Page 160 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Regulatory Aspects for the Drugs and Chemicals Used in Food-Producing Animals Chapter | 7 127

VetBooks.ir (i.e., 500 g). For milk the denominator is 1.5 kg and for form, route of administration, or dosage regimen, the with-
drawal period stated in the product labeling applies only to
eggs 0.1 kg.
that particular formulation when administered via the
Drug Withdrawal/Withholding Periods recommended route and in accordance with the dose
regime. Alteration to any of these factors affects the phar-
A critical factor in the medication of all food-producing macokinetics behavior of the drug in the animal and inva-
animals is the mandatory withdrawal period, defined as lidates the withdrawal period.
the time during which a drug must not be administered In the EU a veterinary prescription is required for vet-
prior to the slaughter of the animal for consumption. The erinary products for food-producing animals. If it is nec-
withdrawal time is the period of time between the last essary for a VMP to be prescribed for a species for which
administration of a drug and the collection of edible tis- it is not licensed or at a dosage higher than the one
sue from a treated animal. The withdrawal period is an licensed, the veterinarian will specify an appropriate with-
integral part of the regulatory authorities’ approval pro- drawal period. In exceptional cases, where no medication
cess and is designed to ensure that no significant drug is authorized, there is a possibility for the veterinarian to
residue is present in the animal at slaughter. Drug resi- use, e.g., products that are authorized in other EU coun-
dues in food-producing animals should comply with the tries or for other animal species. This exception exists to
MRL values for their target tissues in the animal species. avoid unacceptable suffering of animals. In these cases
The withdrawal period is intended to ensure that no the veterinarian has to follow specific steps, the so-called
harmful residues remain in edible tissues after slaughter “cascade,” and has to make sure that there is no risk for
and it is usually established at slaughter time when resi- the animal(s) concerned and for consumers of food pro-
due levels in all the edible tissues are below the MRL. ducts of animal origin. The exceptional off-label (extra-
Compliance with the preslaughter withdrawal period label) (cascade) use of authorized medications is allowed
ensures that total residues deplete to below the safe con- under specific conditions described in Directive 2001/82/
centration, and the marker residues deplete to below the EC (EC, 2001) as amended by Article 11 of Directive
MRL. Adherence to the withdrawal period provides 2004/28/EC (EC, 2004b)(Table 7.10).
assurance that food derived from treated animals will not The veterinarian may administer the medicinal product
exceed the MRL for the drug substance. Failure to keep personally or allow another person to do so under the
the preslaughter withdrawal period while using veterinary veterinarian’s responsibility. For food-producing animals,
drugs is the major cause of violative drug tissue residues these provisions apply to animals on a particular holding
in food animal production in the EU. Even if the with- only. The pharmacologically active substances in the
drawal period involves only a few days or a few hours, medicinal products used must be listed in the Annex of
the resulting residues can violate the national regulations the Commission Regulation (EU) No. 37/2010 (Table 7.1,
against sale of adulterated foodstuffs, which can originate allowed substances) (EC, 2010). The pharmacologically
distortions of competition between member states of the active substances in the medicinal products must have
EU. Withdrawal period, based on the MRL, is fixed by been assessed according to Regulation (EC) No. 470/2009
the regulatory authorities and will take into account the on the residue limits of pharmacologically active sub-
use of veterinary drugs in avian species. Regulatory stances in foodstuffs of animal origin (EC, 2009c), and a
authorities determine withdrawal periods on the basis of veterinarian must specify an appropriate withdrawal
residue depletion data generated using healthy animals period, which shall be at least 7 days for eggs, 7 days for
representative of those normally treated with the veteri- milk, 28 days for meat from poultry and mammals (includ-
nary drug. For example, for the determination of the ing fat and offal), and 500 days for fish.
withdrawal period in avian species, six animals per
slaughter time are needed. An appropriate withdrawal INDUSTRIAL CHEMICALS
period is then established to ensure that the residues in
edible tissues are depleted below the MRLs. A with- The area of regulations covering industrial chemicals is
drawal period should be established for the substances one of increasing harmonization within the EU. This is
with MRLs included in Annex (Table 7.1) of Regulation particularly true with regard to the need for providing
(EC) No. 37/2010 (EC, 2010). The EMA recommends the adequate toxicity data on new chemicals, to allow any
harmonization of withdrawal periods using linear regres- potential hazard to humans to be identified, and in the
sion analysis of log-transformed tissue concentrations area of labeling of dangerous substances and preparations
determined at the time when the 95% upper one-side toler- (i.e., mixtures of substances). A key directive is Council
ance limit was below the MRL with 95% confidence Directive 67/548/EEC on the approximation of the laws,
(Anado ´n et al., 2008a,b, 2011, 2012). Unlike an MRL, regulations and administrative provisions relating to the
which applies to a veterinary drug regardless of the dosage CLP of dangerous substances, commonly referred to as