Erythrosine was evaluated for an acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives at its eighth,
    thirteenth, eighteenth, twenty-eighth and thirtieth meetings (Annex
    1, references 8, 19, 35, 66 and 73). Toxicological monographs were
    published after the thirteenth, eighteenth, twenty-eighth and
    thirtieth meetings (Annex 1, references 20, 36, 67 and 74). At its
    eighteenth meeting the Committee allocated an ADI of 0-2.5 mg/kg
    bw; this was reduced at the twenty-eighth meeting to 0-1.25 mg/kg
    bw and made temporary following observations that erythrosine
    produced effects on thyroid function in short term studies in rats
    and that, in long-term studies, male rats receiving 4% erythrosine
    in the diet developed thyroid tumours. At the thirtieth meeting,
    the Committee reduced the temporary ADI to 0-0.6 mg/kg bw, based on
    studies of the biochemical effects of erythrosine on thyroid
    hormone metabolism and regulation and required further data from
    pharmacokinetic studies relating the amount of absorption to the
    amount ingested, which would enable a correlation to be established
    between blood/tissue levels of erythrosine and effects on the

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following
    monograph addendum.

    Observations in man

         Thirty normal men were divided into three groups and were
    given erythrosine orally (in capsules) for 14 days at doses of 20,
    60 or 200 mg/day. Assays for serum T4, T3, reverse T3, T3-
    charcoal uptake, thyrotropin (TSH), protein bound iodine (PBI),
    total iodide and total urinary iodide excretion were carried out on
    days 1, 8 and 15; TRH test were performed on days 1 and 15.

         There were no significant changes in serum T3, T4, rT3 and
    T3-uptake in any group. In the top dose group (200 mg/day), the
    mean basal serum TSH concentration increased from 1.7  0.1 on day
    1 to 2.2  0.1 U/ml on day 15 (p< 0.05) and the mean peak TSH
    increment after TRH increased from 6.3  0.5 to 10.5  1.0 U/ml
    (p< 0.05). There were no significant changes in basal or peak TSH
    responses at the two lower dose levels. Significant dose-related
    increases in serum total iodide and PBI concentrations occurred in
    all three groups and significant dose-related increases in urinary
    iodide excretion occurred in the 60 and 200 mg/day dose groups.

         These data were taken to indicate that the increase in TSH
    secretion was related to the effect of increased serum iodide
    rather than a direct effect of erythrosine on thyroid hormone
    secretion or peripheral metabolism (Gardner et al., 1987).

         The statistical design and interpretation of the preceding
    study (Gardner et al., 1987) has been re-evaluated independently
    in relation to the effects on basal TSH concentration and maximum
    TSH increment after TRH provocation. With respect to basal TSH, it
    was suggested that there was no statistical evidence for variation
    due to treatment over the dose range studied when appropriate
    statistical methods were used to control for apparent initial
    differences among treatment groups. The maximum TSH increment
    following TRH provocation did show a slight but significant
    increase in the top dose group (200 mg/day) only (Crump & Farrar,

         In a study designed to determine whether relatively small
    supplementary amounts of iodine in the diet would affect thyroid
    function, normal, euthyroid human subjects received 250, 500 or
    1500 g iodine daily for 14 days; the doses were selected to
    correspond to the amounts of iodine that might be bioavailable from
    the doses of erythrosine used in the study by Gardner et al.,
    (1987). Following administration of 1500 g/day there were small
    but significant decreases in serum T4 and T3 concentrations, a
    small compensatory increase in serum TSH concentrations and in the
    TSH response to TRH. However, all values remained within the normal
    range. In contrast, no changes occurred following daily
    administration of 250 or 500 g I2 (Paul et al., 1987).


         Additional human studies confirmed that erythrosine is poorly
    absorbed. The data did not indicate the mechanism by which
    erythrosine exerted its effect on the thyroid; however, it appeared
    that inorganic iodine  per se was not the causative agent. The
    no-effect-level with respect to thyroid function in man was 60 mg
    per person per day (equivalent to 1 mg/kg bw/day). The effect on
    thyroid function detected at a higher dose level of 200 mg per
    person per day was a small change in thyrotropin responsiveness to
    thyrotropin releasing hormone.

         The pharmacokinetic studies required by the previous Committee
    were not forthcoming, therefore it was decided to extend the
    temporary acceptable daily intake pending the results of such


    Level causing no toxicological effect

         Man: 60 mg/day (approx. 1 mg/kg bw/day) (Based on effects on
    thyroid metabolism in a 14-day study).

    Estimate of temporary acceptable daily intake for man

         0-0.05 mg/kg bw.

    Further work or information

    Required (by 1990)

         Pharmacokinetic studies which relate the amount of absorption
    to the amount ingested which would enable a correlation to be
    established between blood/tissue levels of erythrosine and effects
    on the thyroid, and which may elucidate the mechanisms of thyroid


    Crump, K.S. & Farrar, D.B. (1987). Effects of erythrosine on basal
    and TRH-stimulated TSH levels: Statistical re-evaluation of data
    from Gardner et al. (1986). Unpublished report of Clement
    Associates Inc., Washington, DC. Submitted to WHO by Certified
    Color Manufacturers Association Inc.

    Gardner, D.F., Utiger, R.D., Schwartz, S.L., Witorsch, P., Meyers,
    B., Braverman, L.E. & Witorsch, R.J. (1987). Effects of oral
    erythrosine on thyroid function in normal men.  Toxicol. Appl.
     Pharmacol., 91, 299-304.

    Paul, T., Meyers, B., Witorsch, R.J., Pino, S., Chipkin, S.,
    Ingbar, S.H. & Braverman, L.E. (1987). The effects of small
    increases in dietary iodine on thyroid function in euthyroid
    subjects.  Metabolism (in press).

    See Also:
       Toxicological Abbreviations
       Erythrosine  (FAO Nutrition Meetings Report Series 46a)
       Erythrosine (WHO Food Additives Series 6)
       Erythrosine (WHO Food Additives Series 19)
       Erythrosine (WHO Food Additives Series 21)
       Erythrosine (WHO Food Additives Series 28)
       Erythrosine (WHO Food Additives Series 44)
       ERYTHROSINE (JECFA Evaluation)