Dichlorvos is an organophosphate insecticide that acts by inhibiting acetylcholinesterase (AChE), which results in a disturbance of nerve signal transmission and induces rapid respiratory failure in most insects. The same mechanism is responsible for the acute toxicity in mammals, including humans. The only use of dichlorvos supported by the applicant is against flower bulb pests during storage.The Scientific Panel on Plant health, Plant protection products and their Residues (PPR Panel) of EFSA was asked if i) related to the increased incidence of tumours observed in various tissues in rats and mice following dichlorvos exposure, it is possible to identify a mode of action (for any of the tumours) and if so, is it possible to set a threshold for this effect; and ii) in considering any identified modes of action for the tumourigenic responses to dichlorvos, is any of them relevant for humans.Dichlorvos has been evaluated for carcinogenicity in five long-term studies in mice and in six long-term studies in rats. The substance was administered orally via the diet in the drinking water or by gavage, or by inhalation (one study in rats). Most of the studies provided no evidence for the induction of neoplasia and only in two gavage studies, one in F344/N rats and the other in B6C3F1 mice, was there some evidence for neoplastic responses. In these studies, increases in the incidence of mononuclear cell leukaemia in male rats, mammary fibroadenomas combined with adenomas in female rats, pancreatic acinar adenomas in male rats and forestomach tumours in male and female mice were reported. After considering all of the available data the PPR Panel concluded that with the exception of tumours of the forestomach in mice, there was no convincing evidence for a compound-related increase in tumour incidence. The response on mouse forestomach was a consequence of local, rather than systemic, exposure.The PPR Panel concluded that the available data clearly demonstrate that dichlorvos is an in vitro mutagen, and that there is some limited evidence that dichlorvos is a site-of-contact in vivo mutagen but that the mechanism of this effect is unclear; the evidence for alkylation of DNA in vivo, a possible mechanism, is very weak.The Panel concluded that there was insufficient evidence to identify a mode of action for the forestomach tumours produced by dichlorvos in the mouse. However, the Panel concluded that irrespective of the mode of action, the response appeared to be a consequence of the high sustained local concentrations of dichlorvos that could be achieved in this specific exposure situation and was therefore limited to this site. The Panel further concluded that there was a threshold dose for this response. The Panel was of the opinion that the weight of evidence suggests that this would not occur at the levels of exposure that would be encountered by the proposed use of the compound. In addition severe systemic toxicity would occur before any concentration in tissues other than in the forestomach is reached that would induce the tumourigenic effect. This is because the forestomach is a unique structure that retains material appreciably longer than the glandular stomach and oesophagus.

The Scientific Panel on Plant Health, Plant Protection Products and their Residues (PPR Panel) was asked to provide observations and/or possible recommendations on draft 9 of the Guidance Document (GD) for the establishment of Acceptable Operator Exposure Levels (AOELs), in particular on the methodology and the approaches presented. The PPR Panel reviewed the draft GD and provided some general and a number of specific comments.The PPR Panel is of the opinion that the results of tests involving humans when ethically and scientifically acceptable should be used to derive reference values, including AOELs, and not be considered simply supportive of reference values derived from animal data. However, this position should not be interpreted as condoning the injudicious study of human subjects involving deliberate or intentional exposure.The PPR Panel is of the opinion that the term bystander needs to be clearly defined and appropriate risk assessment developed, if deemed necessary for this category. In particular, the PPR Panel is of the opinion that the term bystander should refer to non-professional exposures. Consequently, the AOEL concept cannot be applied to bystanders and a different risk assessment procedure should be developed.The PPR Panel is also of the opinion that the GD should focus only on the specifics of the AOEL in order to avoid incurring the risk of being unclear or of missing some relevant points, especially when discussing issues that are common to risk assessment of any possible human exposure to chemical substances.The PPR Panel is of the opinion that the GD should comment on the potential role of physiologically-based pharmacokinetic modelling1. In fact, although unlikely to be adopted routinely for the present time, it is anticipated that its application in areas such as AOEL setting will increase. Amongst its advantages, it can help improve route-to-route, dose and species extrapolation, in evaluating inter-individual variability, and in using quantitatively human data derived in vitro.In general, the PPR Panel points to the need to refer to other existing GDs or international consensus documents, to avoid duplications of efforts or inconsistencies. The PPR Panel made also comments related to the combined exposure to more than one active ingredient, acute local effects and sensitisation, as compared to respiratory/inhalatory effects, the threshold for the toxicological consequences of interaction with DNA, the distinction between DNA-reactive genotoxicants/carcinogens and non-DNA-reactive genotoxicants/carcinogens, the possibility of using LOAELs in the absence of NOAELs, the determination of bioavailability, and choice of the relevant study for AOEL establishment based on study duration.

