Those present:
Chairman: Professor J G Ayres
Members: Ms A Baker; Prof C Brown; Dr J Cocker; Dr C Harris; Prof G Hawksworth; Ms R Howell; Dr A Leake; Prof P Matthiessen; Dr M McPherson; Prof C Ockleford; Dr D Osborn; Dr W Parker; Prof J Parry; Dr A Povey; Dr H Rees; Dr S Waring.
Assessors: Ms G Asbury (FSA); Mr D Bench (PSD); Dr C Griffiths (SASA).
Advisers: Mr J Battershill (HPA); Mr R Davis (PSD); Dr L Hetherington (HPA); Dr S Jess (AFBINI/DARDNI); Mr B Maycock (FSA); Dr R Turner (HSE).
Secretariat: Ms J Wilder (PSD) Secretary; Mr P Fisher (PSD) Minutes Secretary; Miss A MacGregor (PSD) Secretariat; Miss S Lickiss (PSD) Secretariat.
Other attendees: Ms C Eiden (EPA on secondment to PSD); Ms C Glennie (PSD); Mr P Hamey (PSD); Mr E Heywood (PSD); Mrs S Mason (PSD); Mr I McManus (PSD); Dr M Percival (PSD); Mr C Pidgeon (PSD); Ms J Reeves (PSD); Dr R Shillaker (PSD); Miss K Trott (PSD); Mr A Warburton (PSD); Miss T Ware (PSD).
1. Apologies
1.1 Apologies were received from: Dr D Ray, Ms G Smith (HSE), Mr S Dyer (DH), Mr M Williams (Welsh Assembly Government, WAG ), Dr E Pemberton (EA), Dr K Wilson (PSD)
2. Preliminaries
2.1 The Chairman reminded Members of the confidentiality of the papers and their discussions. If Members believed that they had a commercial or financial interest in any of the items being discussed, they should declare their interest as soon as the meeting moved on to that agenda item. They would then not take part in the discussion, nor would they be involved in any decision taking, unless invited to do so by the Chairman.
2.2 The Chairman welcomed a new member, Dr Waring to his first ACP meeting. He also welcomed Ms Eiden currently working at PSD on secondment from the US EPA pesticides program.
3. Agenda item 1:
3.1 a) 334th Meeting: Minutes [ACP 1 (335/2009)]
3.1.1 Agreed subject to one amendment
3.2 b) 334th Meeting: Detailed record of discussion [ACP 2(334/2009)]
3.2.1 Agreed as drafted subject to two amendments.
4. Agenda item 2: Secretary’s report [ACP 3 (334/2008)]
4.1 The Secretary to the Committee reported that Ministers had accepted advice given at the previous two meetings.
5. Agenda item 3: Matters arising
5.1 The ACP noted the letter received from the Committee on Mutagenicity following their recent discussion of thresholds of mutagenic activity. Members were interested to hear of the latest research and asked to be kept informed as Committee on Mutagenicity (COM) work progressed towards the production of updated guidance in this area.
5.2 Other matters arising [ACP 5 (335/2009)]
5.2.1 Members noted progress on other matters arising. Members heard that the National Poisons Information Service had been invited by PSD to review the various monitoring programmes currently in place for recording possible impacts on human health arising from exposure to pesticides. The report was expected to be available fairly soon and members agreed that this would be a very useful document for the proposed working group. Members also heard that work had been done by spatial epidemiologists at Imperial College considering mapping of pesticide usage information. This too would be interesting to the group. Members also discussed the possible membership of the working group and noted that submission of any additional relevant information from other sources would be welcomed.
6. Pyroxsulam [ACP 7 (336/2009)]
6.1 Dr Harris declared a non-personal non-specific interest as her employer had undertaken work for this company but not on this compound.
6.2 Members recalled that Pyroxsulam had been considered at meetings in November 2007 [link] and March 2008 [link], following which approval had been granted for use in the UK. The approval holder had now produced additional data in support of a request to increase the ADI.
