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    LIGHT PETROLEUM

    Explanation

         This substance was evaluated for acceptable daily intake for man
    (ADI) by the Joint FAO/WHO Expert Committee on Food Additives in 1970
    and 1980 (see Annex, Refs. 22 and 54). A toxicological monograph was
    issued in 1971 (see Annex, Ref. 23).

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously issued monograph has been expanded and is reproduced in
    its entirety below.

         Commercial "hexane" may contain up to 50% of 2-methylpentane and
    3-methylpentane, as well as n-hexane and small amounts of various
    pentanes, heptane, dimethyl butane, etc.

         Heptane is not a well-defined and specified solvent. Various
    hydrocarbon mixtures are separated from crude oils into a number of
    solvents having specific boiling point ranges (SBP). They are natural
    products of variable composition depending on the crude oil from which
    they have been fractionated but having a given boiling point range
    (van Raalte, 1970).

         Heptane is more specifically a fraction boiling at 43-65C.
    Gasoline boils at 40-70C, pentane at 34-37C. Higher boiling
    fractions are hexane 65-69C, SBP 62/82 boiling at 64-72C, SBP 80/100
    boiling at 83-120C. Detailed accounts of these various refined
    aliphatic hydrocarbon solvents and their nomenclature and toxicity are
    available (Gerard, 1963a; NIOSH, 1977a, 1977b).

         Analysis of extracted oils and remaining cakes reveals only a few
    ppm of solvents, e.g. 0.3 ppm (0.00003%) SBP 63/82 in cocoa utter.
    Other data on residues in food is not readily available.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

    Metabolism

         n-hexane is oxidized by microsomal enzymes predominantly to
    2-hexanol and to a lesser extent to 1- and 3-hexanol. 2-hexanol is
    further oxidized to 2,5-hexanediol and 2-hexanone (methyl n-butyl
    ketone). These latter two are then oxidized to 5-hydroxy-2-hexanone
    and subsequently to 2,5-hexanedione. All of these hydrocarbon
    metabolites that are capable of forming a gamma-diketone (i.e.,
    2,5-dione) by w-1 oxidation produce polyneuropathy (DiVincenzo,
    1980; O'Donoghue & Krasavage, 1980). 2-hexanone is also capable of

    being biotransformed to 2,5-dimethyl-2,3-dihydrofuran,
    2,5-dimethylfuran, and gamma-valerolactone among other products
    (DiVincenzo, 1980a).

    Effects on enzymes and other biochemical parameters

         Liver DNAse, RNAse, and ATPase activities were found to increase
    in rats administered petroleum ether intraperitoneally daily at 3
    ml/kg for two to seven days (Rao et al., 1977). Liver alkaline
    phosphatase was also increased upon similar treatment (Dhasmana et
    al., 1977). n-hexane has been found to potentiate chloroform induced
    hepato- and hepthrotoxicity (Hewitt et al., 1980). Petroleum ether has
    also been found to alter enzyme activities in Salmonella typhimurium
    (Veljanov et al., 1977).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenesis

         n-hexane was tested as a tumour-promoter on chemically induced
    mutation in cultured Chinese hamster cells and was found negative.
    n-hexane by itself was also negative as a mutagen in this system
    (Lankas et al., 1978).

         Several studies have been undertaken to determine the amount of
    polycyclic aromatic hydrocarbons in hexane as some of these may have
    carcinogenic activity. Some samples contain less than 0.01 ppm
    (0.000001%) which is the limit of the sensitivity of the existing
    analytical method (Ryder & Sullivan), 1962) but traces have been found
    in hexane derived from cracking processes (Tye et al., 1966). Others
    have found 0.023 ppm (0.0000023%) of 2,4-Benzpyrene (Lijinsky & Raha,
    1961). Polycyclic aromatic hydrocarbons have also been detected in
    such natural products as cold pressed olive oil at 0.01-0.026 ppm
    (0.000001-0.0000026%) (Jung & Morand, 1962) and in other crude
    untreated oils at 0.0022-0.011 ppm (0.00000022-0.0000011%) (Grimmer &
    Hildebrandt, 1967).

