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    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.

    5.  REFERENCES

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    BRUSICK, D.J. (1977).  Mutagenic evaluation of P-135766459T, final
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    COULSTON, F. (1982).  Influence of glutathione and diethyl maleate on
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    1201-4.


    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)