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.
PROPAN-2-OL
Biological Data
Biochemical aspects
When 65-90 ml of CH3CHOH CH3 were administered to 3 dogs, 55-71
mg per cent. were excreted as acetone, 120-134 mg per cent. were
excreted unchanged in the urine. 28-29 mg acetone and 63-70 mg
unchanged material were excreted in the faeces (Kemal, 1937). Dogs
oxidise iso-propyl alcohol at a rate of 0.001 per cent. per minute and
this reaction is probably quantitative (Neymark, 1948). I.v.
administered iso-propyl alcohol disappears from the blood of dogs at
inconstant rate and much appears in urine, saliva and stomach (Lehman
et al., 1944). I.v. and i.p. administered propan-2-ol is excreted
twice as fast by the rat as by the dog (Abshagen & Rietbrock, 1969).
Dogs absorb it rapidly from the intestine but slowly from the stomach
and metabolise it at a rate proportional to the concentration
(Browning, 1965). Instillation of iso-propyl alcohol into isolated
loops of dog intestine showed that absorption occurs from all
positions of the G.I. tract and quickly distributes to all tissues and
the C.S.F. 82% of absorption occurs within 30 minutes (Wax et al.,
I949). Single oral doses of 4 or 6 g/kg iso-propyl alcohol given to
rats considerably increase liver triglycerides but cholesterol and
phospholipids levels are not effected. The blood lipid fractions were
not affected (Gaillard & Derache, 1966).
Ingestion of 720 mg iso-propyl alcohol by man produced 335.9 mg
of iso-propyl alcohol (46.7 per cent.) and 17.1 mg acetone in the
exhaled air over a period of 3 hours (Hahn, 1937). Iso-propyl alcohol
is secreted by the salivary glands and by the gastric mucosa in man
(Juncos & Taguchi, 1968). I.v. injected iso-propyl alcohol in cats,
rabbits, rats and pigeons was cleared at rates for rabbit, rat and
pigeon, indicating initial rapid metabolism while the cat appears to
have a constant rate of metabolism (Lelman et al., 1945). Rabbits
excrete 10 per cent. of the dosage as glucuronide (Kamil, 1953) and
excrete acetone in the urine for up to 72 hours after a single large
oral dose (Morris & Lightbody, 1938).
Alcohol dehydrogenase probably also converts iso-propyl alcohol
to acetone and then to acetate, formate, CO2, etc. There is no
cumulation (Williams, 1959). Iso-propyl alcohol given intragastrically
to rats, rabbits and cats raised the convulsion threshold thus acting
as anticonvulsant (Chue et al., 1948).
Acute toxicity
LD50 LD100
Animal Route mg/kg mg/kg References
body-weight body-weight
Mouse oral - 4970 Spector, 1956
oral - 6.0-7.6 ml Browning, 1965
s.c. - 6000 Spector, 1956
s.c. - 7.6 ml Browning, 1965
Rat oral 5840 - Spector, 1956
oral 6.73 cc - Lehman & Chase, 1944
Guinea-pig i.p. - 5 ml Keil, 1953
Rabbit oral - 5000 Spector, 1956
oral - 10ml Browning, 1965
Browning, 1965
oral 6.41 cc - Lehman & Chase, 1944
cutaneous 16.4 cc - Spector, 1956
i.v. - 8.2 mil Oxygenated Solvents, 1964
Lelunan & Chase, 1944
Cat i.v. - 1962.5 (Spector, 1956 Macht, 1920
Dog oral 6.15 cc - Lehman & Chase, 1944
i.v. - 5.1 Ml Oxygenated Solvents, 1964
(Lehman & Chase, 1944
Man oral - 166 ml Oxygenated Solvents, 1964
(estimated)
The acute toxic effects of iso-propyl alcohol are similar to
those of ethyl alcohol but it is 1.5 to 2 times as toxic as ethyl
alcohol (Browning, 1965). Sublethal doses produced no delayed toxic
effects in rats, rabbits and dogs (Lehman & Chase, 1944). 5 rats
injected s.c. daily with 0.23 cc/kg iso-propyl alcohol for 1 week
showed slight parenchymatous hepatic degeneration (Abreu et al.,
1944). Reversible fatty changes have been reported in the liver of
mice after repeated inhalation (Weese, 1928).