    Special studies on neurotoxicity

         The aliphatic hydrocarbon had been considered to be relatively
    non-toxic (Williams, 1959). One of the main components of many
    petroleum solvents, n-hexane was one of those considered to be
    nontoxic, but recently has been found to cause polyneuropathy and
    damage to both the peripheral and central nervous systems. After
    removal from the toxic environment, the peripheral axons usually
    regenerate whereas many CNS changes are permanent (Schaumburg &
    Spencer, 1978). Both efferent and afferent nerves are impaired
    (Takeuchi et al., 1980).

         The gamma-diketone is most certainly the ultimate neurotoxic
    moiety and any hydrocarbon amendable to oxidation to gamma-diketones
    may be neurotoxic (DiVincenzo, 1980b). In fact, when synthetic
    2,5-heptanedione was administered at doses of 1000 and 2000 mg/kg (to
    rats) it produced neurotoxicity identical to that associated with
    2,5-hexanedione. 3,6-octanedione yielded similar results (O'Donoghue &
    Krasavage, 1980). 2,4- or 3,5-diketones lack the potent neurotoxicity
    exhibited by the 2,5-hexanedione. It has been proposed that the axonal
    toxicity of 2,5-hexanedione may be due to its high water solubility
    and its facile formation of stable conjugated Schiff bases by reaction
    with the amino groups of proteins (Graham & Abou-Donia, 1980).

         n-hexane was found to produce a series of cytotoxic effects at
    the light and electron microscopic levels and caused a dose-dependent
    inhibition of proliferation in cultured neuroblastoma cells (Selkoe et
    al., 1978). Other tissue culture studies have also provided insight
    into the spatial-temporal pattern of nerve-fibre degeneration
    (Veronesi et al., 1980). The metabolism and neurotoxicity of
    n-hexane has recently been reviewed (DiVincenzo et al., 1980a, b;
    Spencer et al., 1980; O'Donoghue & Krasavage, 1980).

    Special studies on reproduction

         Pregnant rats were exposed seven hours per day for 15 days prior
    to conception and through the eighteenth day of gestation to
    n-hexane at air concentrations of 0, 100, 2000, or 10 000 ppm
    (0, 0.01, 0.2, or 1%). Litters exhibited no physical terata or
    differences in size, sex ratio, or growth rate. Some effects in visual
    response were seen in the progeny of animals exposed at 10 000 ppm
    (1%) (Howell, 1979).

         Pregnant rats were exposed to n-hexane at 1000 ppm (0.1%), six
    hours per day on days 8-12, 12-16, or 8-16 of gestation. No
    significant alterations in foetal resorptions, visible anomalies, or
    incidence of soft tissue and skeletal anomalies were observed in
    progeny of treated dams. Only a transient delay in postnatal growth
    was observed and was normal by week 7. Foetal concentrations of
    n-hexane and its metabolites were similar to those in maternal
    blood. The half-lives of n-hexane, methyl n-butyl ketone, and
    2,5-hexanedione in maternal blood were found to be 1.24, 0.99 and 3.9
    hours. Tissue elimination of n-hexane was rapid whereas the tissue
    concentration of 2,5-hexanedione increased between 0 and four hours
    after exposure and thereafter had a significantly slower elimination
    rate when compared to n-hexane (Bus et al., 1979).

         Pregnant female rats were exposed to n-hexane at concentrations
    of 0, 93 or 409 ppm (0, 0.0093 or 0.0409%) in air on days 6-15 of
    gestation. There were no adverse effects reported in the dams that
    were compound-related. There was no evidence of n-hexane induced
    terata, variation in sex ratio, embryo toxicity or inhibition of
    foetal growth and development (Litton, 1979). 

         Male CD-1 mice were exposed to n-hexane at concentrations of 0,
    100 or 400 ppm (0, 0.01 or 0.04%) in air six hours per day, five days
    per week for eight weeks. Positive controls were given one i.p.
    injection of triethylenemelamine at 0.3 mg/kg. No statistically
    significant increases in either pre- or post- implantation loss of
    embryos was found in the n-hexane group when compared with negative
    controls. Significant induction of dominant lethal mutations were
    found in the positive controls (Litton, 1980).

