Prepared by the Fifty-second meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)

    World Health Organization, Geneva, 2000
    IPCS - International Programme on Chemical Safety


    CARAZOLOL (addendum)

    First draft prepared by L. Ritter
    Canadian Network of Toxicology Centres
    Department of Environmental Biology, University of Guelph, Guelph,
    Ontario, Canada

         Carazol is a nonspecific beta-adrenoceptor blocking agent that is
    used primarily in pigs to prevent sudden death due to stress during
    transport. It was reviewed by the Committee at its thirty-eighth and
    forty-third meetings (Annex 1, references  97 and  113). At its
    forty-third meeting, the Committee established an ADI of 0-0.1 g/kg

         The Tenth Session of the Codex Committee on Residues of
    Veterinary Drugs in Foods (Codex Alimentarius Commission, 1996)
    reviewed the issue of the safety of residues of pharmacologically
    active drugs at injection sites. In particular, it noted that the goal
    should be to ensure that the presence of residues at injection sites
    did not pose a risk to human health  The Codex Committee noted in
    particular that the 'calculation of risk' due to consumption of
    residues at the injection site should be based on the principle of an
    acute reference dose (acute RfD). The no-observed-effect level (NOEL)
    for the acute RfD would be based on the effects of a single dose that
    was of toxicological and/or pharmacological relevance.

         The Committee considered the beta-adrenoceptor-blocking activity
    of carazolol to be a relevant acute effect and concluded that the
    establishment of an acute RfD was appropriate in this case.

         The Committee had previously reviewed data on the
    beta-adrenoceptor-blocking activity of carazolol in rabbits and in
    volunteers. The latter studies were conducted in healthy subjects and
    in patients suffering from either chronic bronchitis or asthma. In a
    study of the capacity of 12 volunteers to perform physical exercise,
    cardiac function was determined after administration of a single oral
    dose of 5 or 7.5 mg of carazolol per person. A no-effect level of 10
    g/kg bw was extrapolated from the dose-response curve. A second
    study, involving patients suffering from either chronic bronchitis or
    asthma, was also reviewed by the Committee. Groups of five patients
    who received a single oral dose of 0.1 or 0.7 carazolol had reduced
    respiratory function, measured as vital capacity and forced expiratory
    volume, 2 h later. The overall NOEL in this study was calculated by
    extrapolation to be 0.5 g/kg bw. The Committee established an acute
    RfD of 0.1 g/kg bw on the basis of a reduction in respiratory
    function in compromised subjects and a safety factor of 5. A safety
    factor was used because the NOEL was observed in highly sensitive
    individuals with chronic bronchitis or asthma, who form a substantial
    part of the general population. The acute RfD provides a margin of

    safety of 100 in healthy subjects, and the Committee concluded that it
    therefore made adequate allowance for variation among individuals in
    the population. The Committee noted that the value of the acute RfD
    was the same as that for the ADI established by the Committee at its
    forty-third meeting. 

         At its forty-third meeting, the Committee evaluated the results
    of a study of the depletion of residues of carazolol in pigs. Sixteen
    pigs were given carazolol at 10 g/kg of body weight in the neck by
    intramuscular injection and were then slaughtered in groups of four 2,
    12, 18, and 24 h after treatment. Since carazolol is used specifically
    in pigs being transported to slaughter, the data obtained at 2 h were
    used to recommend maximum residue limits for carazolol of 5 g/kg for
    muscle and fat or skin and 25 g/kg for liver and kidney. The
    concentration of residue at the injection site 2 h after treatment was
    57 g/kg (range, 31-83 g/kg); none was detectable at 12 h. As there
    were no data on the concentrations of residues between 2 and 12 h
    after treatment, the Committee used the data at 2 h to estimate the
    concentration of residues at the injection site. If that concentration
    were 60 g/kg and if 300 g of injection-site muscle were ingested, the
    acute RfD would be exceeded; the dietary intake of parent carazolol
    would be 18 g, or three times the acute RfD.

         Consumption of residues of carazolol at the injection site 2 h
    after treatment could result in an intake that exceeds the acute RfD.
    Therefore, unless appropriate measures can be taken to ensure that the
    concentrations of residues at the injection site do not result in
    intake exceeding the acute RfD, use of carazolol during the transport
    of animals to slaughter is not consistent with safe use of the drug.


    Codex Alimentarius Commission (1996) Report of the Tenth Session of
    the Codex Committee on Residues of Veterinary Drugs in Foods, San
    Jos, Costa Rica, 29 October-1 November 1996. Rome, Food and
    Agriculture Organization of the United Nations (unpublished document
    ALINORM 97/31A; available from FAO or WHO).

    See Also:
       Toxicological Abbreviations