Scientific Documents

Opinion of the Scientific Panel PPR related to the revision of Annexes II and III to Council Directive 91/414/EEC concerning the placing of plant protection products on the market - Toxicological and metabolism studies

Question number: EFSA-Q-2006-118
Adopted: 31 January 2007

Summary (63 KB)

Opinion (514 KB)

Annex (55 KB)


The PPR Panel has reviewed the proposed revisions to toxicological data requirements in Annexes II and III of Directive 91/414/EEC, as set out in the Commission Working Document, SANCO/10482/2006. The Panel concludes that the proposed revisions are generally appropriate in the context of current scientific understanding, but that there are a number of ways in which they could be improved or usefully augmented.

The PPR Panel makes the following main recommendations:
  • It should always be open to the notifier to submit a reasoned scientific argument as to why a particular study is not needed. Guidance on modifications to the standard data requirements may be helpful for some categories of plant protection product (e.g. pheromone mating disruptors).
  • As a general rule, the PPR Panel believes that the data requirements should specify the use of validated test protocols (accepted either by the EU or the OECD) where they are available and fit for purpose. Where no validated method is currently available, notifiers should justify their choice of non-standard tests, and provide details of their performance. Furthermore, should a suitable validated test be developed in the future, this should then be used in preference to non-standard tests.
  • To allow for the possibility that, in the future, benchmark doses may come to be viewed as a preferable reference point to No Observed Adverse Effect Levels (NOAELs), it may be better to refer in the data requirements to “reference points” rather than specifically to NOAELs.
  • Data requirements that are out of line with those of other regulatory agencies could in some circumstances lead to undesirable duplication of effort, with unnecessary use of animals. OECD protocols should therefore be referenced in the data requirements where they would be acceptable as alternatives to EU protocols. Furthermore, data requirements should be drafted in a way that facilitates harmonisation with those of other regulatory authorities as scientific understanding evolves, for example, by allowing, where appropriate, several alternative methods to address a particular aspect of the risk assessment.
  • The use of a tiered approach to toxicity testing is already embraced in some sections of the draft data requirements, and the PPR Panel believes that this strategy could be developed further in the future. In Section 1.3.2, the Panel identifies several other circumstances in which it believes that a tiered approach to data generation would be appropriate.
  • The PPR Panel recommends better integration of data on disposition and kinetics when interpreting the relevance of animal tests to toxicity in humans. In Section 1.3.2, the Panel discusses how this might be approached.
  • In general, the PPR Panel believes that there should be a drive towards use of fewer but more informative studies in toxicological risk assessment for plant protection products.
  • The value of several individual tests that currently form part of the standard data package for plant protection products – in particular, the 1-year dog study and the mouse carcinogenicity study – is questionable. The PPR Panel suggests that the need for these studies should be reviewed.
  • The draft data requirements incorporate separate exposure assessments for residents and bystanders. However, any exposure experienced by a bystander could also occur in a resident (since residents can be bystanders on the day of spraying). Thus, separate exposure assessments should only be necessary if the estimated exposures will be assessed against different reference values.
  • The PPR Panel believes there is a need for further scientific development in the assessment of potential exposures to operators, workers and bystanders/residents. To this end, the Panel proposes that an expert group be established to assess critically new predictive modelling approaches, and develop further guidance on the assessment of operator, worker and bystander/resident exposures.
  • The PPR Panel notes with concern the proposal in the draft data requirements that toxicological studies in humans should never be used to derive regulatory reference values. The Panel believes that this approach is both scientifically unsound and ethically dubious.
  • The PPR Panel recommends that where they are available, historical control data should be provided routinely in relation to studies of carcinogenicity, developmental toxicity and in vivo genotoxicity, and also for measurements of blood chemistry, haematological parameters and urinalysis in other studies. The data submitted should only be for endpoints that could represent critical adverse effects, and should be strain-specific and from the same laboratory as that which carried out the index study. They should come from a five-year period, centred as closely as possible on the date of the index study.
  • The PPR Panel considers that the assessment of findings from toxicological studies will be facilitated if, where possible, results are presented in a standardised format. To this end, the Panel suggests that guidelines be produced setting out templates for the reporting of results.
  • One area of development in regulatory toxicology, which the PPR Panel believes is not adequately reflected in the draft proposals is the consideration of combined toxicity, in particular where two or more active substances are co-formulated in the same product. The Panel suggests that in these circumstances, there should be a routine requirement for the notifier to provide adequate reassurance that adverse health effects will not occur as a consequence of combined action or interaction. In most cases, this should be possible through reasoned argument, but occasionally it might be necessary to generate additional data.
  • The PPR Panel notes that the draft data requirements in several places use terms such as “relevant” and “appropriate” without making clear exactly what is implied. Some guidance on this, with examples, might be helpful.
  • The PPR Panel anticipates that before the revised Annexes are finalised, their wording will be amended in some places to improve the clarity of the English. When such revisions are made, it will be important to check that the intended scientific meaning has not been altered or obscured.
  • It is important to ensure that the data requirements in each individual area of risk assessment for plant protection products are consistent with those for the other areas. Therefore, there needs to be an holistic check of all six proposed revisions to the data requirements before they are finalised.
In addition to these main recommendations, the PPR Panel makes specific comments and recommendations on various sections of the draft data requirements.

Published: 20 February 2007
Last updated: 20 February 2007