First draft prepared by
    Dr R. Walker
    University of Surrey
    United Kingdom


         This substance was previously reviewed at the twentieth meeting
    of the Committee (Annex 1, references 41, 42) but no ADI was
    allocated because of inadequacies in the toxicological data. In
    particular, the lack of metabolic and reproduction/teratogenicity
    studies was noted, and the carcinogenicity studies did not meet
    current standards. At its present meeting, the Committee reviewed
    new data on metabolism and excretion in humans, together with
    studies on reproduction and teratogenicity in mice and rats, and a
    number of genotoxicity studies that were generally negative. It was
    also aware of a number of other studies on pharmacological activity
    and irritancy.

         Since the last review, additional data have become available
    and are summarized and discussed in the following monograph. The
    previously published monograph has been expanded and is incorporated
    into this monograph.


    2.1  Biochemical Aspects

    2.1.1  Absorption

         In an  in vitro system for assessing percutaneous absorption
    using human epidermal membranes, the "donor" chambers contained
    undiluted diethylene glycol monoethyl ether (> 98% pure) and
    diffusion was monitored at 30 min intervals for 8 h using GC. The
    absorption rate was 0.21 ± 0.15 mg/cm2/h. Measurement of tritiated
    water transfer before and after exposure to the test compound
    indicated that there were slight irreversible changes in barrier
    function during exposure to the test compound (Dugard  et al.,

    2.1.2  Metabolism and pharmacokinetics

         Diethylene glycol monoethyl ether administered orally or
    subcutaneously in doses of 3-5ml/kg bw to rabbits produced an
    increased urinary excretion of glucuronic acid. The increase could
    account for only 0.8-2.3% of the dose administered, the major part
    of the dose being oxidized (Fellows  et al., 1947).

         The quantitative urinary excretion of diethylene glycol
    monoethyl ether was investigated in the rabbit after oral,
    intravenous, subcutaneous and percutaneous administration. After
    oral dosing of two animals at a level of 5 ml/kg bw, both animals
    died during the first day and total excretion was only 0.8% and
    0.33%. After intravenous administration to 15 rabbits at dose levels
    of 0.5-3.4 ml/kg most of the dose was excreted during the first day
    (for 13/15 rabbits), the percentage excreted tending to increase
    with dose.

         After a single parenteral dose of 1.0-3.0 ml/kg, urinary
    excretion was monitored for up to 4 consecutive days. Excretion was
    high in the first 24 h and the total percentage of the dose excreted
    in urine increased with dose. After repeated daily parenteral doses
    of 0.16, 0.32 or 0.63 ml/kg bw, total urinary excretion increased
    with dose and equalled 4.7, 5.0 and 11.6%, respectively.

         Groups of 2-3 rabbits received daily applications of 0.08 to
    2.5 ml/kg bw to a clipped area of skin for up to 30 days. Total
    urinary excretion was small and variable (1.3-9.4%); there was no
    correlation between percentage excretion and period of application
    over the period 9-30 days.

         Blood samples were collected for up to 2.5 h after
    administration of diethylene glycol monoethyl ether intravenously to
    rabbits at doses of 1.0-3.0 ml/kg bw. Clearance was rapid with less
    than half of the dose detectable within 5 min and only small/trace
    amounts present in blood after 30 min.

         When a single dose of diethylene glycol monoethyl ether
    (11.2 mmol) was given to an adult human volunteer (sex and age not
    specified) about 68% of the dose was excreted in the urine as
    (2-ethoxyethoxy)acetic acid within 12 h (Kamerling  et al., 1977;
    Miller, 1987).

