FAO Nutrition Meetings
Report Series No. 48A
WHO/FOOD ADD/70.39
TOXICOLOGICAL EVALUATION OF SOME
EXTRACTION SOLVENTS AND CERTAIN
OTHER SUBSTANCES
The content of this document is the
result of the deliberations of the Joint
FAO/WHO Expert Committee on Food Additives
which met in Geneva, 24 June -2 July 19701
Food and Agriculture Organization of the United Nations
World Health Organization
1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
Org. techn. Rep. Ser., in press.
PETROLEUM HYDROCARBON FRACTIONS Hexane and Heptane)
Commercial "hexane" may contain up to 50% 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.
Analysis of extracted oils and remaining cakes reveals only a few
ppm of solvent, e.g. 0.3 ppm SBP 62/82 in cocoa butter.
Biological Data
Biochemical aspects
This aliphatic hydrocarbon is considered to be as inert
biochemically as it is chemically in parallel to other hydrocarbons
(Williams, 1959). No information exists whether ingested hexane is
metabolized but, of the little absorbed after inhalation most appears
to be re-excreted unchanged via the lungs and perhaps a trace appears
in the urine (Estler, 1939).
Actute toxicity
Animal Compound Route LD 100 Reference
mg/kg
bodyweight
Rat Hexane i.p.(at 8°C) 4000 Keplinger et al., 1959
" i.p.(at 26°C) 9100 Keplinger et al., 1959
" 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, 1963). 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 or vapour of SBP 62/82. No gross changes were
seen at autopsy (Shell Research Ltd., 1962).
Short-term studies
Prolonged inhalation of hexane causes occasionally anaemia and
nephropathy in animals. Injection of 0.5 - 1.0 cc/kg into animals also
lowers the RBC and causes erythroblastosis (Estler, 1939).
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 6 months at 0, 0.5 ml/kg and 2.5 ml/kg
bodyweight levels. Controls received the emulsion without SBP. Growth
and bodyweight 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 spleens and lighter adrenals at the lower level. No
histopathological evidence of liver, kidney or heart changes was
detected (Shell Research Ltd., 1962).
Dog
Five groups of male and three female dogs were given daily for 6
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. Bodyweight 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.
Special studies
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 (the
limit of the sensitivity of the analytical method (Ryder & Sullivan,
1962)) but traces have been found in hexane derived from cracking
processes (Tye et al., 1966). Others have formed 0.023 ppm of
3,4-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 (Jung & Morand, 1962) and in
other crude untreated oils at 0.0022-0.011 ppm, (Grimmer &
Hildebrandt, 1967).
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 for 10 minutes caused dizziness and
giddiness in man (Patty, 1958). The TVL for hexane, heptane and octane
is 500 ppm. (Amer. Conf. Gov. Ind. Hyg., 1969).
Comments
These solvents appear to be resistant to chemical or biochemical
attack in the mammalian gastro-intestinal tract but data directed
towards elucidating the effects of oral ingestion should be provided.
Studies with hexane and with a specific product (SBP 62/82), both
which may contain up to 50% of hexane as well as various amounts of
heptane, showed no deleterious effects in short-term studies at levels
up to 2.5 ml/kg bodyweight in the rat and 0.5 ml/kg bodyweight in the
dog. No long-term studies are available on either hexane or heptane.
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. It should be noted that trace
amounts of polycyclic aromatic hydrocarbons occur naturally in edible
oils.
Tentative Evaluation
The use of hydrocarbon solvents should be restricted to that
determined by good manufacturing practice, which is expected to result
in minimal residues unlikely to have any significant toxicological
effect.
Further work required
Specific information on possible content of carcinogenic
polynuclear aromatic hydrocarbons in petroleum hydrocarbon fractions
used as solvents.
REFERENCES
Amer. Conf. Gov. Ind. Hyg. (1969) Threshold Limit Values for 1969
Estler, W. (1939) VIII Intern. Kirg. Unfallmed. Berufsk., 2, 892
Gerarde, H. W. (1963) Arch. Environ. Hlth., 6, 329
Grimmer, G. & Hildebrandt, A. (1967) Chemistry and Industry, 2000
Jung, L. & Morand, P. (1962) Acad. Sci. Seance 1/2/1962, 1489
Keplinger, M. L., Lanier, G. E. & Deichmann, W. B. (1959)Toxicol.
appl. Pharmacol.,1, 156
Lijinsky, W. & Raha, C. R. (1961) Toxicol. appl. Pharmacol. 3
469
Patty, F. A. (1958) Industrial Hygiene & Toxicology, Interscience, New
York
van Raalte, H. G. S. (1970) Unpublished report submitted to WHO
Ryder, I. W. & Sullivan, G. P. (1962) J. Amer. Oil Chem. Soc., 39,
263
Shell Research Ltd. (1962) Unpublished studies on SBP 62/82 submitted
to WHO
Shell Research Ltd. (1965) Unpublished studies on SBP 62/82 submitted
to WHO
Tye, R. et al. (1966) Arch. Environ. Hlth., 13, 202
Williams, H. T. (1959) Detoxication Mechanisms, Chapman & Hall, London
See Also:
Toxicological Abbreviations