6.3 Members agreed that the additional data on the occurrence of large granular lymphocyte (LGL) leukaemia in the Fischer rat was very important to the understanding of the toxicology of this compound. They agreed that their previous advice on the ADI for pyroxsulam had been very precautionary, and it was now clear that there was no substance-related increase in the incidence of LGL leukaemia in male rats exposed to pyroxsulam. They were now content that the appropriate NOAEL for male rats in the 2-year dietary study was 1000mg/kgbw/d, and the ADI should be increased from 0.1mg/kgbw/d to 0.9mg/kgbw/d as set out in this paper. This increase made no difference to current approvals.
6.4 The FSA commented that they were happy to accept this further advice from the Committee as it was in part due to their questions that the original very precautionary approach had been adopted.
7. Bixafen [ACP 6 (336/2009)]
7.1 Dr McPherson and Dr Harris both declared non-personal non-specific interests and Dr Ray declared a personal non-specific interest with his written comments on this application.
7.2 Members heard that bixafen was a new broad spectrum fungicide being developed to control a range of diseases in cereals. This application was for a provisional approval in the UK and also for Annex I inclusion as PSD was the EU rapporteur for this substance.
7.3 Members noted that the method of analysis for water had only been specifically validated for surface water. PSD explained that it had previously been accepted that validation for the more difficult (dirtier) matrix, surface water, was sufficient to meet the requirement for validated methods of analysis in groundwater and drinking water. Members asked that advice be sought from EFSA, but meanwhile asked that the applicant provide an assessment of validity of the current method for drinking water.
7.4 Although acceptable methods of analysis had been provided, members noted that the requirement for microwave extraction in the method proposed would make this less attractive for inclusion in routine monitoring programmes. This extraction technique was also not in line with the findings in the metabolism data where a high level of extraction had been found without the need for microwave extraction. Whilst this was not a point that would affect a decision on approval, it would be useful to raise the issue with other EU regulatory authorities.
7.5 Members noted that the company had suggested the observed increase in prothrombin time was related to P450 enzyme induction, however the induction in the relevant study was minimal. Members were also unconvinced about the argumentation based on analysis of vitamin K in the laboratory diet. Taking the package as a whole they could not rule out the possibility that bixafen had a direct effect on coagulation. Other possible explanations for the effects seen were liver toxicity, or enterohepatic circulation. It was clear that there was some interaction with vitamin K as the vitamin K supplemented diet reversed the effect, and the effects on coagulation were most apparent in groups exposed to highest bixafen concentrations. Members noted that there were no haemorrhagic effects seen in the rat study at low doses, but because the diet had been supplemented part way through the study it was not clear whether effects might also have been seen at the low dose after a longer period on the unsupplemented diet. Members agreed that further data considering coagulation effects at standard dietary vitamin K levels should be required.
Action: Secretariat to agree a suitable data requirement with tox members.
7.6 Members also noted that ‘dark content’ of the stomach had been reported, but yet the content had not apparently been checked for blood.
7.7 Members expressed some concern about the scientific approach in continuing the study once the applicant had identified that there might be a problem related to the diet. However it was recognised that the study did in fact provide more information about possibly sensitive populations because of the flaws in the study. However without the additional data proposed by the ACP to clarify the results, they considered that the 2 year study would need to be repeated.
7.8 Members noted the relatively high mortality seen at top dose in the rabbit reproductive toxicity study. The ‘range-finding’ study did not test doses as high as the study top dose, so this level of mortality would not have been expected. However members commented that there was a statistically significant effect seen at a lower dose, so the mortality seen at the highest dose did not affect the overall findings of the study. The study was therefore considered acceptable.