    2.2  Toxicological studies

    2.2.1  Acute toxicity


    Species          Route               LD50            Reference

    Mouse            oral                6.6             Laug et al., 1939
                     oral               12.5             Latven & Molitor, 1939
                     oral                8.0             Berte et al., 1986
                     s.c.                2.5-6.0         Hanzlik et al., 1947a
                     s.c.                5.5             Latven & Molitor, 1939
                     i.v.                 ..             Latven & Molitor, 1939
                                         4.3             Latven & Molitor, 1939
                     i.v.                3.9             Stenger et al., 1971
                     i.p.               <2.0             Latven & Molitor, 1939
                     i.p.                3.9             Karel et al., 1947
                     i.p.                2.3             Budden et al., 1979
                     i.p.                5.4             Berte et al., 1986

    Rat              oral                8.0             Berte et al., 1986
                     oral                5.5-9.7         Hanzlik et al., 1947a
                     oral                5.3-5.7         Laug et al., 1939
                     oral                7.3-10.4        Smyth et al., 1941
                     oral                6.3             Weil, 1972
                     s.c.                6.0             Hanzlik et al., 1947a
                     s.c.                3.4             Stenger et al., 1971
                     i.v.               >4.0-<5.0        Stenger et al., 1971
                     i.v.                2.2             Budden et al., 1978
                     i.v.                2.9             Stenger et al., 1971
                     i.p.                5.4             Berte et al., 1986
                     i.p.                3.0             Sanderson, 1959


    Species          Route               LD50            Reference

    Guinea-pig       oral                3.7-5.0         Laug et al., 1939
                     oral                3.1-4.3         Smyth et al., 1941

    Rabbit           i.v.                2.5             Smyth et al., 1941
                     i.v.                0.9             Stenger et al., 1971
                     s.c.                2.0             Stenger et al., 1971
                     p.c.                8.5             Hanzlik et al., 1947a
                     p.c.               10.3             Carpenter, 1947

    Cat              s.c.                1.0-2.0         Lehmann & Flury, 1943
                     i.v.                4.2             Laug et al., 1939
                     i.v.                1.0             Budden et al., 1978

    Dog              i.v.                3.0             Smyth et al., 1941
                     i.v.                1.0             Budden et al., 1978
         No abnormalities were obvious below a dosage level of 1 ml/kg
    bw by any route. Ataxia with initially increased and later decreased
    respiratory rate occurred with 2-2.5 ml/kg bw while higher dosage
    levels led to central nervous depression and coma followed by
    recovery or death. Delayed deaths were associated with renal
    glomerular and tubular degeneration.

    2.2.2  Short-term studies  Mice

         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 for 90 days. The test material contained less than 0.4%
    ethylene glycol. Six males of the 5.4% group died between the
    5th-12th weeks with signs of advanced renal damage (hydropic
    degeneration). The growth rate was reduced and anaemia was found in
    males at the highest dose level. Serum transaminase and urea levels
    were unaffected by treatment. The relative kidney weight was
    increased in both sexes receiving the 5.4% diet and in males fed on
    the 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 proximal
    tubular degeneration and atrophy were seen in all groups, including
    controls, 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 bw/day (Gaunt  et al., 1968).

         In a pilot study to determine the MTD for a subsequent
    reproduction study, groups of 10 female CD1 mice were given daily
    doses of diethylene glycol monoethylether by gavage for 8
    consecutive days. No necropsies were performed. The MTD was reported
    to be 5500 mg/kg bw (Piccirillo  et al., 1983).

         In a pilot study to determine the MTD for a subsequent
    reproduction study, groups of 8 male and 8 female mice, 8 weeks of
    age were given 0.0, 1.0, 2.0, 3.0, 4.0, or 5% diethylene glycol
    monoethyl ether (> 99% pure) in drinking water for 14 days. During
    the exposure period, one male in the top dose group exhibited
    dehydration on days 8-10 and tremors prior to death on day 11. The
    weight gain was reduced significantly in the 4.0% and 5.0% dose
    groups. No necropsies were performed. The MTD was estimated to be
    2.5% in drinking water (NTP 1984).  Rats

         Groups of 5 male and 5 female rats were given pure diethylene
    glycol monoethyl ether in drinking water at doses of 0.21-3.88 g/kg
    bw for thirty days. The maximum No Adverse Effect Level was reported
    to be 0.49 g/kg bw. In a similar experiment using carbitol solvent
    containing ethylene glycol, the NOEL was less than the lowest dose
    tested, 0.41 g/kg (Smyth & Carpenter, 1948).

