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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 (see Annex,
    Ref. 54). No toxicological monograph was issued. Since the previous
    evaluation, data have become available and are summarized and
    discussed in the following monograph.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Ingestion of either 2-nitropropane or 1-nitropane by rabbits
    resulted in the formation of nitrite (Scott, 1963). Metabolism to
    acetone and nitrite is effected in the liver (Ullrich 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).

         In vitro studies with microsomal preparations from the induced
    livers of rats show that in the presence of NADPH, nitropropane
    degrades the haeme moiety of hepatic microsomal P-450 (Ivantich et
    al., 1978; Sakurai, 1981).

    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 1, 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).

         Groups of 50 male rats and 15 male rabbits were exposed to either
    27 or 207 ppm (0.0027 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 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
    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 1, 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-nitropane 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 day 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 loci and in nine 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 carcinoma occurred in males after 12
    months of exposure and in females after 18 months (Griffin et al.,
    1978; Griffin et al., 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 Ál/plate) confirmed the mutagenic effect (Brusick, 1977).

    Special studies on reproduction

         A group of adult female Sprague-Dawley rats 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 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     LCLo 1513 ppm (0.1513%)/   Treon & Dutra 1952
                          4.5 h

                 Inhl     LC50 3712 ppm (0.3712%)/   IMC, 1979
                          1h

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

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

    Rabbit       Oral     LCLo 500 mg/kg             Machle et al., 1940

                 Inhl     LCLo 2381 ppm (0.2381%)/   Treon & Dutra, 1952
                          4.5 h

    Cat          Inhl     LCLo 714 ppm (0.0714%)/    Treon & Dutra, 1952
                          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, 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 haemorrhage, 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, 1952).

         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).

    OBSERVATIONS IN MAN

         Five or six people exposed daily in an industrial setting to
    2-nitropropane at concentrations ranging from 20-45 ppm (0.002-0045%)
    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 where 0.4 was
    expected in the female population; (3) there were 7 deaths from
    "sarcomatous" cancer in the "no exposure" population (Miller & Temple,
    1979).

    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. 2-nitropropane has been shown to be
    mutagenic in the Ames assay. 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

         This substance is unsuitable as a food additive.

    REFERENCES

    Brusick, D. J. (1977) Mutagenic Evaluation of P-135766459T, Final
         Report, Litton Bionetics, Inc., 5516 Nicholson Lane, Kensington,
         Maryland 20795

    Dequidt, J., Vasseur, P. & Potencier, J. (1972) Etude toxicologique
         experimentale de quelques Nitroparaffines, Bull. Soc. Pharma.
         Lille, 83-87; Experimental 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. & Enviro. Safety, 4, 267-281

    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
         the Salmonella Typhimurium/Mammalian-Microsome Test and the
         Micronucleus Test, Enviro. Mutagen., 1, 383-389

    IMC (1977) A Review of Toxicology Studies on the Nitroparaffins with
         Particular Emphasis on 2-Nitropropane, International Minerals &
         Chemical Corporation, NP Division, 666 Garland Place, Des
         Plaines, Illinois, 2 pp.

    IMC (1979) Review of Safety Data on 2-Nitropropane, International
         Minerals & Chemical Corporation, NP Division, 666 Garland Place
         Des Plaines, Illinois, 5 pp.

    Ivantich, K. M. et al. (1978) Organic Compounds - Their Interaction
         with and Degradation of Hepatic Microsomal Drug Metabolizing
         Enzymes In Vitro, Drug Metab. Dispos., 6, 218-225

    Lewis, T. R., Ulrich, C. E. & Busey, W. M. (1979) Subchronic
         Inhalation Toxicity of Nitromethane and 2-Nitropropane,
         J. Envir. Path. Toxicol., 2, 233-249

    Machle, W., Scott, E. W. & Treon, J. (1940) The Physiological Response
         of Animals to Some Simple Mononitroparaffins and to Certain
         Derivatives of These Compounds, J. Ind. Hyg. Toxicol., 22,
         315-332

    Miller, M. & Temple, G. (1979) 2-NP Mortality Epidemiology Study of
         the Sterlington, La Employees, International Minerals and
         Chemical Corporation, Mundelein, Illinois

    NIOSH (1977) NIOSH Current Intelligence Bulletin: 2-Nitropropane, The
         National Institute for Occupational Safety and Health, U.S.
         Department of Health and Human Services, Rockville, Maryland
         20857

    OSHA (1975) U.S. Department of Labor, Occupational Safety & Health
         Administration, U.S. Code Fed. Regul., Title 29, part
         1910.1000, July 1, 1975

    Sakurai, H. et al. (1980) The Interaction of Aliphatic Nitro Compounds
         with the Liver Microsomal Monooxygenase System, Biochem.
         Pharmacol., 29, 341-345

    Scott, E. W. (1943) Metabolism of Nitroparaffins, J. Ind. Hyg.
         Toxicol., 25, 20-25

    Skinner, J. B. (1947) The Toxicity of 2-Nitropropane, Ind. Med.,
         16, 441-443

    Squire, R. A. & Levitt, M. H. (1975) Report of a Workshop on
         Classification of Specific Hepatocellular Lesions in Rats,
         Cancer Res., 35, 3214-3215

    Treon, J. F. & Dutra, F. R. (1952) Physiological Response of
         Experimental Animals to the Vapor of 2-Nitropropane, Arch. Ind.
         Hyg. Occup. Med., 5, 52-61

    Ullrich, V., Hermann, G. & Weber, P. (1978) Nitrite Formation from 2
         Nitropropane by Microsomal Monooxygenases, Biochem. Pharmacol.,
         27, 2301-2304
    


    See Also:
       Toxicological Abbreviations
       Nitropropane, 2- (EHC 138, 1992)
       Nitropropane, 2- (WHO Food Additives Series 19)
       Nitropropane, 2- (WHO Food Additives Series 26)
       Nitropropane, 2- (IARC Summary & Evaluation, Volume 71, 1999)