7.9 Members also drew attention to uncertainty about the dosing in the 2-generation study. During the study it seemed that increased food consumption would have significantly increased the dose of bixafen delivered, so the dose in the diet had been adjusted. However in calculating dietary intakes the initial dietary concentrations had been used rather than the adjusted concentrations, which had been reduced by about 50% during the lactation period. Members commented that although the applicant had suggested effects seen in the pups were due to transfer in the milk, the goat metabolism study provided evidence that very little bixafen occurred in goat milk, so members thought effects were unlikely to be related to bixafen in milk.
7.10 The ACP agreed to defer commenting on possible reference doses pending the further data they required.
7.11 The estimates of exposure arising from the use of bixafen were confirmed to be appropriate. A typographical error introducing a difference between volumes 1 and 3 of the draft assessment report was identified. Members suggested that the explanation of the assumptions made in estimating exposure could be significantly improved by clarifying that an assessment was made of residential exposure to vapour as the estimated intake was considered over a 24 hour period.
7.12 Members agreed that the residues assessment and consumer exposure estimates were acceptable. They noted some variation in the description of the des-methyl metabolite as either being of similar/lower toxicity or as of similar toxicity to bixafen and suggested that a consistent description would improve the document. Three metabolites were recorded as being found in plants but not animals. However members noted that the carboxylic acid stated to be found in plants only was also found in the rat metabolism study. The desmethyl pyrazole metabolite has two tautomeric forms. Whilst this was not considered by members to be of concern as it was only detected at very low levels, they suggested the discussion of the toxicology of this metabolite might need to be expanded slightly to take this into account.
7.13 Turning next to consider the environmental assessments members noted that bixafen was very persistent in soil. Pesticide residues in Northern EU dissipation trials had only declined to around 50% of initial concentrations after two years.. Whilst accepting that such persistence in itself was not sufficient to refuse an approval, members commented that it was therefore particularly important to be as clear as possible about the possible impacts bixafen might have on the environment.
7.14 The soil accumulation study was not yet complete. This was not unusual for a new active substance at this stage of development. However the field study results to date indicated greater accumulation than had been calculated by the standard method. In view of this deviation from the calculation, members considered that either the accumulation study should be completed, or the calculation should be adjusted to reflect the current field data more closely, and this peak value then used to complete risk assessments for the relevant sectors.
Post meeting note: The graph in the DAR at Figure B.8.40 for accumulated PECsoil was produced by PSD. It differed from that provided by the applicant (not shown in DAR) in that the ‘upper saw teeth’ curve represented peak concentrations that included addition of the annual loading over 5 cm soil depth for individual years. Whereas the applicant’s graph (not shown in the DAR) showed only the plateau concentration averaged over 20 cm depth, to which the applicant subsequently added the annual soil loading over 5cm depth, to derive the same peak plateau concentration value as PSD.
The rate of accumulation in PSD’s graph for the peak (‘upper saw teeth’ curve) is much slower, appearing to be ca. 25% over the first 3 applications. However, the rate of accumulation based on the plateau (‘lower saw teeth’) curve in the same graph, (which correlates with the applicant’s graph) is about 2-2.5 fold. This is more in line with the results seen over the first few years of the field accumulation trial. The PSD approach has been confirmed to be appropriate and on this basis the field accumulation results are explainable and consistent with the modelling.
However, given the very persistent nature of the compound, the applicant should request analysis and reporting of residues up to and including the fourth application for confirmation of the trend in field data. Then repeat the tier 1 calculation, using the field reporting conditions, to demonstrate that the assumptions built into the PECsoil calculation are conservative. Provided the predicted accumulation (and rate of increase in peak concentration) is at least as great as that observed in the field after 4 applications, the calculation approach to date will be justified and the risk assessment considered satisfactory.
7.15 It would be anticipated from the environmental fate data that although bixafen would persist in the environment, it was likely to be strongly adsorbed to soil particles. Some reassurance was provided in that there were no residues likely to occur in following crops. However where it reached the aquatic environment it would be expected to move to sediment and persist for a long period. Although the applicant had suggested that only bixafen in the water phase would be bioavailable, this had not been proven. It was known that in some cases substances adsorbed to soil could become bioavailable in the gut of sediment feeders.
