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    2-NITROPROPANE

    Explanation

         This extraction solvent has been previously considered by the
    Joint FAO/WHO Expert Committee on Food Additives in 1979 and 1981 (see
    Annex 1, Ref. 50, 56). A toxicological monograph was issued in 1982
    (see Annex 1, Ref. 57). Since the previous evaluation, additional data
    have become available and are summarized and discussed in the
    following monograph. The previously published monograph has been
    expanded and reproduced in its entirety below:

    BIOLOGICAL DATA

    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 is effected 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 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. 2-nitropropane was found in the liver at 1.34 mg/100 g of
    tissue. There was no trace in the other organs and pulmonary excretion
    amounted to 76% of the injected dose. Injection of 0.11 g/kg/day for
    15 days followed by killing the rats 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 (0.008%) 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 6 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)NP was rapidly metabolised and eliminated. About
    50% was excreted as 14CO2 at both exposure levels after 48 hr. The
    fraction of unchanged 2-NP excreted was approximately 4% and 25% at
    the low and high exposure levels. Urine and feces represented minor
    routes of excretion.

         The distribution of 14C in the tissues of the 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. 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).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

         A group of 125 male and 125 female Sprague-Dawley rats were
    exposed to 2-nitropropane by inhalation at a concentration of 25 ppm
    (0.0025%) for seven hours per day, five days per week for 22 months.
    The control group also consisted of 250 rats evenly divided between
    sex. 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. Only a slight increase in relative liver
    weights was apparent. This increase was significant at the P 0.05
    level for the 6-month exposed animals and at the P 0.01 level for
    the 22-month exposure group.  Detailed microscopic examination was
    performed only on liver tissue. Liver congestion was present in 1
    of 125 control males versus 8 of 125 exposed. In females, the
    corresponding incidence was 0 versus 7. Focal areas of hepatocellular
    nodules were present in 2 of 125 control males versus 10 of 125
    exposed, and 1 of 125 control females versus 3 of 124 exposed. Focal
    vacuolization of hepatocyte cytoplasm was observed in 46% of exposed
    males versus 18% in controls. One liver angioma was observed in a
    control male and one liver adenoma in an exposed female. The authors
    concluded that no significant pathologic changes or malignancies were
    attributable to exposure of rats to 25 ppm (0.0025%), seven hours per
    day, five days per week, for 22 months (Griffin et al., 1980). A
    complete histologic study of tissues and organs of the rats from this
    study showed that apart from the 2-NP related changes in the liver,
    the distribution of tumors and lesions was similar in control and
    exposed groups (Griffin et al., 1981).

         Groups of 50 male rats and 15 male rabbits were exposed to either
    27 or 207 ppm (0.0025% or 0.0207%) of 2-nitropropane seven hours per

    day, five days per week for periods up to 24 weeks. Groups of equal
    size were expsoed 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
    discernable exposure-related effect was seen in haematological
    evaluations. The liver weights were significantly elevated in the rats
    exposed to 207 ppm (0.0207%) for 2, 3, and 6 months, however, those of
    rabbits did not show any consistent exposure-related weight gain. No
    gross or microscopic changes were apparent in rat or rabbit tissues
    from the low exposure groups. Nor were any seen in rabbit tissues from
    the high exposure 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 haemorrhagic 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. During the six
    months of the experiment very few classical signs of toxicity were
    observed in any exposure group. It should be noted that LC50 for a
    six hour exposure to 2-nitropropane in male rats was found to be
    approximately 400 ppm (0.04%). No females died after an exposure to
    580 ppm (0.058%), whereas all male rats died at this concentration
    (Lewis et al., 1979).

         A group of male and female rats were exposed to 2-nitropropane at
    a concentration of 200 ppm (0.02%), seven hours per 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 and included hepatocellular nodules, hyperplasia, necroses,
    and multivacuolated fatty metamorphosis. The livers of six of 10 rats
    had pre-neoplastic foci and in nice out of 10 rats that were held six
    months postexposure metastasizing tumours were apparent. A similar,
    though not as severe, pathology was encountered after exposing rats to
    2-nitropropane at a concentration of 100 ppm (0.01%) for 18 months.
    Hepatocellular carninoma occurred in males after 12 months of exposure
    and in females after 18 months (Griffin et al., 1978, 1980).

    Special studies on mutagenicity

         The mutagenic activity of 2-nitropropane was studied in the
    Salmonella typhimurium (Ames) test with and without microsomal
    activation (Hite & Skeggs, 1979). 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. However, negative results
    were obtained in the mouse micronucleus test.

         In another study, 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 ul/plate) confirmed the mutagenic effect (Brusick, 1977).

         2-nitropropane (2-NP) was subjected to the following battery of
    mutagenic tests.

