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    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
    


    See Also:
       Toxicological Abbreviations
       Dichloroethane, 1,2- (EHC 176, 1995, 2nd edition)
       Dichloroethane, 1,2- (EHC 62, 1987, 1st edition)
       Dichloroethane, 1,2- (WHO Food Additives Series 30)
       Dichloroethane, 1,2-  (WHO Pesticide Residues Series 1)
       Dichloroethane, 1,2- (Pesticide residues in food: 1979 evaluations)
       Dichloroethane, 1,2- (CICADS 1, 1998)
       Dichloroethane, 1,2- (IARC Summary & Evaluation, Volume 71, 1999)