7.16 The chironomid study submitted did not provide detailed measurement of bixafen levels in all compartments although there were data showing that levels of bixafen in overlying water were 97%-103% of initial nominal dose at day 0, and by day 7 levels in water had declined to 20-37% in overlying water. There was no measure of levels in sediment or adsorbed to the container. PSD pointed out that data from the water-spiked study had assumed that exposure for the sediment organism was to the full applied dose. Members commented that whilst it had been assumed that the estimates of exposure made in the risk assessment were very precautionary, there were no data available to demonstrate this with certainty. Using the existing data there were some FOCUS scenarios (including some relevant to the UK) where the TER was <10. The UK specific exposure estimates did not include estimates of exposure due to erosive run-off. It was clarified that the EU assessment using FOCUS surface water scenarios did include exposure due to run-off, (& was worst case as no interception was assumed). Whilst this would not usually be a route of exposure for surface waters of particular concern in the UK, the persistence of bixafen in the soil made it more likely that an unusual event would transport the substance to surface waters.
7.17 Members commented that PSD had completed a very good assessment of the available data but that further data were required to resolve the areas of uncertainty. A further Chironomid study would be required following OECD 218, using sediment dosing and measuring concentrations in water, sediment and container. The dose levels should be set so as to include the PECsed that PSD had estimated. The FOCUS scenarios used in the resultant risk assessment should include erosive run off. Members agreed that the estimated exposure of the aquatic environment from drainflow was appropriate as presented by PSD.
7.18 Members observed that there were important problems encountered in the bird reproduction study. There was a much higher than expected level of aggression seen, which was at least suggestive that the animals selected were not in a suitable state to undertake this type of study. Birds in the reproductive phase do not usually fight, so it was possible there were problems in timing of the study or the handling of the animals or some other behavioural issue. Whatever the cause, this meant it was not possible to determine with any certainty from this study whether for example there were behavioural or neurotoxic effects seen as a result of exposure to bixafen. Members sought further reassurance by requesting a further bird reproduction study-either a mallard study if one was available or failing that a further study using bobwhite quail.
7.19 Soil dwelling organisms would also be exposed to bixafen for some time. Members noted that the earthworm species tested was a ‘surface’ dwelling species and these are generally not considered to be as good at absorbing substances from the soil as some other species.
7.20 Overall members were concerned that effects were seen in many of the ecotoxicology studies but not at levels that would usually trigger concerns. For example it was moderately bioaccumulative with a BCF of about 700 in fish, where the trigger value is 1000. Bixafen was very persistent and members wanted to be as sure as possible that this did not cause problems in years to come.
7.21 Members agreed the efficacy data were comprehensive, and demonstrated bixafen was effective against several cereal disease targets. Members noted that it was shown to be active against powdery mildew in dicotyledonous plants, but this use was not claimed for cereals. They asked for clarification on this point.
Post meeting note: It was expected that bixafen would be used on cereals in combination with other active substances.
7.22 The ACP concluded that further methods of analysis, toxicology, environmental fate and ecotoxicology data were required before they could recommend approval.
8 Garden Pesticides and Children’s Exposure [ACP 9 (336/2009)]
8.1 Following discussions at the 334th Meeting of the ACP , PSD met with the Crop Protection Association (CPA) ‘gardens group’, to consider a package of measures designed to further reduce the risk to children from home and garden pesticides. This meeting had generated some further ideas to help reduce the exposure of children to pesticides used in the home garden.