    Special studies on teratogenicity

         Groups of pregnant albino mice (CD-1) received daily by gavage a
    single dose of n-hexane dissolved in cottonseed oil at dose levels
    equivalent to 0.26, 0.66, 1.32 or 2.20 g/kg/day, on days 6-15 of
    pregnancy, n-hexane was not teratogenic at any dose level, and only
    one of the treated dams in the high level group died (Marks et al.,
    1981). In another study, groups of pregnant albino mice (CD-1)
    received daily by gavage three doses of n-hexane dissolved in
    cottonseed oil at total daily dose levels equivalent to 2.21, 2.83,
    7.92 or 9.0 g/kg/day. Two out of 25 dams treated with 2.83 g/kg/day,
    3/34 treated with 7.92 g/kg/day and 5/33 treated with 9.9 g/kg/day
    died. At the 7.92 and 9.9 g/kg/day, the average foetal weight was
    reduced. However, the number of inplants, resorptions, percentage of
    live foetus and distribution of skeletal or visceral malformations did
    not differ significantly in the treated and control groups (Marks et
    al., 1981).

    Acute toxicity
                                                                        

                                        LD100
    Animal  Compound      Route      (mg/kg bw)        Reference
                                                                        

    Rat     Hexane    i.p. (at 8C)       4 000   Keplinger et al., 1959
            Hexane    i.p. (at 26C)      9 100   Keplinger et al., 1959
            Hexane    i.p. (at 36C)        530   Keplinger et al., 1959
            SBP       Oral             20 ml/kg   Shell Research Ltd, 
                      (intragastric)              1962
                                                                        

         0.2 ml hexane, when aspirated by the anaesthetized rat, produced
    convulsions and death within a few seconds. Cardiac arrest,
    respiratory paralysis and asphyxia occurred (Gerarde, 1963b). Hexane
    is only a weak anaesthetic but paralyses the respiratory centre before
    the spinal reflexes are abolished. It is irritant to skin and mucosa
    (Estler, 1939).

         Many rats died with signs of pulmonary congestion due to asphyxia
    from inhaled droplets of vapour of SBP 62/82. No gross changes were
    seen at autopsy (Shell Research Ltd, 1962).

         Exposure of animals to n-hexane above a concentration of
    48 000 mg/m3 for four hours resulted in higher accumulations in body
    tissues than in blood. It was found to accumulate more slowly in the
    brain than in other tissues (Babenov, 1977). Prolonged inhalation of
    hexane occasionally causes anaemia and nephropathy in animals.
    Injection of 0.5-1.0 cc/kg into animals also lowers the RBC and causes
    erythroblastosis (Estler, 1939).

    Short-term studies

    Rat

         Three groups of 10 male and 10 female rats were given either
    water or 1 ml/kg or 5 ml/kg SBP three times per week for 90 days.
    Macroscopic examination revealed no lesions related to SBP
    administration (Shell Research Ltd, 1962).

         Three groups of 25 male and 25 female rats were given an
    emulsion of SBP 62/82, once a week for six months at 0, 0.5 ml/kg and
    2.5 ml/kg bw levels. Controls received the emulsion without SBP.
    Growth and body weight gain were similar to controls. Blood tests
    showed no deleterious effects on RBC, plasma urea or total plasma
    protein in the test animals. Nor was there any effect on SGOT. The
    high mortality was probably due to aspiration pneumonia. Male rats had
    lighter spleens at all levels tested. Females showed lighter livers at
    the high intake level and heavier spleen and lighter adrenals at the
    lower level. No histopathological evidence of liver, kidney or heart
    changes was detected (Shell Research Ltd, 1962).

