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.
ACETONE
Biological Data
Biochemical aspects
Acetone is readily absorbed by solution into the blood after
inhalation (Kagan, 1924) and progressive accumulation in tissues has
been noted after 6 hours inhalation (Haggard et al,, 1944). Skin
absorption occurs only slowly in animals (Lazarew et al., 1931). Large
oral doses are mostly excreted unchanged through the lungs (40-70%)
and the kidneys (15-30%) but small amounts are metabolised slowly to
formate and acetate within 24 hours (Williams, 1959). Dogs excrete in
their urine some 1-4% of acetone when administered orally at rates of
0.2-1.6 g/kg. Some 60% is excreted through the lungs (Schwarz, 1898).
Small doses (1.7 mg/kg body weight) are oxidised mainly to CO2 (53%)
while some 7-14% is exhaled unchanged (Price & Rittenberg, 1950;
Sakami & Lafaye, 1950).
Acetone labelled with C14 in the methyl group was shown to be
converted by rats to liver glycogen, serine, choline and methionine
via formate and acetate (Sakami & Lafaye, 1950), while another
metabolic pathway involved direct conversion to pyruvate in the liver
(Sakami & Lafaye, 1951). Acetone injected into dogs produced high
hepatic levels of ß-hydroxybutyric acid (Valdiguie, 1935). Of 1 g.
administered to man some 24% are excreted through the lungs (Rothkopf,
1936). I.v. injection into rabbits markedly increased acetoacetic acid
and ß-hydroxybutyric acid and glucose levels in their blood (Caccuri,
1937). After i.v. injection at constant rate of 10 g acetone into man
over 2 hours some 110 mg were lost through the lungs (1 normal, 5
diabetic subjects). Total urinary ketone excretion did not rise
significantly in 7 fasting normal subjects but some 360 mg acetone
were excreted in 24 hours by this route. 12 normal subjects maintained
high blood levels of acetone for 4 hours after injection but almost
all had disappeared from the blood after 24 hours. Acetoacetic acid
levels rose less high in the blood and also remained elevated for 4
hours after injection. No ß-hydroxybutyric acid appeared. Simultaneous
i.v. glucose or i.v. insulin did not affect blood acetone levels in 7
normal fasting subjects. I.v injection of acetone into 12 diabetics
showed similar levels as in 19 normal subjects. Hence no impairment in
ability to destroy acetone occurs in diabetics. The rate of breakdown
is so slow, however, as to preclude that more than a small part of
normal fat metabolism passes through an acetone stage (Koehler et al.,
1941). The rat and the dog excrete acetone from the blood at
approximately similar rates (Abshagen & Rietbrock. 1969).
Acute toxicity
Animal Route LD50 LD100 References
mg/kg mg/kg
bodyweight bodyweight
Mouse inhalation - 46000 ppm Schultze, 1932
oral 10700 - (Smyth et al., 1962
(Shell Chemical Co., 1969
9700 - Spector, 1956
i.v. - 4ml/kg Walton et al., 1928
inhalation - 32000 ppm/ (Smyth et al., 1962
4 hrs (Shell Chemical Co., 1969
Rabbit intragastric 5340 - Spector, 1956
- 5-10ml/kg Walton et al., 1928
i.v. - 6-8 ml/kg Walton et al., 1928
percutaneous > 20 ml/kg - (Smyth et al., 1962
(Shell Chemical Co., 1969)
Dog intragastric - 8 g/kg Albertoni, 1884
The acute effects of acetone are essentially that of a fairly strong
anaesthetic (Browning, 1965). Repeated intragastric administration of
8 ml to rabbits for 5-22 days or 8-10 ml to dogs for 8-35 days
produced albuminuria and epithelial necrosis of convoluted renal
tubules (Albertoni and Pisenti, 1887). Daily administration of 1-2.5
g/kg acetone intragastrically to 5 dogs for 9-19 days produced
nephritis with tubular destruction (Poliak, 1925).
Special tests
Mouse
Acetone was painted on the clipped dorsal skin of 60 female mice three
times a week for 447 days (64 weeks) as part of another experiment. No
local papillomata or carcinomata were seen (van Duuren et al., 1965).
Rat
The single injection of 0.1 ml, as part of another experiment,
into one or both salivary glands of 35 male and 7 female rats produced
local necrosis and complete regenerative repair after 3 weeks. Animals
observed for 8 months showed no local or distant tumour formation
either macroscopically or histologically (Cherry & Glücksmann, 1965).
Chicken
At dose levels of 39, and 78 mg/egg hatchability of fresh fertile
unincubated eggs injected into the yolk sac was reduced to 76% and 47%
of the normal (McLaughlin et al., 1964). Preincubation injection of a
maximum dose of 0.1 ml/egg resulted in a 37% hatch, the remainder
being killed due to yolk coagulation. The hatchability of 3 days
incubated eggs injected at similar doses was reduced to 20% (Waller,
1967).
Observations in man
Widespread industrial use over many years (e.g. 2000 ppm inhaled
for 15 years) only yielded a few cases of mild intoxication, but no
reports of permanent haematological or organ damage (Browning 1965;
Rowe & Wolf, 1963; Fassett, 1963). Reversible effects resulting from
high oral doses occur on liver and kidney and are manifest by
albuminuria, presence of red and white cells in urine sediment,
urobilinuria. and increased serum bilirubin, Acute lethal doses are
estimated to be about 50 ml/man and death is a result of respiratory
depression, (API Toxicological Reviews. 1955). The TLV is 1000 ppm
(Amer. Conf. Gov. Industr. Hygienists, 1969).
15.20g given orally daily to man over several days produced only
slight drowsiness but no other ill effects (Albertoni, 1884).
Acute massive intoxication in man has caused collapse and
possible liver and kidney injury (Sack, 1940, Smith & Mayers, 1944,
Harris & Jackson, 1952). Dermatitis from frequent sustained skin
contact and irritation of eyes and the nasal mucosa have been observed
in man (Browning 1965). Some 10% of inhaled acetone is excreted
through human skin (Parmeggiani & Sassi, 1954).
Comments
The principal toxic action of large doses results in narcosis and
repeated smaller doses have produced headache, drowsiness and
irritation of eyes and mucosal surfaces in man. There is minor
circumstantial evidence of some toxic effect on the liver and kidney
in man after acute massive intoxication. Early findings suggest severe
toxicity in dogs and rabbits on prolonged oral administration of large
doses. The small amounts likely to be found as residues in food are
probably oxidised and metabolized by well known pathways. Many years
of human industrial experience have shown no evidence of significant
organ damage.
Tentative Evaluation
The use of this solvent should be restricted to that determined
by good manufacturing practice, which is expected to result in minimal
residues. Within these limits residues are unlikely to have any
significant toxicological effect.
REFERENCES
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23. 393
4. Amer. Conf. Gov. Ind. Hyg. (1969) Threshold limit values for 1969
5. A.P.I. Toxicological Review (1965) Unpublished data
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Exptl. Ther., 33, 175
34. Williams, R.T. (1959) Detoxication Mechanisms, Chapman & Hall,
London
See Also:
Toxicological Abbreviations
Acetone (EHC 207, 1998)
Acetone (ICSC)
ACETONE (JECFA Evaluation)