Short-term studies
Rat. Seven groups of 5 male or 5 female rats received in their
drinking water either 0 per cent. (male and female), 0.5 per cent.
(males), 1.0 per cent. (females), 2.5 per cent. (males), 5.0 per cent.
(females) or 10 per cent. (males) iso-propyl alcohol for 27 weeks. All
animals at the 10 per cent. level died within 7 to 28 days. The
females at 1 per cent. and 5 per cent. showed no gross abnormalities
but there was some depression of growth and body-weight compared with
controls. Two male rats at the 0.5 per cent. and 3 at the 2.5 per
cent. level died from causes not related to the test substance. Growth
and bodyweight was reduced during the first 13 weeks but increased
during the remaining 14 weeks to exceed controls. Gross and
histopathological examination of brain, pituitary, lung, heart, liver,
spleen, kidneys and adrenals showed nothing of note related to the
test substance (Lehman & Chase. 1944).
In another experiment 8 rats received a 5 per cent. solution of
iso-propyl alcohol as drinking water for 9 months. All drank less than
controls. All showed some 23 per cent. reduction in body-weight
compared with controls and developed noisy breathing after several
months. When put on tapwater after 9 months all rats gained weight
over the next 30 days. Noisy breathing disappeared (Boughton, 1944).
Mouse. Three groups of 10, 27 and 49 mice of different strains
received 20 or more s.c. injections of 0.025 ml iso-propyl alcohol
over periods of 5 to 9 months. No difference was observed in the
tumour incidence of tests and controls. Three groups of 36, 41 and 47
mice of different strains were exposed to iso-propyl alcohol 5 days a
week 7 hours a day by inhalation over 5 to 8 months. There was no
significant difference in tumour incidence between test animals and
controls (Weil et al., 1952).
Cat. One cat was given 15.20 cc per cent. iso-propyl alcohol daily
over 13 days. After each dose the cat became stuporous but recovered
after some hours. At autopsy there was evidence of sub-acute gastritis
and enteritis and some cloudy swelling of the kidneys. No eye signs
were noted (Fuller & Hunter, 1927).
Rabbit. Five rabbits were given 5, 10 or 15 cc iso-propyl alcohol
daily over 28 days. The animals lost weight and at autopsy showed
gastritis and enteritis (Fuller & Hunter, 1927).
Chicken. One bird was given 10, 15 and 20 cc iso-propyl alcohol
daily over 28 days. There was weight loss but recovery occurred after
termination (Fuller & Hunter, 1927),
Monkey. One monkey was given 13 doses of 5 cc 50 per cent.
iso-propyl alcohol over 19 days. Mild intoxication and loss of
appetite occurred. The eyes showed some temporary congestion. The
animal survived but remained in poor health (Fuller & Hunter, 1927).
Dog. Following a single i.v. injection of either 2.56 or 3.84 ml
iso-propyl alcohol, three dogs were given fluid containing 1-4 per
cent. iso-propyl alcohol during one month and then kept on 4 per cent.
alcohol for a further six months. The dogs became inebriated once a
day but then recovered. One dog lost weight over 7 months and died on
retesting with i.e. injection of iso-propyl alcohol. At autopsy no
evidence of pathological changes were seen. Only the animal which died
showed some evidence of renal tubular necrosis and central
haemorrhages in the brain. A second dog also showed a few capillary
haemorrhages in the brain (Lehman et al., 1945). In another experiment
one dog was given 30 cc or 50 per cent. iso-propyl alcohol daily over
10 days. The animal uncoordinated for 10 minutes but developed
tolerance later. No ophthalmological changes were seen (Fuller &
Hunter, 1927).
