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 43-65°C.
Gasoline boils at 40-70°C, pentane at 34-37°C. Higher boiling
fractions are hexane 65-69°C, SBP 62/82 boiling at 64-72°C, SBP 80/100
boiling at 83-120°C. 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 8°C) 4 000 Keplinger et al., 1959
Hexane i.p. (at 26°C) 9 100 Keplinger et al., 1959
Hexane i.p. (at 36°C) 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)