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.
1,2-DICHLORETHANE (Ethylene dichloride)
Biological Data
Biochemical aspects
1,2-dichloroethane is absorbed through the shaved rabbit skin and
partially excreted through the lungs. Absorption also occurs via the
lungs or gastro-intestinal tract (Patty, 1958). It probably
metabolises to oxalic acid but rabbits exhale it mainly unchanged
(Williams, 1959). Oral administration to female rats depressed hepatic
glutathione level by approximately 50% (Johnson, 1965).
Acute toxicity
Animal Route LD50 LD100 Reference
mg/kg
body weight
mouse inhalation - 9 000 ppm Lazarew, 1929
oral 910 - Spector, 1955
i.p. 470 - Baganz et al., 1961
rat oral 680-770 - McCollister et al., 1956
s.c. 1 000 - Highman et al., 1951
inhalation 1 000 - Carpenter, 1949
guinea-pig inhalation - 3 000 ppm Heppel et al., 1944
rabbit percutaneous 2 800 - Patty, 1958
s.c. - 1.6 g/kg Barsoum & Saad, 1934
oral 910 - Spector, 1955
dog oral 5 700 2.5 g/kg Spector, 1955
i.v. - 175 mg/kg Barsoum & Saad, 1934
man oral - 56 ml Hueper & Smith, 1955
The compound has the anaesthetic and CNS depressant properties common
to chlorinated hydrocarbons and causes lacrimation, conjunctivitis and
nasal irritation followed by vertigo, ataxia and shallow respiration
(Browning, 1965). Inhalation and s.c. injection produce corneal
opacities but only in dogs and foxes, not in man. These lesions were
usually reversible and not due to direct vapour contact. Tolerance may
develop. Histology revealed corneal oedema, endothelial degeneration
and polymorph infiltration (Browning, 1965). Rats exposed to 3 000 ppm
showed liver, kidney and adrenal changes (Spencer et al., 1951). Oral
administration in dogs caused kidney, liver and G.I. tract irritation
van Oettingen, 1955). Ethylene dichloride has slight haemolytic
activity (Heppel et al., 1946; Spencer et al., 1951). Single i.p.
administration to male mice produced a non-related proteinurea but no
glycosurea (Plaa & Larson, 1965).
Short-term tests
Inhalation exposure of guinea-pigs, rats, rabbits, cats, monkeys
and dogs, on a 5x weekly basis, for 7 hours/day for over 6 months,
indicates 100 ppm in air to be a "no effect" level. Species
sensitivity is variable, but effects on guinea-pig liver parenchyma
and on body weight were observed at 200 ppm levels. The only
consistent abnormal findings in all species were fatty changes in the
liver. Monkeys and guinea-pigs also showed changes in renal tubular
epithelium histology.
Observations in man
In man, acute poisoning by ingestion produces depressed
consciousness, haemorrhagic colitis, nephrosis, renal tubular
calcification, and circulatory failure, death occurring with doses of
0.3-0.9 g/kg (Hueper 9, Smith, 1955; Hinkel, I965). Repeated skin
application causes dermatitis (Patty, 1958). Excessive single or
repeated inhalation by man causes pulmonary oedema, fatty degeneration
of the liver and kidney injury (Hadengue & Martin, 1953; Torkelson et
al., 1966). Chronic individual exposure for 9 weeks to 5 months
produced nausea, vomiting, loss of weight and epigastric pain, some
tongs tremor and nystagmus but no haematological, urinary or ECG
changes (McNally & Fostvedt, 1941), Chronic exposure also produces
liver, kidney and adrenal lesions (Patty, 1958). The TLV is 50 ppm
(Amer. Conf. Gov. Ind. Hyg., 1969).
Special studies
Ethylene dichloride - extracted whole fish flour was fed at 11.5%
and 23% of the protein of the diet to groups of 6 male rats for 3
weeks. No toxic effect on growth rate or liver weight were noted.