The Scientific Panel on Plant Health, Plant Protection Products and their Residues (PPR Panel) was asked by EFSA for an opinion on the ecotoxicological relevance of observed parameters in long term toxicity studies on mammals in the field, and the most appropriate parameter and study to assess the long term risk to mammals. The PPR Panel was further asked how these endpoints can be used in an appropriate refined assessment of long-term risk to mammals, including interpretation of the magnitude of effects in such studies.The PPR Panel divided the breeding cycle of mammals into four key phases for the purposes of risk assessment. These were: pre-breeding up to mating, pregnancy, pup growth, and postweaning development and survival.The PPR Panel then identified test endpoints relevant to each phase. Information on all of the suggested endpoints is normally available from standard toxicology studies. For some endpoints (e. g. body weight) it may be necessary to re-evaluate the endpoint for the exposure period relevant to the ecotoxicological assessment.The PPR Panel emphasises that there are limited data and knowledge on most of the endpoints, and on the quantitative relationships between effects on test species in the laboratory and effects on wild mammals in the field. Therefore the suggested endpoints should be kept under review as new findings emerge.The PPR Panel has outlined some options for using the suggested endpoints in risk assessment. The key element is the use of appropriate time periods for estimating exposure. These vary from endpoint to endpoint.For some endpoints, it is appropriate to compare the No Observed Effect Level (NOEL) with a peak one day exposure. These endpoints can be identified from the toxicological profile of each compound. For other endpoints, the NOEL should be compared with a time weighted average exposure. The PPR Panel agrees with the statement made in the guidance document (EC, 2002) that there is no identifiable scientific basis for picking any one particular period as a default time period for calculating the average exposure. The guidance document concludes that ". for the time being, a period of three weeks is proposed as the convention unless there are good reasons to take shorter or longer times." The PPR Panel recognises that this is a pragmatic approach but wishes to point out that it may not be conservative. The PPR Panel recommends that research should be undertaken to provide a scientific basis for defining appropriate time weighted average exposure durations in the future.In higher tier risk assessments, it may be appropriate to use different exposure estimates for the different reproductive phases. This will lead to a separate risk assessment for each phase, which should give better information on the nature of potential effects. This approach also provides the option of taking account of the temporal relationship between timing of pesticide application and the timing of breeding activities of wild mammals, and the possibility of identifying options to reduce risk.The PPR Panel considered how the magnitude of effects could be taken into account. The opinion of the PPR Panel is that replacing NOEL values in the TER with higher dose levels would not be justified unless better data become available to support extrapolation to effects in the field.

Since its appointment in 2003, EFSA's Scientific Panel on Plant health, Plant protection products and their Residues (PPR Panel) has to date adopted and published six opinions related to methamidophos, dinocap, daminozide, alachlor, mepanipyrim, and dichlorvos -in the field of human toxicology in response to questions posed by the Commission, or EFSA's pesticide risk assessment peer review unit. Based upon these opinions the PPR Panel selftasked the production of an overarching opinion, which summarizes the scientific principles in the assessment and guidance on the toxicology of plant protection products provided in its published opinions, produced between May 2003 and May 2006.The questions given to the Panel were grouped into four themes according to the scientific issues raised, i. e. dermal absorption, cancer/genotoxicity, species specific organ toxicity; and relevant metabolites.In reaching its opinions on dermal absorption, the Panel demonstrated the need to utilize all available data, some of which might help overcome deficiencies in the specifically tailored dermal absorption studies. The importance of establishing biological coherence was also emphasized, for example that the toxicological effects observed after dermal and oral administration are consistent with the estimated extent of absorption by these routes, and vice versa. Concerning carcinogenicity, the PPR Panel accepted a threshold mode of action for induction of tumours even though the mechanism of action is not unequivocally demonstrated, if the evidence for the absence of genotoxic potential is sufficiently well demonstrated. In addition the opinion on dichlorvos shows that the Panel under certain circumstances will not necessarily accept the default position that there is no threshold for any compound that is carcinogenic in rodents by a mode of action in which potential DNA-interaction cannot be excluded. Given the importance of the genotoxicity issue to several Panels for the assessment of carcinogenicity, the PPR Panel suggests that the Scientific Committee consider the proposals for refining the current default position.With regard to species specific organ activity, the Panel noted that it would gain from using a Mode of Action (MOA) approach as in the IPCS1 Human Relevance Framework (HRF) for cancer, e. g. by extending this to cover non-cancer endpoints as well.On relevant metabolites, the Panel highlighted that both chemical structure and some toxicological support are necessary for the use of structure activity relationships and readacross2 approaches for their determination.For the future activity, the PPR Panel emphasises the continuous importance of discussions to draft precise terms of reference and that there is a need to build up "case lore" for various mechanisms/modes. The revision of the Annexes of Council Directive 91/414/EEC on the placing of plant protection products on the market offers a possibility to address deficiencies in data provisions and the utility of well-designed metabolic and mechanistic studies, including those in human-derived in vitro systems, should be emphasized on data submission for toxicology.