Synonyms                      Dulcin; Sucrol; Valzin

    Chemical name                 4-Ethoxyphenylurea

    Empirical formula             C9H12O2N2

    Structural formula


    Molecular weight              180.21

    Description                   Colourless or white crystals, or a
                                  white crystalline powder, which is
                                  odourless and has a very sweet taste
                                  which is appreciable even after a
                                  3000-fold dilution.

    Biological Data

    Biochemical aspects

         Early experiments indicated p-aminophenol as a metabolite in
    human urine after oral intakes at 1 g of 4-ethoxyphenylurea (Rost &
    Braun, 1926). More recent studies in rabbits and rats, given oral or
    intragastric: 4-ethoxyphenylurea at the rate of 500 mg/kg body-weight,
    showed rapid absorption into the blood within 3 hours and slow
    disappearance from the body. Three per cent. was excreted in the urine
    in 48 hours, none appeared in the faeces, the rest being metabolized
    slowly. Most tissues except fat contain 4-ethoxyphenylurea which
    disappears slowly (Akagi & Aoki, 1962; Akagi et al., 1965).
    Twenty-three per cent. 4-ethoxyphenylurea is absorbed from rat stomach
    within 1 hour end over 80 per cent. absorbed from rat small intestine
    within 2 hours, probably by simple diffusion (Kojima et al., 1966).

         In the rabbit 4D per cent. of orally administered
    4-ethoxyphenylurea is de-ethylated to p-hydroxyphenylurea as the
    principal metabolite. This appears in the urine either as free
    compound (7 per cent.) conjugated as O-sulfate (23 per cent.) or as
    O-glucuronide (11 per cent.). Three per cent. of 4-ethoxyphenylurea ix
    excreted unchanged as p-ethoxyphenylurea 27 per cent. as
    N-glucuronide or p-ethoxyphenylurea, which appears to be the major
    common pathway for disposal of arylureas, and a trace as
    p-ethoxyphenylurea sulfamate. Small amounts of p-phenetidine,
    p-aminophenol and urea have also been isolated (Akagi & Aoki, 1962;
    Akagi et al., 1966).

    Acute toxicity


    Animal         Route     LD50             References

    Mouse          oral      700-1000         Tanaka, 1964

    Rat (young)    oral      4900 )           Bekemeier et al., 1958
        (adult)    oral      3200 )

    Dog            oral      1000 (LD)        Flury

         Doses of 0.4-0.6 g/day caused ataxia, vomiting and weight loss in
    dogs but O.1 g/day for 30 days had no adverse effects. Similar effects
    were seen in monkeys, cats and guinea-pigs (Rost & Braun, 1926).

    Teratogenicity studies

         Mouse. Groups of 3 or 4 female mice were mated and given 50
    mg/kg body-weight 4-ethoxyphenylurea intragastrically on days 8-10 and
    6-7 post-conception, 30 mg/kg body-weight on days 6-7 post-conception
    and 10 mg/kg body-weight on days 4-5 post-conception. Foetuses were
    examined on the eighteenth day of pregnancy. 50 mg/kg had no
    deleterious effect on development or foetal survival on days 8-10, but
    retarded development and caused foetal death on days 6-7. Similar
    effects occurred with 30 mg/kg and 10 mg/kg, including subnormal, as
    well as retarded development in almost all foetuses (Tanaka, 1964).

    Long-term studies

         Rat. Groups of 7-10 male and 7-9 female rats were fed 0, 0.01,
    0.1, 0.25, 0.5 and 1.0 per cent. 4-ethoxyphenylurea in their diet for
    up to 2 years. Survival and growth rate were adversely and
    significantly affected in the 0.5 and 1.0 per cent. groups. The
    weights of liver, kidney and spleen were significantly raised at the
    0.5 and 1.0 per cent. levels. Histopathology showed liver tumours,