         Groups of male Charles River rats were administered 6.6 to
    46.2 mmol/kg of n-hexane by gavage five days per week over a 90-day
    period. A control group received distilled water. The highest dose
    rats were treated over a 120-day period. The neurological endpoint of
    severe hind limb weakness or paralysis with dragging of a hind foot
    was measured. The rats were killed by CO2 inhalation and a necropsy
    performed. n-hexane at the lower dosages did not produce any
    neuropathy within 90 days whereas the highest dose (46.2 mmol)
    produced clinical and histological signs of neuropathy within 101
    days. Body weight gain was decreased at all dosage levels.
    Histological changes at the high dose level were indicative of "giant
    axonal" neuropathy and included multifocal axonal swellings, adaxonal
    myelin infolding and paranodal myelin retraction. Histological
    examination of testicular tissue revealed varying stages of atrophy of
    the germinal epithelium in the high dose group. Similar treatment with
    synthetic metabolites of n-hexane produced similar effects. The
    neurotoxic potency was directly related to the amount of
    2,5-hexanedione produced by each compound, measured from the area
    under the serum concentration-time curve of this gamma-diketone
    (Krasavage et al., 1980).

         Groups of male Wistar rats were exposed to 3000 ppm (0.3%) of
    n-pentane, n-hexane, or n-heptane for 12 hours per day for 16
    weeks. Nerve conduction velocity, measured at various times in the
    rats tails, was decreased with n-hexane but not with the C5 and C7
    hydrocarbons. Microscopic examination showed severe impairment in the
    peripheral nerve, the neuromuscular junction and the muscle fibre with
    n-hexane but not with the other two hydrocarbons. The authors
    concluded that n-hexane is far more toxic than the other two
    (Takeuchi et al., 1980). The authors also discussed other studies: in
    which 2,4-pentanedione, a possible metabolite of n-pentane, produced
    ataxia and disturbances of gait in rats injected for 45 days; in which
    a technical grade heptane mixture (containing 52% n-heptane, 16%
    3-methylhexane, 10% other heptanes and 22% octanes) produced decreased
    nerve condition velocity in rats with five to six months exposure at
    1500 ppm (0.15%); and in which n-hexane exposure at 400-600 ppm
    (0.04-0.06%) for 24 hours per day produced foot drop in rats after 130
    days.

    Guinea-pig

         Twenty albino guinea-pigs were administered n-hexane
    epidermally by placing 1 ml onto their clipped back skin (closed cup).
    The animals were killed at various times and skin biopsies taken.
    Pyknotic nuclei were already observable 15 minutes after application.
    Degeneration of the nuclei and separation of the basement membrane
    progressed with increasing time of exposure. Pseudoeosinophil
    infiltration was noted in the upper dermis after four hours. No
    changes in liver or kidney morphology were observed (Kronevi et al.,
    1979).

    Rabbit

         Twelve New Zealand rabbits were exposed to n-hexane at 3000 ppm
    (0.3%) in air for eight hours per day for eight days. At day 9 the
    animals were killed for necropsy. Various morphological changes were
    found in the lung parenchyma of all exposed animals. Centriacinar
    emphysema, micro-haemorrhages and degenerative and necrotic lesions in
    the bronchiolar epithelium were among the effects noted. Focal
    subplural atelectasis, alveolar and interstitial oedema were also
    found (Lungarella et al., 1980).

    Dog

         Five groups of male and three female dogs were given daily for
    six months capsules containing SBP 62/82 at the following rates:
    0.005 ml/kg, 0.02 ml/kg, 0.10 ml/kg, 0.50 ml/kg and 0.50 ml/kg olive
    oil in capsules as control. Haematology and clinical chemistry of
    urine and blood as well as liver function tests at the highest dose

    level showed no significant differences from controls. Body weight and
    organ weights showed no abnormalities compared with controls. Gross
    and histopathology revealed no abnormalities due to the administration
    of SBP 62/82 (Shell Research Ltd, 1965).

    Long-term studies

         None available.

    OBSERVATIONS IN MAN

         Acute poisoning in man due to hexane leads to excitement,
    delirium, hallucinations, tremor, acrocyanosis and addiction (Estler,
    1939). Inhalation of 5000 ppm (0.5%) for 10 minutes caused dizziness
    and giddiness in man (Patty, 1958). Many cases of polyneuropathy in
    man have been reported to be due to occupational exposure to
    n-hexane (NIOSH, 1977a, 1977b; Takeuchi et al., 1980). The severe
    cases characterized by profound motor disorders like disturbances in
    gait, foot drop and pronounced muscular atrophy with or without
    sensory impairment. Less severe cases involve complaints of fatigue,
    anorexia, weight loss, followed by impairment of sensation and
    strength in distal extremities (Egan et al., 1980). Vision, memory and
    mental state deterioration have also received some attention
    (Schaumburg & Spencer, 1978; Spencer et al., 1980).