         An unscheduled DNA synthesis (UDS) asssy was carried out in human
    diploid fibroblasts with exposures of 3 hr duration and concentrations
    up to 5.000 ug/ml of culture medium. There was no increase in UDS in
    cells treated with 2-NP.

         A dominant lethal test was carried out in male rats with exposure
    to atmospheres containing 25 ppm or 200 ppm 2-NP for 7 hr/day for 5
    consecutive days. There were no large effects attributable to 2-NP in
    the dominant lethal test on pregnancy frequency, with 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 (P 0.05).

         A sperm abnormality test was carried out in male mice with
    exposure to atmospheres containing 25 ppm or 200 ppm 2-NP for 7 hr/day
    for 5 consecutive days. Sperm abnormality frequency was not increased
    by 2-NP treatment, but neither was the frequency increased in EMS
    treatment. These results must be considered 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-NP for 7 hr/day for 5 consecutive days. A single exposure
    of 7 hr duration 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 (SLRL) test was carried out in
    Drosophila melanogaster with exposure to atmospheres of 700 ppm 2-NP
    for 4.5 hr. Sex-linked recessive lethal mutation frequency was
    increased except in mature spermatozoa in one stock of flies. Since
    the increase was not reproduced, its significance is doubtful
    (McGregor, 1981).

    Special studies on reproduction

         A group of adult female Sprague-Dawley rats were injected i.p.
    with 170 mg/kg b.w. of 2-nitropropane on days 1-15 of gestation. 
    Litters were examined one day prior to parturation. A 1-2 day
    retardation of heart development was observed in pups from nine out of
    10 litters (Harris et al., 1979).

    Acute toxicity

                                                                       

    Animal      Route   Lethal dose                Reference
                                                                       

    Rat         oral    LD50  725 mg/kg            IMC, 1977
                inhl    LCL0 1513 ppm (0.1513%)/   Treon & Dutra, 1972
                        4.5 h
                inhl    LC50 3712 ppm (0.3712%)/   IMC, 1979
                        1 h

    (males)     inhl    LC50  400 ppm (0.04%)/     Lewis et al., 1979
                        6 h

    Guinea-pig  inhl    LCL0 4622 ppm (0.4622%)/   Treon & Dutra, 1972
                        5.5 h

    Rabbit      oral    LCL0  500 mg/kg            Machle et al., 1940
                inhl    LCL0 2381 ppm (0.2381%)/   Treon & Dutra, 1972
                        4.5 h

    Cat         inhl    LCL0  714 ppm (0.0714%)/   Treon & Dutra, 1972
                        4.5 h
                                                                       

    Short-term studies

         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 was present in all animals dying from exposure.  Oedema,
    cloudy swelling, fatty infiltration, and necrosis were seen in the
    liver. Changes in the kidney, myocardium and other organs and tissues
    were marked by oedema, pallor and cloudy swelling (Machle et al.,
    1940).

         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 acute toxic effects were
    observed. Toxic effects after acute exposure decreased in the
    following order: cat, rat, rabbit, guinea-pig. Signs of toxicity
    included, weakness, dyspnoea, cyanosis, prostration, convulsions, and
    coma. Pathologic changes included general vascular endothelial
    damage/pulmonary oedema and haemorrage, selective disintegration of
    brain neurones, 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 (0.0328%) or 83 ppm (0.0083%) in the tissues of rats, rabbits,
    guinea-pigs, or monkeys. In the cat, 328 ppm (0.0328%) 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 (0.0328%) 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).

    Special studies

    Effect of glutathione and diethylmaleate on the hepatoxicity of 2-NP

         The study was carried out on groups each of 25 male Sprague-
    Dawley rats. The control groups consisted of Group I, untreated Group
    II was administered 100 mg/day glutathione by gavage and Group III was
    administered diethyl maleate (0.6 ml/kg) i.p. The test groups
    consisted of similar groups exposed to 200 ppm, 2-NP by inhalation,
    7 hr/day, 5 day/week. The glutathione treated animals in the test
    group were treated 5 day/week prior to exposure, to 2-NP, and the
    diethyl maleate group, 5 day/week and later 3 day/week prior to
    exposure to 2-NP. Interim sacrifices (5 rat/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).

    OBSERVATIONS IN MAN

         Five of six people exposed daily in an industrial setting
    to 2-nitropropane at concentrations ranging from 20-45 ppm
    (0.002-0.0045%) complained of daily episodes of anorexia, nausea,
    diarrhoea, vomiting, and occipital headaches. Two workers in another
    plant, where the concentration of 2-nitropropane in their breathing
    zone varied between 10 and 25 ppm (0.001 and 0.0025%) were apparently
    symptom free (Skinner, 1947). 25 ppm (0.0025%) is the current United
    States occupational exposure standard (OSHA, 1975).

