Chairman: Professor J G Ayres
Members: Ms A Baker, 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 D Ray, Dr H Rees
Assessors: Ms G Asbury (FSA); Mr D Bench (PSD); Dr C Griffiths (SASA).
Advisers: Mr J Battershill (HPA); Mr R Davis; Mr D Renshaw (FSA); Dr R Turner (HSE); Dr K Wilson (PSD).
Secretariat: Ms J Wilder (PSD ) Secretary; Mr P Fisher (PSD ) Minutes Secretary; Mr S Robson (PSD ) Secretariat.
Other attendees: Mr P Adamson (PSD); Mr M Burns (PSD); Mr M Clook (PSD); Mr P Hamey (PSD); Mr R Mason (PSD); Mrs J Reeves (PSD); Mrs S Tessier (PSD); Miss K Trott (PSD).
1.1 Apologies were received from: Prof C Brown, Dr S Waring, Dr S Jess (AFBINI/DARDNI), Ms G Smith (HSE), Mr S Dyer (DH), Mr M Williams (Welsh Assembly Government, WAG ), Dr E Pemberton (EA), Dr L Hetherington (HPA).
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 two new members of the Committee, Drs Cocker and Harris, and informed the Committee that a third new member, Dr Waring had been appointed but was unfortunately unable to attend this meeting.
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.
4. Agenda item 2: Secretary’s report [ACP 3 (334/2008)]
4.1 The Secretary to the Committee reported that Ministers were considering the advice given at the previous meeting.
5. Agenda item 3: Matters arising
5.1 Nemguard – Detailed Record discussion [ACP 7 (335/2009)]
5.1.1 In line with agreed procedures, the applicants for Nemguard had been asked to check the record of the May discussion prior to publication to ensure that there had been no inadvertent breach of the company’s confidentiality. The company had confirmed that there were no breaches of confidentiality in the record as presented, but suggested a number of other changes to the record. Members considered each of the applicant’s suggestions.
5.1.2 Members agreed that it was not appropriate for the applicant to suggest changes to the record of those parts of the meeting where they had not been present, however they were content to expand the introductory paragraph to cross reference to earlier discussions to provide the context of the application and to add a summary description of the data presented by the applicant. Members also accepted a post meeting note explaining a little more about applicant’s comments on the possibility that the fanging seen might have been caused by Pythium, and the Committee’s assessment of this point.
5.1.3 Members agreed that throughout the record of discussion between the committee and the applicants it was very important to clearly identify the views expressed by the applicant and those of the Committee. Points of clarification including post meeting notes were agreed and –subject to amendment to ensure the clear attribution of the various points made were accepted.
5.1.4 Members asked that the amendments agreed be made to the detailed record of discussion prior to publication.
5.2 Other matters arising [ACP 5 (335/2009)]
5.2.1 Members noted progress on other matters arising. Following the suggestion at November’s meeting that local authorities’ be asked to include a warning notice to parents at the start of the spraying season in spring in their newsletters, members noted that it would be a good time to contact local authorities to communicate this message. However it was noted that it had been agreed to discuss the suggestions further with the Amateur Use Strategy Group and this group had not yet met or had a chance to consider the suggestions made in November.
5.2.2 Members noted that the paper suggested that work had been planned to commence on the revision of pesticide container guidelines in the autumn, and they asked for further information on this project. PSD explained that unfortunately the resource that had been identified to take that work forward had been diverted to considering the outcome of the judicial review. However the Pesticide Forum group had been able to start work, recently having visited a recycling plant and PSD hoped to be able to take account of the conclusions of that group in re-drafting the guidelines.
6. Application for UK provisional approval (PPPR) for Movento containing spirotetramat [ACP 10 (335/2009)]
6.1 Dr Ray declared a personal non-specific interest as he had completed other work for the company in 2006. Dr Harris declared a non-personal non-specific interest as her employer had received funding for work on other compounds for this company. Dr McPherson declared a non-personal specific interest as other colleagues at Stockbridge Technology Centre (STC) had completed some work on this substance and the manufacturer had also used STC facilities for trials work. Dr Parker declared a personal specific interest as he had been involved in designing some trials including this substance (not those submitted for this approval). Dr Parker was asked to leave the room for this discussion, but others were allowed to remain and contributed to the discussion only on invitation by the Chairman.
6.2 Members heard that the initial evaluation of this dossier had been prepared as a global joint project between the USA, Canada and Austria. PSD had taken this assessment and had added UK specific assessments where appropriate e.g. for calculation of UK specific risk assessment to aquatic organisms.
6.3 Members agreed that it was sensible to reduce the global duplication of effort by working together in this way.
6.4 Members were content with the physico-chemical properties and agreed that the methods of analysis were appropriate for the proposed residue definitions.