8.2 In addition the paper included the suggested ‘reverse risk assessment’ which calculated the number of different sized slug pellets children of varying sizes would need to consume to reach an intake equivalent to the ARfD. For the largest pellets and the smallest children this was around 6 pellets. This emphasised the importance of the guidance to avoid ‘piles’ of slug pellets where a very small child could easily grab a handful of pellets. This point was illustrated in one of the suggested graphics. It also initiated a discussion about the selection of the most appropriate colour to use for slug pellets. The colouration was required for a number of purposes. It helped the user to see the distribution of pellets on the soil but it was important also that the colour selected was not attractive to birds or children. In this context members noted the recent marketing campaign on blue Smarties with some concern as most slug pellets were coloured blue. Relatively little work was available to help inform members of the attractiveness of various colourings to small children, but there had been some work in pharmaceuticals suggesting that there was a range of colour preference. Members noted that slug pellets were usually coloured the same for use in agriculture and in the home garden, but whilst one would expect to find birds in both crops and gardens it was significantly less likely that children would be playing within arable crops than in gardens.
8.3 Members also commented that the move towards the smaller mini pellets in the home garden was a good idea. In addition to increasing the number of pellets required to deliver a dose that might cause effects in small children it was possible that the increased number of pellets might also increase the deterrent effect of the bittering agent. However members noted that there was little hard data on the effectiveness of deterrent bittering agents.
8.4 Members next considered suggestions for lawn treatments. Here the industry had pointed out that it was important for users to have clear guidance on re-entry. The traditional advice was to keep out of treated areas until the spray had dried. PSD explained that this was because it was assumed to be easier for wet spray to be picked up in skin contact and generally less was removed once the spray deposit had dried. However it was accepted that there were some shortcomings to this position. Whilst it was usually the case, some re-entry studies had shown that in some cases this assumption did not hold good. In addition it was clear that rainfall after the spray had dried might make the spray deposit more easily dislodged again.
Post meeting note: If harm would be expected from dislodgeable residues, it was clear that the product would not receive approval for use as a home garden lawn treatment.
8.5 Some other lawn products provided advice to keep children and pets out of treated areas until the product had been watered in. Members agreed that it was important to provide clear advice to users. Members agreed that for small children there was a very important responsibility on parents to use the products correctly and to provide appropriate supervision. In this context members agreed that the provision of clear information to help parents was important. They asked about progress with an advisory leaflet to be made available at the point of sale and PSD responded that given the relatively low rate of incidents compared to product purchases it was relatively unlikely that such additional information would have an effect. However the product label would always be present so it was particularly important to focus on the advice given on product labels.
8.6 Members noted that the industry had suggested various logos that might be used to draw attention to the advice of specific relevance for children and pets. Members agreed that a neutral simple identifiable dog and/or child could be used. Wording, whether used with or without the logo should give a very clear message giving the relevant advice for the product. They also suggested that the wording of advice might need to take into account the ease of translation into languages other than English (eg Welsh).
8.7 Members thanked the industry group for the positive way they had engaged with the debate and the good ideas they had put forward. Members also asked PSD to continue to pursue seasonal contact with local authorities in an attempt to use local newsletters as a means of passing more general safety information on pesticides to the public.
9. FSA nutrition research consultation [ACP 13 (336/2009)]
9.1 The ACP agreed that comments would be forwarded to the Secretariat by email for collation and transmission to FSA.
10. Pesticide Usage Surveys Consultation [ACP 12 (336/2009)]
10.1 Members agreed to forward comments by email to the Secretariat, who will prepare a draft paper for consideration at the next meeting.
11. Date of the next meeting
11.1 12th May 2009 at Foss House York
12. Any other business
12.1 Review of the Approval Process: Consideration of risk to bystanders/residents [ACP 14 (336/2009)]
12.1.1 Members held a wide ranging discussion on the recent decision from the Court of Appeal that PSD should begin work on this review of the approval process ahead of a full hearing of an appeal against recent judicial review findings.
12.1.2 The ACP noted that some valuable studies were in progress that would be very informative for such a review. They asked the secretariat to provide some additional information to assist a further discussion at the 337th Meeting of the ACP.
Action: Secretariat
J G Ayres
May 2009