         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 generally 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 oxaloacetic 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. Renal
    tubular dilatation with inflammatory cell infiltration was present
    in all groups, including controls, 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 monoethylether
    (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 nucleii. 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 bw/day (Gaunt  et al.,

         Groups of male and female rats were given daily s.c. doses of
    diethylene glycol monoethyl ether of 100, 200, 400 or 800 µl/kg
    bw/day for 4 weeks. No deaths were reported but doses of
    200-400 µl/kg bw/day caused dyspnoea, somnolence and mild ataxia,
    with some growth retardation in females; 800 µl/kg bw/day also
    caused growth retardation in males. Pathological changes in the
    liver, kidney and testes were also seen at doses of 200 µl/kg bw/day
    (Stenger  et al., 1971).  Rabbits

         Technical diethylene glycol monoethyl ether (containing 30%
    ethylene glycol) was applied daily to the clipped abdominal skin of
    adult rabbits for up to 30 days. The animals were then observed for
    a further 30 days after which they were sacrificed for histological
    examination. The mortality varied from 57-65% and histological
    examination revealed marked hydropic degeneration of renal tubular
    epithelial cells (Hanzlik  et al., 1947c)

         Tests of renal function (phenol red clearance and blood urea)
    were carried out on 18 males and hepatic function (rose Bengal) in 6
    males exposed as above to daily doses of 0.02 to 1.5 ml/kg bw. Renal
    function was impaired in 83.3% of the animals (15/18) and hepatic
    function reduced in 88.3% (5/6) animals. Similar function tests
    applied to animals dosed parenterally at daily doses of 0.16 to 0.63
    ml/kg bw until death confirmed decreased renal function but hepatic
    function was not impaired (Hanzlik  et al., 1947d).  Ferrets

         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 bw/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).  Pigs

         Groups of 3 male and 3 female pigs were given 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. Proteinuria 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
    bw/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 dose 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 dose 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 bw/day (Gaunt
     et al., 1968).

    2.2.3  Long-term/carcinogenicity studies  Mice

         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 2nd and 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 at 18
    months 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 changes
    in the kidney (Hanzlik  et al., 1947b).  Rats

         A group of 8 female and 12 male rats was 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 stone was found in the kidney of one animal (Morris
     et al., 1942).

         A group of 10 male and 5 female rats were given 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 untreated water; both received diet and drinking fluid
     ad libitum. The intake of the diethylene 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 approximately 12 months, 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., 1947b).

         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
    purer substance/kg bw/day for up to 757 days. Feed and drinking
    fluids were available  ad libitum.

         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 reported.

         The lifespan 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
    bw groups.

         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
    attributed to treatment and these were seen in animals receiving
    950, 190 and 40 mg mixture/kg bw/day and 920 mg purer diethylene
    glycol monoethyl ether/kg bw/day.

         The no adverse effect level for diethylene glycol monoethyl
    ether containing less than 0.2% ethylene glycol was 200 mg/kg bw/day
    (Smyth  et al., 1944, 1964).

    2.2.4  Reproduction studies  Mice

         In a reproduction study, CD1 mice, 11 weeks of age at
    commencement, were given diethylene glycol monoethyl ether in
    drinking water at concentrations of 0, 0.25, 1.25 or 2.5%. Animals
    of each sex (F0 generation) were exposed for a premating period of
    7 days, then throughout a 98-day cohabitation period, followed by a
    further 21 day segregation. Animals from the last litter produced by
    the control and 2.5% groups were weaned and two male and two female
    animals selected from each of 10 litters (F1 generation). The F1
    animals were caged in groups of two or three by sex and received the
    same drinking fluid as the parental groups for 74 ± 10 days. A male
    and female from different litters within treatment groups were then
    cohabited for one week, the pairs then separated and the females
    allowed to produce their litters.