    some benign some malignant, at the 0.1 per cent. and higher levels.
    Splenic enlargement also occurred at the 0.1 per cent. level with
    congestion, hyperplasia and haemosiderosis. Pigmentation of the renal
    proximal convoluted tubules and anaemia were noted at the 0.5 and 1.0
    per cent. levels (Fitzhugh et al., 1951). In another experiment,
    groups of 15 young and adult rats were given 0.2 g 4-ethoxyphenylurea
    per animal daily for up to 22 months. No malignant tumours were noted
    (Lettre & Wrba, 1955). In another experiment, 20 male and 30 female
    rats were given 0.2 g 4-ethoxyphenylurea/kg body-weight
    intragastrically daily for 13 months without any adverse effects being
    noted on organ weight or tumour incidence; but 60 per cent. of the
    animals died during this time. No deleterious effects were noted on
    fertility, litter size and development of pups. Thirty-nine males of
    the F1 generation were kept on 0.2 g 4-ethoxyphenylurea/kg daily for
    22 months without any noticeable effect on weight gain, incidence of
    malignant tumours or mortality (Bekemeier et al.,  1958). In another
    experiment groups of 30 rats were fed 0 or 1.0 per cent.
    4-ethoxyphenylurea in the diet for 21-24 months. Over 75 per cent. of
    test animals developed tumours (1/3 malignant) of the urinary tract,
    66 per cent. had also stones of the renal pelvis and bladder.
    Splenomegaly and haemosiderosis of the spleen were also noted
    (Griepentrog, 1959).


         Up to 0.6 g daily in 4 male and 7 female volunteers and 0.1 g
    daily for 14 days in 30 volunteers produced no adverse effects and no
    evidence of p-aminophenol in the urine (Rost & Braun, 1926). Two
    deaths, accompanied by abdominal pain, vomiting, coma and fits, have
    been reported in children after an intake of 8-10 g. Doses of 20-35 g
    taken by adults produced dizziness, nausea, methaemoglobinuria with
    cyanosis, hypotension, dyspnoea, paraesthesiae, and coronary
    disturbance in one case (Buhr, 1948).

         Five volunteers received approximately 0.11 9 4-ethoxyphenylurea
    daily for 41 weeks without any apparent ill effects; 1.5 g/day for 3
    weeks is harmless to man, apart from slight temperature lowering.
    Diabetics have received 4-ethoxyphenylurea for 1 year without
    deleterious effects (Roest & Braun, 1926).


         Biochemical studies show that 4-ethoxyphenylurea is rapidly
    absorbed and slowly excreted. In the rabbit the greater amount is
    excreted in the urine as metabolites, of which the principal one is
    the de-ethylated 4-ethoxyphenylurea, p-hydroxyphenylurea. Early
    human studies indicated that approximately 0.1 g daily had no
    deleterious effects; however, long-term studies in rats revealed
    tumour production at relatively low dosage levels. In one study
    dietary levels of 0.1-1.0 per cent. 4-ethoxyphenylurea produced liver
    tumours, and in another a level of 1.0 per cent. produced malignant
    bladder lesions and urinary stones. Other studies at 0.2 and 0.3 per

    cent. levels did not confirm either observation. Therefore long-term
    animal studies are inconclusive.


         The data are not satisfactory for the evaluation of
    4-ethoxyphenylurea as an artificial sweetener in foods. Although the
    substance has been used by humans without any observed deleterious
    effect, animal studies indicate that 4-ethoxyphenylurea may possess
    tumourigenic properties. Until satisfactory studies are completed to
    show that 4-ethoxyphenylurea is safe this substance should not be used
    as a food additive.


    Akigi, M. & Aoki, I. (1962) Chem. Pharm. Bull., 10, 200

    Akagi, M., Oketani, Y. & Vematsu, T. (1965) Chem. Pharm. Bull.,
    13, 1200

    Akagi, M., Aoki, I. & Vematsu, T. (1966) Chem. Pharm. Bull., 14, 1

    Bekemeier, H., Hannig, E. & Pfennigsdorf, G. (1958) Arzneim.-
    Forsch., 8, 150

    Buhr, G. (1948) Med. Klinik, 43, 105

    Fitzhugh, O. G., Nelson, A. A. & Frawley, J. P. (1951) J. Amer.
    Pharm. Assoc., 60, 583

    Griepentrog, F. (1959) Arzneim. Forseh., 9, 123

    Kojima, S., Ichibagase, H. & Iguchi, S. (1966) Chem. Pharm. Bull.,
    14, 965

    Lettre, H. & Wrba, H. (1955) Naturwiss., 42, 217

    Rost, R. & Braun, A. (1926) Arb. Reichsg. Amter, 57, 212

    Tanaka, R. (1964) Jap. J. Public Hlth, 11/14, 909

    Flury, F. Abderhaldens Handbuch 4, 7b, 1345

    See Also:
       Toxicological Abbreviations