         An epidemiological study on 1481 employees of a Sterlington,
    Louisiana 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 informal subjective
    odour threshold evaluation. Between 1962 and 1977 measured
    concentrations were made above 25 ppm (0.0025%). These excursions
    above 25 ppm (0.0025%) 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 (0.001%) (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 does 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 relatively short, one cannot
    conclude from these data that 2-NP 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; (2) there were 4 deaths from all cancers 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-NP, 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 system were noted that could be
    associated with exposure to 2-NP (Tabershaw, 1980).

    Comments

         Most of the available data relates to exposure of animals to
    2-nitropropane by inhalation. There is very limited acute oral data
    which indicates that under these conditions of exposure, the toxic
    effects are similar to those observed by the inhalation route under
    acute conditions. Inhalation data clearly indicate that 2-nitropropane
    is hepatoxic to rodents and at high levels of exposure there is
    evidence of a carcinogenic effect.

         Information on the metabolism of 2(14C) NP suggest that the
    dose-dependant changes in the metabolism of 2-NP may account for the
    marked increase in toxicity observed in rats exposed to high
    concentrations of 2-NP. Although the toxicity is decreased at lower
    dose levels, the available information suggests that even at these
    dose levels, there is some indication of a possible pre-neoplastic
    response.

         2-nitropropane has been shown to be mutagenic in the Ames assay,
    but gave inconclusive results in mammalian systems. The limited human

    data shows that 2-nitropropane can cause headaches, anorexia, nausea,
    diarrhoea, and vomiting at air concentrations as low as 20 ppm
    (0.002%). An epidemiological study on a population of industrially
    exposed workers proved to be inconclusive in establishing
    carcinogenicity in man.

    EVALUATION

         2-nitropropane is carcinogenic to rats at relatively high
    concentration of exposure by inhalation (between 25 and 200 ppm).

    Estimate of temporary acceptable daily intake for man

         For use as a fractionating solvent for fats and oils with
    residues levels, the lowest technologically possible (below the
    current limit of detection - 10 ug/kg in the fractionated oil).

    FURTHER WORK

    Required by 1989

    Carcinogenicity studies using per os dosing.

    REFERENCES

    BRUSICK, D.J. (1977) Mutagenic evaluation of P-135766459T, final
    report, Litton Bionetics, Inc., 5516 Nicholson Lane, Kensington,
    Maryland 20795.

    COULSTON, F. (1982) Influence of glutathione and diethyle maleate on
    the induction of hepatocellular carcinomas in rats exposed to 200 ppm
    of 2-nitropropane. Unpublished data, submitted to WHO, by Durkee Foods
    Division, SCM Corp., USA.

    DEQUIDT, J., VASSEUR, P., & POTENCIER, J. (1972) Etude toxicologue
    expérimentale de quelques nitroparafinnes, Bull. Soc. Pharm. Lille,
    83-87: Experiemntal toxicologic study of some nitroparaffins,
    translation by International Minerals & Chemical Corporation,
    666 Garland Place, des Plaines, Illinois 60016.

    GRIFFIN, T.B., et al. (1978) Chronic inhalation toxicity of
    2-nitropropane in rats. Pharmacologist, 20: 145.

    GRIFFIN, T.B., COULSTON, F., & STEIN, A.A. (1980) Chronic inhalation
    exposure of rats to vapors of 2-nitropropane at 25 ppm. Ecotoxicol.
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    GRIFFIN, T.B., STEIN, A.A., & COULSTON, F. (1981) Histologic study of
    tissues and organs from rats exposed to vapors of 2-nitropropane at
    25 ppm. Ecotoxicol. & Environ. Safety, 5: 194-201.

    HARRIS, S.J., BOND, G.P., & NIEMEIER, R.W. (1979) The effect of
    2-nitropropane, naphthalene, and hexachlorobutadiene on fetal rat
    development. Toxicol. Appl. Pharmacol., 48: A35.

    HITE, M. & SKEGGS, H. (1979) Mutagenic evaluation of nitroparaffins in
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    micronucleus test. Environ. Mutagen., 1: 383-389.

    IMC (1977) A review of toxicology studies on the nitroparaffins with
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    Chemical Corporation, NP Division, 666 Garland Place, des Plaines,
    Illinois. 2 pp.

    IMC (1979) Review of safety data on 2-nitropropane. International
    Minerals and Chemical Corporation, NP Division, 666 Garland Place,
    des Plaines, Illinois. 5 pp.

    IVANTICH, K.M., et al. (1978) Organic compounds - their interaction
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    in vitro. Drug Metab. Dispos., 6: 218-225.

    LEWIS, T.R., ULRICH, C.E., & BUSEY, W.M. (1979) Subchronic inhalation
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    MILLER, M. & TEMPLE, G. (1979) 2-NP mortality epidemiology study of
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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 26)
       Nitropropane, 2- (IARC Summary & Evaluation, Volume 71, 1999)