         Continuous exposure of the F0 generation to diethylene glycol
    monoethyl ether in drinking water from 11 weeks of age had no effect
    on the number of pairs able to produce at least one litter, number
    of litters per pair, live pups per litter, proportion of pups born

    alive nor sex ratios. At the highest (2.5%) concentration, the mean
    live pup weights were significantly reduced (P <0.05) relative to
    controls. Deaths among the parent groups during the study were not

         In the F1 generation the body weights of males and females
    were slightly depressed relative to controls at birth, weaning and
    at the start of the mating period. Continuous exposure of this
    generation to diethylene glycol monoethyl ether  in utero, via
    mother's milk, and subsequently at 2.5% in drinking water, had no
    significant effects on mating behaviour, fertility rate, number of
    live pups per litter, proportion of pups born alive, sex ratio or
    live pup weight. At terminal necropsy, sperm assessment indicated no
    significant differences in sperm concentration nor percentage of
    abnormal sperm in the cauda epididymis between treated and control
    males, but the percentage motile sperm was significantly reduced in
    treated animals. Body weights were not affected by treatment but the
    relative liver weight was significantly increased and relative brain
    weight significantly decreased.

         The authors concluded that diethylene glycol monoethyl ether
    was not a reproductive toxicant under the conditions of this study
    in either F0 or F1 breeding pairs (NTP, 1984; Williams  et al.,

         Groups of 50 pregnant CD-1 mice were given diethylene glycol
    monoethyl ether (>99% pure) by gavage in aqueous solution at the
    MTD on days 7-14 of gestation. Maternal body weights were recorded
    on days 7 and 18 of gestation and day 3 postpartum. Reproductive
    indices reported included pup survival  in utero, pup perinatal and
    postnatal (2.5d) survival and pup body weights. The dose of
    5500 mg/kg bw caused 14% maternal mortality and reduced body weight
    in maternal survivors, and slightly reduced mean pup birth weight
    but did not affect reproduction indices (97% viable litters and 98%
    postnatal survival) (Schuler  et al., 1984; Piccirillo  et al.,

    2.2.5  Special studies on teratogenicity  Drosophila melanogaster

         In a teratology screen using  Drosophila melanogaster
    diethylene glycol monoethyl ether was incorporated into medium at
    the MTD. The eggs were deposited on the medium and the insects
    exposed throughout incubation, larval stage and pupa formation. The
    emergent adult insects were examined for external morphological
    anomalies. At a concentration of 7.5 ml/kg medium, developmental
    effects were observed in the form of an irregular shaped abdomen in
    7.7% of the treated insects; the abnormality was rare in the control
    insects (Schuler  et al., 1982).

         In a similar study, no morphological abnormalities were
    observed at the same concentration of 7.5 ml/kg in the medium
    (Schuler  et al., 1983).  Rats

         Groups of 15 pregnant Sprague-Dawley rats were exposed to
    diethylene glycol monoethyl ether by inhalation of the vapour at an
    aerial concentration of 100 ppm for 7 h/day on days 7-15 of
    gestation. The dams were sacrificed on day 20 and 2/3 of the fetuses
    examined for visceral defects by Wilson's technique and 1/3 for
    skeletal defects by Staples technique. At this level of exposure,
    diethylene glycol monoethyl ether was not maternally toxic and no
    teratogenic or embryotoxic effects were observed (Nelson  et al.,
    1982, 1984).

         Diethylene glycol monoethyl ether was applied to the shaved
    interscapular skin of pregnant Sprague-Dawley rats four times daily
    on days 7-16 of gestation in doses of 0.35 ml at 2.5 h intervals.
    The dams were killed on day 21 and the fetuses weighed and examined
    for external malformations. Half of the fetuses were examined for
    visceral abnormalities and half for skeletal malformations. There
    was no evidence of teratogenicity or fetotoxicity although maternal
    body weight was significantly lower than controls (Hardin, 1983;
    Hardin  et al., 1984).

    2.2.6  Special studies on genotoxicity


    Test system      Test object       Concentration     Results     Reference
                                       of DEGMEE

    Ames test        S.typhimurium     0-1 ml/plate      Negative    Berte et al.,
    (1)              TA97,             (1986)
                     TA100, TA102                        Negative
                     TA1535, TA1537                      Weak pos.   Berte et al.,
                     TA1538                              Weak pos.   (1986)

    Yeast gene       Saccharomyces     1% & 10%          Negative    Berte et al.,
    mutation                           cerevisiae D7                 (1986)

    Micro-nucleus    Mice CD-1         2 x 2 ml/kg bw    Negative    Berte et al.,
    test                                                             (1986)

