INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
TOXICOLOGICAL EVALUATION OF CERTAIN
VETERINARY DRUG RESIDUES IN FOOD
WHO FOOD ADDITIVES SERIES: 43
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
ß-ADRENOCEPTOR BLOCKING AGENT
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 µg/kg
BW.
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
µg/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 µg/kg bw. The Committee established an acute
RfD of 0.1 µg/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 µg/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 µg/kg for
muscle and fat or skin and 25 µg/kg for liver and kidney. The
concentration of residue at the injection site 2 h after treatment was
57 µg/kg (range, 31-83 µg/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 µg/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 µg, 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.
Reference
Codex Alimentarius Commission (1996) Report of the Tenth Session of
the Codex Committee on Residues of Veterinary Drugs in Foods, San
José, 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).