The evaluations contained in this document were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Rome, 21-29 April 1976

    Food and Agriculture Organization of the United Nations

    World Health Organization

    *Twentieth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1976, WHO Technical Report Series No. 599, FAO Food
    and Nutrition Series No. 1.


    Biological Data


         Diethylene glycol monoethyl ether administered orally or
    subcutaneously in doses of 3-5 ml/kg BW to rabbits produced an
    increased urinary excretion of glucuronic acid. This increase could
    account for only 0.8-2.3% of the dose administered. (Fellows et al.,


    Acute Toxicity


    Animal       Route    (ml/kg body-weight)   Reference

    Rat          oral        5.5-9.7            Hanzlik et al., 1947a
                 s.c.        6.0                "

    Mouse        oral        6.6                Lang et al., 1939
                 s.c.        2.5-6.0            Hanzlik et al., 1947a
                 i.p.       <2.0                "

    Guinea, pig  oral        3.7-5.0            Lang et al., 1939

    Rabbit       i.v.        2.5                "

    Dog          i.v.        3.0                "

    Cat          s.c.        1.0-2.0            Lehmann and Fury, 1943
                 i.v.        4.2                Lang et al., 1939

         No abnormalities were obvious below a dosage level of 1 ml/kg by
    any route. Ataxia with initially increased and later decreased
    respiratory rate occurred with 2-2.5 ml/kg while higher dosage levels
    led to central nervous depression and coma followed by recovery or



         Groups of 20 male and 20 female mice were fed on diets containing 
    0, 0.2, 0.6, 1.8 or 5.4% diethylene glycol monoethyl ether (containing 
    less than 0.4% ethylene glycol) for 90 days. Half of the 5.4% group 
    died between the 5-12th weeks and of these 6 showed hydropic
    degeneration of the kidney. The growth rate was reduced and anaemia
    was found in males at the highest dosage level. Serum transaminase and
    urea levels were unaffected by treatment. The relative body-weight was
    increased in both sexes receiving the 5.4% diet and in males fed on
    1.8% diet. In females receiving the highest dosage level the relative
    heart and liver weights were greater than in controls. Centrilobular
    hepatocyte enlargement was found at the 5.4 and 1.8% dietary levels.
    Renal tubular cell enlargement with nuclear pyknosis occurred in
    animals at the 5.4% dietary level. Areas of tubular degeneration and
    atrophy were seen in all groups but they appeared with greater
    frequency at the top feeding level. No oxalate crystals were seen in
    the kidneys or bladder. The no-effect level was 0.6%, equivalent to an
    intake of 850-1000 mg/kg/day. (Gaunt et al., 1968)


         Groups of 12 male and 12 female rats were fed for 90 days on
    diets containing 0, 0.25, 1.0 or 5.0% diethylene glycol monoethyl
    ether contaminated by 0.64% ethylene glycol. The condition and health
    of the animals remained good but 1 male on the 5% diet died after 23
    days following a period of weight loss. No abnormalities were found on
    haematological examination. Urinary glutamic oxalacetic transaminase
    activity was significantly increased and the relative kidney weight
    raised in both sexes and the relative testes weight raised in males of
    the 5% group. Tubular dilatation with inflammatory cell infiltration
    was present in all groups but was accentuated in the 5% group.
    Hydropic degeneration was seen in 2 males and 1 female and slight to
    moderate fatty infiltration in most animals was also found in this
    group. The no-effect level was 1% in the diet, equivalent to 800 mg/kg
    BW/day. (Hall et al., 1966)

         Groups of 15 male and 15 female rats were fed on diets containing
    0, 0.5 or 5.0% diethylene glycol monoethyl ether (containing less than
    0.4% ethylene glycol) for 90 days. No animals died. The growth rate
    and food intake were reduced and slight anaemia was seen in females
    after 6 weeks and in males at the end of the study at the highest
    dosage level. Serum urea and transaminase levels were unaffected by
    treatment. The relative weight of kidneys was increased in the 5%
    group and cells of the proximal tubular cells were grossly enlarged
    with pyknotic nuclei. No oxalate crystals were found in the kidneys
    or bladder. The no-effect level was 0.5% in the diet, equivalent to
    250 mg/kg/day. (Gaunt et al., 1968)


         Groups of 2 or 3 male ferrets were fed on diet providing
    0, 0.5, 1.0, 2.0 or 3.0 ml diethylene glycol monoethyl ether/kg
    body-weight/day for 9 months. The sample of solvent contained less
    than 0.4% ethylene glycol. The body-weights of the two highest dosage
    levels tended to be lower than those of controls and their food intake
    was also diminished. No abnormal constituents were found in urine. The
    water intake of all treatment groups was greater than controls during
    the period of measurement (first seven weeks). The concentrating power
    of the kidney was decreased consistently at the two highest dosage
    levels. However at necropsy organ weights were not changed by
    treatment and no abnormal gross or histopathological abnormalities
    were detected. The no-effect level was 0.5 ml/kg BW. (Butterworth et
    al., 1975)