         Occupational exposure has been suggested to be limited to 100 ppm
    (0.01%) hexane, 85 ppm (0.0085%) heptane, or 75 ppm (0.0075%) octane
    (350 mg/m3 in the aggregate) (NIOSH, 1977a). The current TLV's are
    600 ppm (0.06%) pentane, 400 ppm (0.04%) n-heptane, 300 ppm (0.03%)
    octane and 100 ppm (0.01%) for n-hexane. An intended change to 50
    ppm (0.005%) for n-hexane and 500 ppm (0.05%) for other hexane
    isomers has been announced (Amer. Conf. Gov. Ind. Hyd., 1980; see also
    Zielhuis & van der Kreek, 1979), Extensive tables of human toxicity
    data can be found in the 1977 NIOSH criteria documents and the 1980
    review by Spencer et al.

         Scelsi et al. (1980) reported three cases of motor polyneuropathy
    in 17-19 year old females who used an adhesive agent containing 80% of
    n-hexane intermittently for two months to three years. Histological
    and electron microscopic studies were performed on sural nerve and
    soleus muscle. There were polymorphous changes in the myelin sheaths
    and axons of large diameter fibres. Polymorphous inclusion bodies were
    noted in the cytoplasm of Schwann cells. The muscles showed
    denervative atrophy and degenerative myopathic changes (Scelsi et al.,
    1980).

         Electrophysiological examination of the peroneal nerve was
    reported for a group of individuals occupationally exposed to
    n-heptane. The authors concluded that n-heptane is capable of
    provoking "minimal" peripheral nerve damage. Although neurological 

    examination did not show any signs of peripheral neuropathy, a common
    complaint was numbness and parasthesiae of the limbs (Crespi et al.,
    1979).

         Lankas et al. (1978) has mentioned that hydrocarbons with chain
    lengths of from six to 16 carbons are present in human sebum.

    Comments

         These solvents appear to be resistant to chemical or biochemical
    attack in the mammalian gastrointestinal tract but they are probably
    absorbed here. Studies with hexane and with a specific product (SBP
    62/82), both of which may contain up to 50% of n-hexane as well as
    various amounts of heptane, showed no deleterious effects in
    short-term studies at levels up to 2.5 ml/kg bw in the rat and
    0.5 ml/kg bw in the dog. Pregnant female mice tolerated doses of
    n-hexane up to 2.20 g/kg/dog without any effect on either the dam or
    the offspring. At higher doses that were toxic to the dam, no compound
    related foetal malformation occurred. No long-term studies are
    available on either hexane or heptane. n-heptane produces neurotoxic
    effects in experimental animals, presumably through the formation of
    neurotoxic metabolites. Occupational exposure to high levels of
    petroleum hydrocarbon fractions result in neurological damage.
    However, 50 ppm (0.005%) n-hexane is considered safe for
    occupational exposure over a working lifetime. Problems could arise
    from the transfer to food of less volatile impurities which would not
    be removed during solvent recovery. Adequate specifications are
    required with regard to aromatic and carcinogenic polycyclic
    hydrocarbons.

         Residues of light petroleum remaining in food when the solvent is
    used according to good manufacturing practice, do not pose any
    toxicological problem.

    EVALUATION

    ADI not specified.*

              

    *    The statement "ADI not specified" means that, on the basis of the
         available data (toxicological, biochemical, and other), the total
         daily intake of the substance, arising from its use or uses at
         the levels necessary to achieve the desired effect and from its
         acceptable background in food, does not, in the opinion of the
         Committee, represent a hazard to health. For this reason, and for
         the reasons stated in individual evaluations, the establishment
         of an acceptable daily intake (ADI) in mg/kg bw is not deemed
         necessary.

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    See Also:
       Toxicological Abbreviations
       LIGHT PETROLEUM (JECFA Evaluation)