Reproduction studies
Rat. Six female and three male rats were given 2.5 per cent,
iso-propyl alcohol in their drinking water for 80 days and then mated
on 6 occasions. Four litters with 44 pups were produced as the F1
generation. 13 F1 females produced 11 litters with 66 pups as the F2
generation. The growth rate of the second generation when given 2.5
per cent. iso-propyl alcohol as drinking water was no different from
controls on water. There was some growth depression of the F1
generation if given iso-propyl alcohol during the early post natal
period only (Lehman ef al,, 1945).
Special studies
0.05 or 0.1 ml of undiluted iso-propyl alcohol were injected into
the yolk sac of fertile hens eggs and subsequently incubated.
Hatchability was reduced to 35% and 15% of normal but no deformities
were noted in the chicks (McLaughlin et al., 1963). 19.5, 39 and 78
mg/egg injected into the yolk sac prior to incubation resulted in
hatches of 65, 35 and 5% of normal respectively (McLaughlin ef al.,
1964).
0.05 ml of iso-propanol was injected into fertile hens eggs and
reduced the survival of embryos to 24% (Walker, 1967).
Fertile hen eggs injected with 0.05 ml after 5 days incubation
resulted in a 33% hatch. Unincubated eggs immersed for 2/3 their
length for 10 seconds in 50%, aq. v.v. iso-propyl alcohol were
unaffected, but 5 day incubated eggs treated similarly showed a 50%
reduction in hatchability (Clegg, 1964).
0.05 ml of iso-propanol was injected into fertile hens eggs and
reduced the survival of embryos to 24% (Walker, 1967).
Human observations
4 subjects received either single doses of 0.1, 0.25, 0,5, 1, 2,
2.5, 5, 10 × 20 g or 3 times 5 g iso-propyl alcohol acetone was found
in the urine and the expired air but it accounted only for a few per
cent. of intake (Kemal, 1927).
Five men drank 30 ml of 50 per cent. iso-propyl alcohol daily on
three consecutive days after various test doses one month previously
and two females drank one dose of 30 ml of 50 per cent. iso-propyl
alcohol. The immediate effects were a fall in B.P. and dizziness. Five
experienced headaches. No untoward effects on vision were noted.
Acetone occurred in the urine within 24 hours and disappeared after 24
hours (Fuller & Hunter, 1927). Inhalation of 400 ppm is irritating
mildly but is regarded as the TLV (Browning, 1965). Groups of 8 men
drank 0, 2.6 mg/kg or 6.4 mg/kg iso-=propyl alcohol daily for six
weeks. No significant changes occurred in the chemical or cellular
composition of blood and urine, liver function tests remained
unaffected, there were no ophthalmological changes (Wills et al.,
1969).
Ingestion by man of 22.5 ml produced no exhilaration, but
dizziness, salivation, flushed face, muscular and nervous disturbance
and prolonged headache (Thompson, 1938). Acute intoxication has been
reported to cause myopathy, renal failure and haemolytic anaemia
(Juncos & Taguchi, 1968). The TLV is 400 ppm (Amer. Conf. Gov, Ind.
Hyg., 1969).
Long-term studies
None available bat a 2-year study in rats at levels of 0, 0.31
per cent., 0.625 per cent., 1.25 per cent. and 2.5 per cent. in the
drinking water is being carried out at BIBRA in the United Kingdom.
Comments
A human study extending over six weeks points to a tolerated
daily intake of about 350 mg/day for adults. However, the
establishment of an ADI will have to await the outcome of long-term
oral studies now in progress in rats.
Tentative Evaluation
The use of this solvent should be restricted to that determined
by good manufacturing practice, which is expected to result in
residues unlikely to have any toxicological significance. It is
recognized that the results of studies now in progress may permit a
more extensive food additive use.
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See Also:
Toxicological Abbreviations