         Groups of 3 male and 3 female pigs were administered diethylene
    glycol monoethyl ether in their diet for 90 days. Initially the daily
    intake was 0, 167, 500 or 1500 mg/kg BW/day but the top dose was 
    reduced to 1000 mg/kg BW/day after 3 weeks since 2 animals had to be
    killed in extremis after 2 and another after 3 weeks. These pigs 
    became lethargic and comatose and autopsy showed subcutaneous and 
    pulmonary oedema and pleural and peritoneal effusions. The livers 
    were of a yellowish colour and they were enlarged, the cut surfaces 
    showing a pale cortex with petechial and medullary congestion. 
    Calculi were found in the urinary tract. Proteinurea with casts also 
    occurred. Serum urea was elevated to above 100 mg% and histological 
    examination showed hydropic degeneration and tubular desquamation with 
    glomerular atrophy. Livers showed extensive hydropic degeneration. 
    There was slight anaemia in males receiving 1000 mg/kg/day for the 
    full 90 days and more severe anaemia in those that died. Serum urea 
    and transaminase levels were normal in all animals killed at the end 
    of the investigation. The kidney weight was elevated in animals 
    receiving the highest dosage level. Hepatocytes of centrilobular and 
    midzonal areas were grossly enlarged with pyknotic nuclei and fatty 
    infiltration occurred at the top dosage level and in one female 
    receiving 500 mg/kg diet. Most of the renal cortex was affected by 
    extensive areas of tubular hydropic degeneration at the highest 
    dosage level but this was less marked at the 500 mg/kg level. Other 
    changes at the 1000 mg/kg level were consistent with uraemia resulting 
    from renal failure. No oxalate crystals were seen in the kidneys or 
    bladder. The no-effect level was 167 mg/kg/day. (Gaunt et al., 1968)



         Groups of 10 male and 10 female mice were fed on control diet or
    diet containing 5% diethylene glycol monoethyl ether (purity: less
    than 0.2% ethylene glycol). This provided males with 7.5 and females
    with 6.0 ml/kg BW/day. The body-weights were reduced in males between
    the 2-6th months but were similar to controls at other times. Body-
    weight was continuously lower than controls in females. Approximately
    40% of test and control females were alive at 12 months while males
    survived longer, the last test male dying at 18 and control at 21
    months approximately. Only one of 30 animals receiving diethylene
    glycol monoethyl ether (pure or containing 1% ethylene glycol) showed
    hydropic degenerative change in the kidneys. (Hanzlik et al., 1947b)


         A group of 8 female and 12 male rats were fed on a diet
    containing 2.16% diethylene glycol monoethyl ether for up to 2 years.
    A similar group of litter mates received control diet. Food and water
    were offered ad lib. No significant decrease in growth rate occurred
    in the test group and the mortality rate was unaffected; however, the
    number of animals surviving for 2 years was not stated. Only animals
    surviving the longest received full pathological examination but the
    number examined was not stated. In the test group there was an
    increased incidence of testicular atrophy with interstitial oedema,
    centrilobular or diffuse atrophy of the liver with bile duct
    proliferation and fatty degeneration and an oxalate concentration was
    found in the kidney of one animal. (Morris et al., 1942)

         A group of 10 male and 5 female rats were administered diethylene
    glycol monoethyl ether (purity: less than 0.2% ethylene glycol) as a
    1% solution in drinking water. Thirteen male and 8 female control rats
    received uncontaminated water; both received diet and drinking fluid
    ad lib. The intake of monoethylene glycol monoethyl ether was
    approximately 1.3 ml/kg BW/day in male and 1.5 ml/kg BW/day in female
    animals. No significant differences were found in growth rate or in
    food or fluid intakes. After 12 months approximately 8 test and 4
    control animals remained alive. No gross or microscopic abnormalities
    were found in the small number of animals examined. (Hanzlik et al.,

         Groups of 8 male and 8 female Wistar rats received drinking water
    incorporating diethylene glycol monoethyl ether containing either
    29.5% ethylene glycol or less than 0.2% ethylene glycol. Groups
    received the equivalent of 0, 10, 40, 190 or 950 mg of the diethylene
    glycol monoethyl ether mixture/kg BW/day or 0, 9, 39, 200 or 920 mg of
    the purer substance/kg BW/day for up to 757 days. Feed and drinking
    fluids were available ad lib.

         Animals were allowed to produce offspring to form a first
    generation and a second generation was produced from these. However,
    the length of the period of treatment of the offspring was not given.