However lysine and methionine levels were slightly reduced (Morrison
et al., 1962). Further examination pointed to reactions between alkyl
halides and -SH groups to form thioethers (R-S-CH2-CH2-S-R).
Extracted fish protein contained less histidine and cystine and
inhibited the release of cystine by in vitro pancreatic digestion.
S,S1-ethylene bis cysteine was isolated from extracted protein but
was found to be unstable to autoclaving (Morrison & Munro, 1965).
Chlorocholine chloride (2-chloroethyl-trimethyl ammonium chloride) is
also formed only under extreme conditions of treatment which is toxic
to rats at intake levels above 2 400 ppm (Munro & Morrison, 1967).
Comments
This solvent has anaesthetic properties and as with many
chlorinated hydrocarbons, large doses appear to exert a toxic action
on the liver, kidney and adrenal. The formation of toxic interaction
compounds with certain food constituents occurs under grossly abnormal
and excessively severe conditions.
Tentative Evaluation
In foods suitable for dichloroethane extraction the use should be
restricted to that determined by good manufacturing practice, which is
expected to result in minimal residues unlikely to have any
toxicological effect. Manufacturing practice must also ensure that
toxic interaction products with treated foods do not occur.
REFERENCES
Amer. Conf. Gov. Ind. Hyg. (1969) Threshold Limit Values for 1969
Baganz H., Perkow, W., Lim, G. T. & Meyer, F. (1961)Agzneimittel
Forsch., 11, 902
Barsoum, G. S. & Saad, K. (1934)Quart. J. Pharmacol., 7, 205
Browning, E. (1965) Toxicity and Metabolism of Industrial Solvents,
Elsevier, Amsterdam
Carpenter, J. (1949) J. Ind. Hy. Tox., 31, 343
Hadengue, A. & Martin, A. (1953) Ann. Méd. lég., 33, 247
Heppel, L. A., Neal, P. A., Endicott, K. M. & Porterfield, V. T.
(1944)
Heppel, L. A., Neal, P. A., Perrin, T. L., Endicott, K. M. &
Porterfield, V.T. (1946) J. Ind. Hyg. Toxicol., 28, 113
Highman, B., Heppel, L. A. & Lamprey, R. J. (1951) Arch. Path.,
51, 346
Hinkel, G. K. (1965) Dtsch. Ges. Wesen, 20, 1327
Hueper, W. C. & Smith, C. (1955) Amer. J. Mod. Sci., 189, 778
Johnson, M. K. (1965) Biochem. Pharmacol., 14 (9), 1383
Kistler, G. H. & Luckhardt, A. B. (1929) Anaesth. Analg. Curr. Res.,
8, 65
Lazarew, N. W. (1929) Arch. Exptl. Pathol. Pharmakol., 141, 19
McCollister, D. D., Hollingsworth, R. L., Oyen, F. & Rowe, V. R.
(1956) AMA Arch. Ind. Health, 13, 1
McNally, W.D. & Fostvedt, G. (1941) Ind. Med. Surg., 10, 373
Morrison, A. B. & Munro, I. C. (1965) Canad. J. Bioch., 45, 33
Morrison, A. B., Sabry, Z. I, & Middleton, E. J. (1962) J. Nutr.,
77, 97
Munro, I. C. & Morrison, A. B. (1967) Canad. J. Bioch., 45, 1779
Patty, F. A. (1958) Industrial Hygiene and Toxicology, Vol. 11,
Interscience, New York
Plaa, G. L. & Larson, R. E. (1965) Toxic appl. Pharmac., 7, 37
Spector, W. S. (1955) Handbook of Toxicology, Vol. 1, 330
Spencer, H. C., Rowe, V. R., Adams, E. M., McCollister, D. D. & Irish.
D. D. (1951) Arch. Industr. Hlth, 4, 482
Torkelson, T. R., Hoyle, H. R. & Rowe, V. K. (1966) Pest Control, July
1966
Williams, R. T. (1959) Detoxication Mechanisms, 2nd ed., Chapman &
Hall, London