    (1) With and without beta-naphthoflavone-induced mouse liver S9 fraction.
    2.2.7  Special studies on cytotoxicity

         In a test to evaluate cytotoxicity against a human hepatoma
    cell line  in vitro as an alternative to the Draize eye irritation
    test, diethylene glycol monoethyl ether was added to the incubation
    medium for 24 h at 37 °C. No effects were observed at the maximum
    tolerated concentration of 0.2% (15 mM) (Stark  et al., 1983). In
    similar studies using human hepatoma cell line HepG2, diethylene
    glycol monoethyl ether caused an inhibition of 3H-uridine uptake
    and the UI50 was estimated to be 191mM (Dierickx & Martens, 1986;
    Jacobs  et al., 1988).

         In further studies of uridine uptake using murine BALB/c 3T3
    cells, the UI50 was found to be 129 mM (Shopsis & Sathe, 1984).

    2.2.8  Special studies on haematology

         Three adult rabbits were given intramuscular doses of
    diethylene glycol monoethyl ether of 0.62, 0.82 or 1.6 ml/kg bw
    daily for 2 weeks and haematological examinations performed. No
    effects were noted on haemoglobin, RBC, total leucocytes, platelets
    or reticulocytes. Similarly, no effects on these parameters were
    seen in three pigeons dosed i.m. at daily doses of 1 ml/kg bw
    (Hanzlik  et al., 1947b)

    2.2.9  Special studies on irritancy

         The inflammatory action of diethylene glycol monoethyl ether
    was tested by instillation of one drop of pure material into the
    rabbit eye. Slight hyperaemia of the conjunctiva was reported (von
    Oettingen & Jirouch, 1931).

         In a similar test in the rabbit the degree of irritation was
    scored on a three point scale (+,++,+++). The effects were graded as
    oedema + and hyperaemia ++ (Latven & Molitor, 1939).

         Ocular irritancy was assessed on solutions of commercial
    diethylene glycol monoethyl ether containing ethylene glycol at
    various concentrations in 0.85% aqueous NaCl solutions. Solutions of
    8%, 10% and 12% of the commercial preparation caused inflammation of
    the mucous membrane persisting for 5, 10 and 30 mins respectively.
    Solutions of 20% caused discomfort (blinking), 25% caused pain
    (eye rubbing) and 30% resulted in inflammation that persisted for 60
    mins. No other adverse effects on the eye were reported (Cranch
     et al., 1942). Ocular effects in similar studies using water,
    propylene glycol or Deobase as vehicle were graded maximally at
    point 2 on a 10 point scale of injury (Carpenter & Smyth, 1946)
    while no evidence of ocular effects was seen when a 10 µl drop of
    diethylene glycol monoethyl ether was applied to the cornea of
    guinea-pigs (Sanderson, 1959).

         The ocular irritation index (OII) was determined in the rabbit
    after application of diethylene glycol monoethyl ether, undiluted or
    as aqueous solutions, according to official French methods. A 10%
    solution was graded as non-irritating (acute OII 1.67) while the
    undiluted material caused slight to moderate irritation (acute OII
    16.0) (Guillot  et al., 1982). Diethylene glycol monoethyl ether
    was tested for ocular irritancy in rabbits using objective
    quantitative procedures involving determination of dry tissue as an
    index of corneal and conjunctival oedema and dye diffusion (Evans
    blue) as a measure of vascular leakage in the conjunctivae and
    aqueous humour. Diethylene glycol monoethyl ether was applied to the
    eye, undiluted or as a solution in distilled water, 1, 3, 6, 7 or 13
    times over 2, 4, 7, 26 and 50 h, respectively. A 25% solution
    produced significant increases in vascular leakage in the
    conjunctivae and aqueous humour while, in addition to these effects,
    100% diethylene glycol monoethyl ether caused significant
    conjunctival and corneal oedema (Laillier  et al., 1976).

         Diethylene glycol monoethyl ether was without effect in ocular
    irritancy tests in the rabbit conducted according to EEC and OECD
    guidelines (Jacobs  et al., 1988).

