This content is current only at the time of printing. This document was printed on 15 December 2018. A current copy is located at https://apvma.gov.au/node/1015
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Extrapolation of data: isomers (Residues)
This guideline establishes the requirements for:
- residue trials when the active constituent (or technical grade active constituent) has various isomeric forms
- residue data when the isomeric form (or ratio of the isomers) of the active constituent is changed.
It should be read in conjunction with the Food and Agriculture Organization of the United Nations’ 1990 guidelines for residue trials, OECD Guidance Documents and Test Guidelines and the other APVMA residue guidelines referenced herein.
Residue guidelines have been written, or are being written, to cover specific agricultural and veterinary chemical situations in which residues may occur in crops or animals. These guidelines should be used as the basis for any residue work undertaken according to the type of product and the situation that is being addressed. In many cases, there is a specific guideline that covers a specific type of study. The residue guideline that applies to specific types of products or situations should always be consulted and followed where relevant.
The purpose of this guideline is to cover those situations in which the active constituent (or technical grade active constituent) has different isomeric forms or where the isomeric composition of the active constituent is altered after registration of the parent product. The changed active constituent will still require approval. The requirements of this guideline are additional to those specified in the guidelines that apply to specific products and situations.
2. Maximum residue limits and isomeric forms of active constituents
Maximum residue limit (MRL) proposals are mainly based on the results of supervised trials conducted under maximum treatment regime test conditions. The chosen test conditions should predict the highest residues that may reasonably arise and be representative of conditions encountered in normal, accepted agricultural practice or animal husbandry.
MRLs are legal limits that are used:
- for enforcement purposes
- for the initial theoretical estimation of consumer exposure to residues of agricultural and veterinary chemicals
- for facilitating trade.
They are established after evaluation of a standard set of data that includes residue studies conducted under supervised conditions.
Some active constituents used in agricultural and veterinary chemicals have different isomeric forms. The ratio of isomers in an active constituent varies to some extent even under standardised synthesis conditions, which means that one batch of active constituent may have a slightly different isomer mix to the next batch. Normally, however, the variation is not significant and is adequately described in the original active constituent specification.
It is common for one or more isomers of an active constituent to be biologically inactive or to possess low activity. At the same time, those isomers may be toxicologically different. Manufacturers sometimes develop new production processes that significantly alter the isomer mix in an active constituent in favour of the form that is more biologically active. This may lower the cost of the product and reduce the output of ‘unnecessary’ chemical onto crops, into animals, and into the environment.
Active constituents that contain different isomeric forms or varying ratios of isomers require special consideration from a residue and toxicology point of view.
3. General principles—new active constituent
3.1. Residue definition and analytical method
Table 3 of the MRL standard lists the residue definitions for agricultural and veterinary chemicals. In the case of active constituents with isomeric forms, the residue definition is usually the sum of all isomers of the compound. This takes into account the toxicological significance of all isomers. Therefore, for products whose active constituent is composed of different isomers, you will need to submit residue analysis method(s) capable of detecting, individually or in total, all isomers of the compound and their metabolites of toxicological significance. For further guidance, refer to the guideline, Definition of residues for the purpose of setting a maximum residue limit.
3.2. Standard residue trials
If you propose to define the residue as ‘the sum of all isomers’, you should conduct the residue trials in accordance with the relevant APVMA guideline using the analysis method that detects all isomers. In this situation, the residue trial is conducted in the same way as any other residue trial.
4. General principles—changed isomeric mixture
A change in isomeric mixture occurs when the isomeric ratio alters by more than 25 per cent and the dose or application rate remains the same as that originally registered.
The usual reason for reconsidering an MRL, withholding period, and residue decline pattern for an isomeric active, aside from a new use pattern, is because of an improved production process that ‘purifies’ the active constituent by removing, or not generating, all or some of the biologically inactive isomers.
Such a situation gives rise to the following requirements.
- Changes to the isomeric composition of an active constituent may result in changes to the metabolic profile of the compound. You should provide argument that addresses the potential change to the compound’s metabolism.
- If the original analytical method measured all isomers, you do not need to develop a new analytical method.
- If biologically inactive isomers have been removed from the active constituent and the same amount of biologically active isomer is applied to the crop or animal, you only need to demonstrate that the maximum use rate complies with the existing MRL. Provision of bridging data is sufficient in most cases.
Trial results should be reported according to the requirements of the guideline, Reporting of residue trials.