Residue limits

Council Regulation (EEC) No. 2377/90 of 26 June 1990 laying down a Commrmity procedure for the establishment of maximum residue limits for veterinary medicinal products in foodstuffs of animal origin. 

The previous chapters examined the process for the development and authorisation of a drug product containing a ne v active ingredient for human use. This represents the most arduous path to market for any medicinal product. This chapter proceeds to examine the process of bringing a veterinary medicinal product to market. While the process shares most of the principles that apply to human drugs, there are some additional features that are unique to veterinary products. These include methods of use and the requirement to evaluate vithdra val periods and maximum residue limits in food-producing species. 

A unique feature of the development of veterinary medicines for food-producing species is the need to consider the establishment of Maximum Residue Limits (M RLs) for the drug or its metabolites in food produce. A MRL is defined in the European Union as ... 

The Community procedure for establishing MRLs of veterinary medicines in foodstuffs of animal origin is set down in Council Regulation (EEC) No. 2377/90 as amended by Council Regulation (EC) No. 1308/1999. The regulations are supported by detailed guidance contained in The Rules Governing Medicinal Products in the European Union, Volume 8 - Maximum Residue Limits. 

Annex II No specific residue limits required for protection of human health Annex III Provisional MRLs valid for a maximum of 5 years... 

Annex IV No safe residue limits can be established. Substance may not be administered to food-producing animals... 

The outcome of the process will result in the inclusion of the substance in one of four Annexes to the regulation. If the conclusion is that safe M RLs can be established, then final MRLs for the substance are added to Annex I. A substance will be inserted in Annex II if it is concluded that residues cannot cause a risk to human health. If some uncertainty remains over the proposed MRLs, then these can be included in Annex III as provisional MRLs for a maximum period of 5 years. Finally, if it is concluded that no safe residue limits can be set, the substance is placed in Annex IV, which means that it cannot be used in medicines for treatment of food-producing animals (Table 7.3). 

The Rules Governing Medicinal Products in the European Union, Volume 8 -Maximum Residue Limits... 

Maximum residue limit Mass spectrometry Tandem mass spectrometry Material safety data sheet North American Free Trade Act N-Hydroxysuccinimide Nitrogen-phosphorus detection Neomycin phosphotransferase II Optical density Office of Plant Protection and Quarantine... 

Legislation related to residues limits for soil, water, and air... 

TheFood Sanitary Law in Japan, which is regulated by theMinistry of Health, Labor and Welfare (MHLW), has established maximum residue limits (MRLs) and monitors the residue levels in food commodities in the market, including both domestic and... 

Today, when a pesticide with no detectable residues is registered for use, a Tolerance or maximum residue limit (MRL) is established at the lowest concentration level at which the method was validated. However, for risk assessment purposes it would be wrong to use this number in calculating the risk posed to humans by exposure to the pesticide from the consumption of the food product. This would be assuming that the amount of the pesticide present in all food products treated with the pesticide and for which no detectable residues were found is just less than the lowest level of method validation (LLMV). The assumption is wrong, but there is no better way of performing a risk assessment calculation unless the limit of detection (LOD) and limit of quantification (LOQ) of the method were clearly defined in a uniformly acceptable manner. 

In this article, an analytical method is defined as series of procedures from receipt of a sample to final determination of the residue. Validation is the process of verifying that a method is fit for purpose. Typically, validation follows completion of the development of a method. Validated analytical data are essential for monitoring of pesticide residues and control of legal residue limits. Analysts must provide information to demonstrate that a method intended for these purposes is capable of providing adequate specificity, accuracy and precision, at relevant analyte concentrations and in all matrices analyzed. 

Codex Guideline EMRL(1)-1997, List of Codex Extraneous Maximum Residue Limits in Food , Codex Alimentarius Commission, Washington, DC (1997). 

Pesticide residues consist of chemicals that might occur in a commodity as a result of application of a pesticide. Such chemicals typically correspond to compounds for which a regulatory agency has or will set a tolerance, i.e., a maximum residue limit, specific to the commodity. In either a field study or a market basket survey, residues to be determined will be those which result from application of the specific pesticide that the study is intended to support. A market basket survey, however, might be intended to support not just one but several different pesticides of the same or different chemical classes. In addition, a market basket survey might include pesticides not used in the USA but for which import tolerances exist. For example, some uses of the parathion family of pesticides on food products have been abandoned in the USA but remain in other countries that export the products to the USA. A market basket survey offers a means to evaluate actual dietary exposures to residues of such pesticides. In addition, tolerance expressions frequently include multiple compounds, all of which must typically be determined in residue field trials. The sponsor of the market basket survey must decide whether to analyze for all compounds in the applicable tolerance expression or to restrict the program to selected analytes, such as the active ingredient. 