         Dermal irritancy was assessed by the trypan blue capillary
    permeability method after exposure of depilated rabbit skin to
    patches soaked in technical carbitol (ca 30% ethylene glycol) for
    2 h daily for 2-6 days. There was no evidence of dermal irritation
    using this technique (Hanzlik  et al., 1947c). Similarly, the
    cutaneous primary irritation index (PII) in patch tests on
    diethylene glycol monoethyl ether according to official French
    protocols was 0.29 (non-irritant). Determination of the cumulative
    cutaneous irritation index by official French methods involving
    cutaneous exposure daily for six weeks showed a 10% solution to be
    non-irritant (mean maximum irritation index 0.13) while undiluted
    material was slightly irritant but well tolerated (MMII 1.13)
    (Guillot  et al., 1982).

         Commercial diethylene glycol monoethyl ether containing
    ethylene glycol caused no irritation  per se when applied to rabbit
    skin for 24 h (Ogiso  et al., 1988).

         Irritation was assessed after injection of 0.1 ml diethylene
    glycol monoethyl ether intradermally into shaved guinea-pig
    abdominal skin. The test compound was graded as moderately irritant
    in this test. No irritant effects were observed in a 24 h patch test
    on shaved, intact abdominal skin of rabbits (Latven & Molitor,
    1939). Conversely, in an occluded patch test on abraded rabbit skin,
    irritant effects were reported with a primary irritation index of
    0.5 (Draize  et al., 1944).

         Wads of cotton saturated with 50% or 70% aqueous solutions of
    commercial grade diethylene glycol monoethyl ether were applied to
    depilated skin of rabbits, wounded by crossed cuts into the cutis
    and replaced daily until healing was complete. No adverse effects on
    healing were reported and scar formation was complete in 4-6 days.
    In similar tests in which major wounds were made by excising the
    epidermal and dermal layers and laying bare the underlying muscle,
    50% carbitol had no significant effect on the healing time relative
    to controls (mean 11.5 days); healing was somewhat prolonged with
    70% carbitol (19.5 days) (Cranch  et al., 1942).

    2.2.10  Special studies on pharmacological activity

         When 1 ml of a 25% aqueous, solution of diethylene glycol
    monoethyl ether was injected into the lymph sac of frogs weighing
    about 30 g, moderate central depression resulted. Diethylene glycol
    monoethyl ether had no effect on reflex excitability as assessed by
    the Turck method in the frog, but muscle response time to a minimal
    effective faradic stimulation of the nerve trunk in frog
    nerve-muscle preparations was slightly depressed (von Oettingen &
    Jirouch, 1931). A lack of effect on reflex reaction time in the frog
    by immersion of the leg was reported by Latven & Molitor (1939).

         Diethylene glycol monoethyl ether had a slight depressive
    action on rabbit ileum smooth muscle contraction using the Magnus
    protocol (von Oettingen & Jirouch, 1931) and in later studies the
    EC50 was found to be 1.21% ± 0.45% in Ringer's solution (Muir,

         Diethylene glycol monoethyl ether caused a marked depression
    and arrest of cardiac activity in perfused frog heart. Dilutions of
    1-4% had no effect on peripheral blood vessels in the Trendelenberg
    frog perfusion method but i.v. injection of a 50% solution to
    lightly anaesthetised rabbits caused a fall in blood pressure
    (von Oettingen & Jirouch, 1931).

         In a CNS-profile test, 3 NMRI male mice were dosed i.p. with
    increasing doses of diethylene glycol monoethyl ether. The minimum
    symptomatic dose was 5.0 g/kg bw at which there was ptosis,
    piloerection, hypothermia, muscle relaxation, inhibition of Haffner
    reflex and cyanosis. The material was classified as a neuroleptic.
    The ED50 in the inclined screen test was also found to be 5.0 g/kg
    bw (Budden  et al., 1979).

         In the rotating rod test on four NMRI male mice, diethylene
    glycol monoethyl ether was given in increasing doses i.p. and the
    time to dropping off measured at intervals after injection. The
    minimal effective dose was 300 mg/kg bw. In a balance rod test the
    ED50 was found to be 3.1 g/kg bw (Budden  et al., 1979).

