In cases where use of a radiolabel is not mandatory their use is often preferred in the Guidance, particularly when information on pathway transformation is required and in order to establish a mass balance.
Recent Guidance Mentioning Radiolabelled Compounds use in Regulatory Studies
EPA and EU guidance on the registration of active substances for pesticide and veterinary use is complex and subject to constant revision. Recently attention has focussed on requiring studies on relevant stereoisomers. New guidance in 2016 from the EMA on poorly extractable substances, most often seen in a soil matrix, recommends using radiolabelled analytes while SANCO 11187/2013 covers pesticide residues in Fish and specifies that studies should be carried out with radiolabelled substances.
New data requirements
For EU Directive 1107/2009 the data requirements were set out in SANCO 11802 (2010) and formalised in Regulations 283/2013 (Active Substance) and 284/2013 (Plant Protection Products) which applied to new compounds from 1 January 2014 and for dossiers with existing AIs submitted after 31 December 2015.
Its full force applies to AIR-3 re-registrations (subject to any translational considerations) and to the AIR-4 re-registrations.
Toxicokinetics (OECD 417)
Toxicokinetics (in vivo) recommend using a 14C Radiolabel unless it can be adequately evaluated using the unlabelled test substance and the analytical specificity and sensitivity of the method is at least equivalent to that using a radiolabel. The radiolabel is most useful for measurements on tissue distribution, biotransformation (i.e. metabolism), excretion, mass balance and time course studies on plasma/blood kinetics. Data requirements usually involve a single species.
Pesticide Registration in the European Union
In the EU, with Regulations 283/2013 (Active Substances) and 284/2013 (Plant Protection Products) now in full force, the use of radiolabelled compounds for studying pesticide metabolism, distribution and expression of residues studies; in crops (OECD 501 & 502), livestock (OECD 503) including lactating goats and laying hens, and in soil (OECD 307), is mandatory. Moreover, if risk assessment requires studies on the effects of processing on residues, then these studies must also be conducted with radiolabelled compounds (OECD 507). These data requirements apply to AIR-3 active substance re-registrations, subject to any transitional arrangements.
Use of radiolabelled compounds in Ecotox bioaccumulation studies (OECD305, 315 & 317) may be optional but their use, when available, aids interpretation and provides the best tool for quantification and recovery.
Environmental fate studies on the fate of compounds in Aerobic and Anaerobic metabolism in soil require a radiolabel as does inherent biodegradability (OECD304) and biodegradation in sea water (OECD306). Radiolabel is recommended for transformation in water (OECD308), surface water mineralisation (OECD309), biodegradability in waste water (OECD314) and phototransformation on the soil surface (OECD in draft) studies.
"Results obtained shall be presented in the form of schematic drawings showing the pathways involved and in the form of balance sheets which show the distribution or radio-label as a function of time (EU 283/2013)."
Guidance on the establishment of the residue definition for dietary risk assessment
The European Food Safety Authority (EFSA) Panel on Plant Protection Products and their Residues issued Guidance in July 2016* on the establishment of the residue definition to be used for dietary risk assessment in line with Commission Regulation (EU) No 283/2013 setting out the data requirements for active substances, in accordance with Regulation (EC) No 1107/2009 of the European Parliament, in line with OECD guidance (2009).
The following elements shall be considered when judging which compounds are to be included in the residue definition for risk assessment:
• the toxicological significance of the compounds;
• the amounts likely to be present.
*doi: 10.2903/j.efsa.2016.4549
This guidance, describes a stepwise approach on the basis of factual information (derived from toxicological data and metabolism data) and non-testing methods, not only the active substance but also any residue in general, including metabolites, degradates, transformation products, and includes information on the possible metabolic conversion of isomers for active substances consisting of a mixture of isomers.
Metabolism studies are in general performed with the radiolabelled parent compound. Such studies in plants and livestock as well as studies simulating food processing conditions aim at identifying the nature and, to a certain extent, the quantity of individual residue compounds in commodities at stages of intermediate and commercial harvest and in by-products. Metabolism studies form the basis for the proposal of the residue definitions while field studies with the non-radiolabelled active substance are destined to support robust quantitative assessments of residue components.
The residue definition should consider all compounds that are of toxicological significance for human and livestock, taking into account the amounts likely to be present in food and feed. It is therefore necessary to consider aspects of both toxicity and dietary exposure to residues and to account for the use specific residue pattern in food commodities of plant origin as well as in animal commodities that result from livestock exposure via feed.
Selcia specialise in providing GLP certified radiolabelled compounds for metabolism studies and can help with structural elucidation of metabolites, using high field GLP capillary NMR and mass spec., on both radiolabelled and non-radiolabelled metabolites.
Examples of studies where Radiolabelled compounds may be used can be found on the following pages:
Examples of EU studies where Radiolabelled Compounds may be used