6.5 Members noted that there had been discussion between the three evaluating states about the brain ventricular dilation reported in the dog. Members heard that this had also been discussed in some detail at the World Health Organisation (WHO) Joint Meeting on Pesticide Residues (JMPR). It is clear that ventricular dilatation is observed in normal beagles. Vullo et al (Veterinary Radiology&Ultrasound vol 38, no4, 1997 pp277-281) had reported only 2/17 asymptomatic beagles with normal MRI scans. It has been suggested that ventricular dilatation may occur either as a developmental anomaly or possibly as a result of a meningococcal infection at an early life stage. Only in extreme cases are clinical signs also seen, but where they occur it would be likely that they would be expressed in young adult dogs. It was thus clear from the literature that there is an endemic effect in beagles which makes it very difficult to determine whether the ventricular dilatation seen in this study is a compound related effect. There was an apparent increase in numbers affected with increased dose, but only one animal showed any clinical signs after about 130 days of exposure. It was thus not surprising that no clinical signs were seen in the 90 day study. The pathology provided was also inadequate to determine whether the effects seen were compound related. Overall, since there were no other neurotoxic signs in either the rat or the dog studies members concluded that the ventricular dilatation in the 1 year dog study was unlikely to be compound related so this was not selected as a regulatory end point. Members asked that their concerns about the poor design of the study be conveyed to the applicant.
6.6 The EU Rapporteur Member State (RMS) had proposed labelling spirotetramat as a reproductive toxin (category 3), with risk phrases R62 –possible risk of impaired fertility and R63 –possible risk of harm to the unborn child. The applicant had presented a case against this labelling. The ACP noted that the final decision on classification and labelling would be taken by the appropriate EU expert group. The applicant had suggested that effects on sperm were a high dose effect of limited relevance to the likely human exposures to spirotetramat. The company also argued that occurrence of sperm effects was the outcome of likely higher feed consumption of the young animals tested. However as this test was a preliminary dose finding study the actual feed consumption had not been measured. As such members agreed that whilst higher feed consumption was likely, it had not been demonstrated. Members noted that the major mammalian metabolite was an –enol derivative. Whilst much of the toxicology of the metabolite had been assumed to be covered by testing of the parent compound, there were no genotoxicity data specifically on this metabolite. Members agreed that at least an Ames test should be provided to clarify the data package. Members agreed that the testicular effects were only seen at very high doses, because of the wide dose spacing in the relevant study the NOEL was about 70mg/kgbw/d. The testicular toxicity and reproductive effects were agreed to be compound related effects at rather high doses. The applicant did not seem to have considered the relatively prolonged period of spermatogenesis (about 60 days in man 55 in rat) in reaching their conclusion that repeated high doses were necessary to cause an effect. It was at least debatable from the data presented that a single high dose at one critical point in development was required, but the effects would not be seen until some time later Members considered that all the available data were consistent with the proposal from the Rapporteur Member State for a classification with R62 . However members agreed that the effects at such high doses were not relevant to any likely human exposures from the proposed use of spirotetramat.
6.7 The Committee noted the good quality package of toxico-kinetic data provided which demonstrated that at high repeated doses there was non-linear elimination.
6.8 Members noted that there were decreases in thyroid hormones T3 and T4 but there was no compensatory increase in TSH. Members commented that the thyroid and reproductive effects may be linked. If the effect on thyroid hormones was being exerted at the hypothalamic or pituitary level, a rise in TSH would not necessarily be expected. Other factors such as releasing factor level or iodine availability might also affect thyroid hormones production. HPA had examined some background studies on the dog to see whether the thyroid effects in the dog would be expected to be similar to those in the rat. References suggested effects would be similar. Members discussed whether these effects in thyroid hormones were of concern for man, and agreed that they were potentially adverse effects. It was also notable that the single case of axonal degeneration was in the hypothalamus. Whilst members agreed that the driver for R62 classification was the testicular effect, it was likely that more information on the levels and efficacy of the thyroid hormones would be required as a part of the case to remove R62 classification.
6.9 Turning next to consider the teratology study members agreed that there were modest teratogenic effects seen at the highest dose tested in the rat. Whilst there was a 7% maternal body weight loss by the end of the study, at day 20 there was 29% body weight loss. Members agreed that R63 labelling looked appropriate but were content that any teratogenic effects were restricted to high, maternally toxic doses.
6.10 Members agreed that the genotoxicity package was acceptable, but noted that the mouse lymphoma study recorded as available did not seem to have been included in the evaluation document. Members asked that the RMS clarify this.
Action: PSD to request clarification from RMS
6.11 The ACP agreed the reference doses as proposed by the RMS: ADI and AOEL of 0.05 mg/kg bw/d derived from the 1 year dog study, ARfD of 1 mg/kgbw/d derived from the acute neurotoxicity study in the rat (members noted that the effects were clear acute effects but not necessarily neurotoxic responses).