         Diethylene glycol monoethyl ether potentiated the hexobarbitone
    sleeping time in female NMR1 mice. The ED50s for a doubling or
    quadrupling of the sleeping time were 0.7 (0.43-1.21) g/kg bw and
    2.4 (1.37-4.25) g/kg bw respectively (Budden  et al., 1979).

    2.3  Observations in humans

    2.3.1  Acute intoxication

         A 44-year old man ingested diethylene glycol monoethyl ether at
    doses of about 2 ml/kg bw. Kidney function was affected but there
    was no oliguria and only slight uraemia. Effects on nervous and
    respiratory functions were also reported (Brennaas, 1960).

    2.3.2  Special studies on skin irritation and sensitization

         Commercial grade diethylene glycol monoethyl ether was rubbed
    on the inner wrist surface for 5 mins daily on 10 consecutive days.
    Irritant effects were noted with 3/60 subjects showing congestion or
    papules, mainly originating at hair follicles and persisting for
    several hours (Cranch  et al., 1942). No irritant effects were
    evident in 48 h closed patch test on 5 male volunteers diethylene
    glycol monoethyl ether was applied at a concentration of 20% in
    petrolatum (Kligman, 1972).

         Patch tests were conducted on undiluted commercial grade
    diethylene glycol monoethyl ether (containing 30% ethylene glycol)
    in 99 subjects using 48 h exposure with subsequent examination at
    intervals up to 1 month. Slight positive reactions (faint erythema
    persisting for 48 h after removal) occurred in 24/99 subjects.
    Similar tests on aqueous dilutions of pure diethylene glycol
    monoethyl ether (0.2% ethylene glycol) or carbitol solvent were
    carried out on 31 subjects. No reactions were seen with 5% solutions
    of either material and a concentration-related increasing frequency
    of reactions (faint erythema) was seen at higher concentrations.
    Undiluted materials led to 14 reactions with the carbitol solvent
    and 5 reactions with the pure material (Meininger, 1948).

         In 48-h closed patch tests on 50% solutions of diethylene
    glycol monoethyl ether, 44% of volunteers showed erythema, oedema or
    vesicles, 18% definite erythema and 34% questionable erythema
    (Motoyoshi,  et al., 1984).

         Patch tests were conducted on commercial grade diethylene
    glycol monoethyl ether in 98 subjects using an initial contact
    period of 7 days, followed by 10 days withdrawal then a further 3
    day test period. Definite reactions were reported in 7/98 persons
    but a standardized scoring method was not used (Cranch, Smyth &
    Carpenter, 1942).

         Repeat patch tests using undiluted commercial grade diethylene
    glycol monoethyl ether (30% ethylene glycol) were carried out on 45
    subjects 4 weeks after initial tests. After a second exposure of
    48 h, examinations were carried out at intervals up to 1 month.
    Positive reactions (faint erythema restricted to test area) occurred
    in 15 subjects (Meininger, 1948).


         The Committee was informed that the use of diethylene glycol
    monoethyl ether as a carrier solvent for flavours could lead to
    carry-over levels as high as 1000 mg/kg in foods as consumed, but no
    data on potential daily intakes were available. In these
    circumstances, the principles previously developed for materials
    occurring in foods in small amounts (Annex 1, reference 76) were not
    applicable. Although the metabolism, reproduction and
    teratogenicity, and genotoxicity studies met some of the
    requirements of the Committee, information on chronic
    toxicity/carcinogenicity was still inadequate. In view of the
    apparent potential for relatively high exposure to this substance,
    the Committee was unable to allocate an ADI because of the lack of
    such information.

         In order to re-evaluate diethylene glycol monoethyl ether the
    Committee would require either:

         (a)  adequate data indicating that human intakes are
              sufficiently low for the principles applicable to
              materials occurring in foods in small amounts to apply:

         (b)  the results of an adequate carcinogenicity/chronic study
              in rats and mice.

         The Committee considered that, in the light of the data
    reviewed at the present meeting, the 6-month study in pigs requested
    at its twentieth meeting would not be needed for a re-evaluation.


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    See Also:
       Toxicological Abbreviations
       Diethylene glycol monoethyl ether (ICSC)
       Diethylene glycol monoethyl ether (WHO Food Additives Series 10)