ranged from
less than 1 year to 40 years. Of the 28 exposed workers examined (out
of a total workforce of 46 examined), no excess abnormalities of the
skin, blood, renal, liver, pulmonary and cardiac systems were noted
that could be associated with exposure to 2-nitropropane (Tabershaw
Occupational Medicine Associates P.A., 1980).
3. COMMENTS AND EVALUATION
Fractionated fats and oils are substances with properties that
limit their application and that present procedures for the processing
of fats and oils with 2-nitropropance does not lead to detectable
levels of this substance in the finished product. On the assumption
that such treated fats and oils may contain 2-nitropropane at the
limit of detection (10 µg/kg) and based on a maximum projected intake
of 2-nitropropane in processed oils in the United States, the intake
of 2-nitropropane was estimated to be 0.13 µg/kg bw/day. The
Committee recognized that this was a worst-case intake estimate and
that actual intakes of 2-nitropropance were probably lower.
The Committee reviewed a new inhalation study in which mice were
exposed to 2-nitropropane; nodular hyperplasia of the liver in females
was observed. At its twenty-eighth meeting, the Committee had also
noted a carcinogenic effect in rats after exposure to relatively high
concentrations of inhaled 2-nitropropane (Annex 1, reference 66). In
addition, the Committee reviewed a new study in which all rats dosed
by gavage with 2-nitropropane at a level of 89 mg/kg bw/day for 16
weeks (3 days per week) developed hepatocarcinomas.
On the basis of these studies, 2-nitropropane was considered to
be a potent rat liver carcinogen. Therefore, the temporary acceptance
of this substance for use as a fractionating solvent in the production
of fats and oils was not extended. If data can be provided on the
technological need for this solvent and if data are provided which can
be used for establishing a safe level of intake of 2-nitropropane, the
Committee would reconsider this substance at a future meeting.
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See Also:
Toxicological Abbreviations
Nitropropane, 2- (EHC 138, 1992)
Nitropropane, 2- (WHO Food Additives Series 16)
Nitropropane, 2- (WHO Food Additives Series 19)
Nitropropane, 2- (IARC Summary & Evaluation, Volume 71, 1999)