         The life span of animals receiving 950 mg of the mixture/kg
    BW/day was significantly shortened compared with controls but other
    groups were unaffected. Growth was reduced compared with controls in
    animals of the parent generation receiving 950 and 190 mg mixture/kg
    BW/day or 920 mg purer diethylene glycol monoethyl ether/kg BW/day but
    the effect on growth in other groups and other generations was
    probably not of significance. No adverse effects were found on
    haematological examination, and blood urea and glucose and serum
    proteins were unaffected by the treatments. No increase in oxalic or
    oxaluric acids were found in the urine of test animals; although the
    urine protein concentration was raised in the 950 mg and 920 mg/kg

         The tumours found were typical of elderly rats and the overall
    incidence (4.4%) was similar to other reported figures for the strain
    of rat. However, the report does not allow a full assessment of the
    incidence and types of tumours in each group. Bladder calculi were
    found only in animals receiving the highest dosage level of the
    mixture. Only the liver and kidney were examined microscopically in
    all animals but a few more organs were examined in others. Epithelial
    necrosis of the renal tubules and cloudy swelling of hepatic tissue
    were the only adverse effects which could be attributable to
    treatment and these were seen in animals receiving 950, 190 and
    40 mg mixture/kg/day and 920 mg purer diethylene glycol monoethyl

         The "no adverse effect level" for diethylene glycol monoethyl
    ether containing less than 0.2% ethylene glycol was 200 mg/kg/day.
    (Smythe et al., 1944)


         Several long-term tests on rats and mice have been reported. The
    results indicate that the solvent has no effects other than those seen
    in short-term tests in these species. However, the study carried out
    in the pig was not of sufficient duration and it is possible that the
    lesions would have occurred at a lower dosage level on longer-term
    feeding. None of the long-term studies are reported fully enough to
    demonstrate lack of carcinogenicity. Although one study suggests no
    adverse effects, no adequate reproduction or teratogenicity studies
    are available.


         No acceptable daily intake for men has been allocated.

    Further work or information required before an ADI can be allocated

    1.   Studies on absorption, distribution, excretion and metabolism of
         diethylene glycol monoethyl ether.

    2.   An adequate carcinogenicity study.

    3.   A 6-month study in the pig.

    4.   Studies on the effects in reproduction and possibly


    Butterworth, K. R., Gaunt, I. F. and Grasso, P. (1975) A nine month
         toxicity study of diethylene glycol monoethyl ether in the
         ferret. Unpublished report by the British Industrial Biological   
         Research Association

    Fellows, J. K., Luduena, F. P. and Hanzlik, F. J. (1947) "Glucuronic
         acid excretion after diethylene glycol monoethyl ether (carbitol)
         and some other glycols", J. Pharmacol., 89, 210-213,

    Gaunt, I. F., Colley, J., Grasso, P., Lansdown, A. B. G. and Gangolli,
         S. D. (1968) Short-term Toxicity of Diethylene glycol monoethyl
         ether in the Rat, Mouse and Pig, Food Cosmet. Toxicol., 6,

    Hall, D. E., Lee, F. S., Austin, P. and Fairweather, F. A. (1966)
         "Short-term feeding study with diethylene glycol monoethyl ether
         in rats", Food Cosmetics Toxicology, 4, 263-268

    Hanzlik, P. J. Luduena, F. P., Lawrence, W. S. and Hanzlik, H.
         (1947a) Acute toxicity and general systemic actions of diethylene
         glycol monoethyl ether (Carbitol), J. Ind. Hyg. Toxicol., 29,

    Hanzlik, P. J., Lawrence, W. S. and Laquer, G. L. (1947b) "Comparative
         chronic toxicity of diethylene glycol monoethyl ether (carbitol)
         and some related glycols: results of continued drinking and
         feeding", J. Ind. Hyg. Toxicol., 29, 233-241

    Lang, E. P., Calvery, H. O., Morris, H. J. and Woodard, G. (1939) "The
         toxicology of some glycols and derivatives", J. Ind. Hyg.
         Toxicol., 21, 173

    Lehmann, K. B. and Flury, F. (1943) Translated by King, E. and Smyth,
         H. F., jr "Toxicology and hygiene of industrial solvents",
         Williams and Wilkins, Baltimore, p. 378

    Morris, H. J., Nelson, A. A. and Calvery, H. O. (1942) "Observations
         on the chronic toxicities of propylene glycol, ethylene glycol,
         diethylene glycol, ethylene glycol monoethyl ether and diethylene
         glycol monoethyl ether", J. Pharmacol., 74, 266-273

    Smythe, H. F., Carpenter, C. P. and Shaffer, C. B. (1944) "Two-Year
         oral doses of Carbitol to rats". Unpublished report No. 7-31 by
         the Mellon Institute of Industrial Research

    See Also:
       Toxicological Abbreviations
       Diethylene glycol monoethyl ether (ICSC)
       Diethylene glycol monoethyl ether (WHO Food Additives Series 30)