Development and Validation of a Proposed Regulatory Method, EMEA/CVMP/573100, Vol. 8, Veterinary Medicinal Products Establishment of Maximum Residue Limits (MRLs) for Residues of Veterinary Products in Foodstuffs of Animal Origin, Committee for Veterinary Medicinal Products, London (2001). Also available on the World Wide Web http //www.emea.eu.int/pdfs/vet/swp/057300en.pdf. 

Sulfonylurea herbicides are generally applied to crops as an early post-emergent herbicide. Crops that are tolerant to these herbicides quickly metabolize them to innocuous compounds. At maturity, residues of the parent compound in food and feed commodities are nondetectable. Metabolites are not considered to be of concern, and their levels are usually nondetectable also. For this reason, the residue definition only includes the parent compound. Tolerances [or maximum residue limits (MRLs)] are based on the LOQ of the method submitted for enforcement purposes and usually range from 0.01 to 0.05 mg kg (ppm) for food items and up to O.lmgkg" for feed items. There is no practical need for residue methods for animal tissues or animal-derived products such as milk, meat, and eggs. Sulfonylurea herbicides are not found in animal feed items, as mentioned above. Furthermore, sulfonylurea herbicides intentionally dosed to rats and goats are mostly excreted in the urine and feces, and the traces that are absorbed are rapidly metabolized to nontoxic compounds. For this reason, no descriptions of methods for animal-derived matrices are given here. 

In Japan, bifenox is the only registered diphenyl ether herbicide. The tolerance and/or maximum residue limits (MRLs) are established at 0.1 mg kg for cereals such as rice grain, barley and wheat, and 0.05mgkg for potatoes (Ministry of Health, Labour and Welfare, Japan). Ibe California Department of Food and Agriculture (CDFA) established the minimum detectable quantity of diphenyl ether herbicides at 0.1 mgkg for bifenox, nitrofen and oxyfluorfen. ... 

Quantitative immunoassays have also been used as screening devices to determine whether drug residues exceed established maximum residue limits (MRLs) or tolerances in edible tissues. " For these applications, a cut-off value is set at the tolerance or MRL samples detected above this level are positive , and samples below this level are negative. ... 

Table 3 Examples of therapeutic agent maximum residue limits (MRLs) (mg kg ) from EU and tolerance levels (TLs) (mgkg- )fromUSEDA ...

The European Community guidelines specify that the maximum residue limit (MRL) for alkylenebis(dithiocarbamates) in fruits and vegetables is 0.05 mg carbon disulfide (CS2)kg ... 

Confirmation of the identity of an analyte should be performed particularly in those cases in which it would appear that a maximum residue limit (MRL) has been exceeded or in which a compound seems to be present which is not to expected in the sample being analyzed. 

Oxime carbamates are generally applied either directly to the tilled soil or sprayed on crops. One of the advantages of oxime carbamates is their short persistence on plants. They are readily degraded into their metabolites shortly after application. However, some of these metabolites have insecticidal properties even more potent than those of the parent compound. For example, the oxidative product of aldicarb is aldicarb sulfoxide, which is observed to be 10-20 times more active as a cholinesterase inhibitor than aldicarb. Other oxime carbamates (e.g., methomyl) have degradates which show no insecticidal activity, have low to negligible ecotoxicity and mammalian toxicity relative to the parent, and are normally nondetectable in crops. Therefore, the residue definition may include the parent oxime carbamate (e.g., methomyl) or parent and metabolites (e.g., aldicarb and its sulfoxide and sulfone metabolites). The tolerance or maximum residue limit (MRL) of pesticides on any food commodity is based on the highest residue concentration detected on mature crops at harvest or the LOQ of the method submitted for enforcement purposes if no detectable residues are found. For example, the tolerances of methomyl in US food commodities range from 0.1 to 6 mg kg for food items and up to 40 mg kg for feed items. ... 

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