6.12 Members confirmed the operator, worker and bystander risk assessments were appropriate. Members had discussed with PSD whether gloves would be appropriate when handling contaminated surfaces due to the sensitising properties of the compound. It was agreed that the proposed labelling was in line with agreed labelling policy, and it would be expected that gloves would be worn as a result of good occupational hygiene rather than as a label requirement. Whilst it was not appropriate to deviate from the current labelling policy for this product, it was agreed that the medical and toxicology panel would review the current policy to ensure appropriate account was taken of maters such as possible accumulation of dried spray deposit on the boom.
Action: Medical and toxicology panel
6.13 Members agreed that a comprehensive residues data package had been provided. The risk assessment was conservative in assuming that the –enol metabolite was at least as toxic as the parent spirotetramat, and it was noted that the residues definition could be reconsidered if at some time in the future further data became available on the –enol metabolite, the main metabolite in both mammals and plants, showing it to be less toxic than parent.
6.14 The proposed MRL of 0.02mg/kg for kidney was likely to be the correct level, but again it was noted that considering both the dose delivered to test animals and the predicted residue , it was conservative. The FSA had asked whether members considered the –enol glucuronic acid should be included in the residue definition. As about 80% of the residue was the –enol metabolite, the estimated consumer exposures were well below the reference doses and complex residue definitions could present difficulties in analysis and hence cost at the monitoring laboratories, members concluded that the –enol glucuronic acid should not be included in the residue definition. Members noted that the residue present in kidney would not be expected to include any parent spirotetramat. As such it was possible that monitoring labs could make further cost savings if this were pointed out to them.
6.15 Members noted that there were only 4 trials on leafy brassicas in North EU member states and 4 in Southern EU member states. A requirement for further residues data in NEU had been identified. However results from leafy brassica and other headed brassica residues trials were remarkably consistent in both northern and southern MSs and members therefore asked if PSD would re-consider the package as a whole in determining whether further data were required for leafy brassicas. Members noted that an MRL in kidney would be required before the requested use on kale could be granted. When this was queried since it was not likely that kale used as animal fodder would be treated with insecticide, members were advised that this was a requirement for crops where there was a possibility that they could be used as animal fodder, for example if they were not able to be sold for human consumption.
Action: PSD to review data on leafy brassica
6.16 Members noted written comments from Prof Brown regarding the assessment of environmental fate and behaviour. Members agreed that whilst there were some concerns about the approach that had been taken by the RMS to calculating the predicted environmental concentration in groundwater, there was no risk of groundwater contamination at levels above 0.1 µg/l. The precautionary approach adopted by PSD in completing UK specific exposure assessments was agreed.
6.17 Members agreed the risk assessment for aquatic organisms was acceptable. Members discussed the need for the warning not to spray when crops were in flower or when flowering weeds were present in order to protect bees. Whilst it could be argued that in the light of the data evaluated it might be over precautionary, members heard that it would be useful from a practical point of view. It was very likely for example that brassica crops would have charlock present in the field as it was very difficult to control by herbicides in the closely related crop. With the decreasing availability of herbicides, particularly in minor crops, there would be an increase in flowering weeds – and thus the importance of bee warnings would increase.
6.18 Members noted that mites were particularly sensitive to the effects of spirotetramat. A key study investigating the effects of treatment on non-target arthropods was a field study in a vineyard in the South of France. As this was not particularly relevant to conditions in the UK, members agreed that the advice to avoid spraying within 5m of the field boundary was a sensible precaution.
6.19 Members noted that there were some unusual effects reported in the longer term bird studies, but as spirotetramat was not very persistent in the environment and as the likely application time was May/June or later and not during the height of the breeding period, members agreed that the use proposed was acceptable. However these findings should be borne in mind if effects were reported amongst birds around these crops.
6.20 Members agreed the efficacy evaluation was acceptable. However they noted that the evaluation needed clarification about whether the lettuce crops treated were outdoor or protected. For example the phytotoxicity assessment did not state whether the crops were protected or outdoor, but the protected crop might be expected to be more sensitive. Similarly whilst the use pattern was 1 or 2 applications per crop, there would be multiple crops per season under protection.
Action: PSD to clarify the assessment
6.21 Finally members agreed that provisional approval for spirotetramat could be recommended to Ministers, subject to a confirmatory data requirement for an Ames test on the –enol metabolite. PSD were to consider the possible use on leafy brassicas outside the meeting.
7. Annual PIAP, NPIS and Human Health Surveys[ACP 18 (335/2009), ACP 17 (335/2009) and ACP 9 (335/2009)]
7.1 Members considered the findings reported in these three papers. They also compared the results and the presentation of the reports.
7.2 The NPIS report presented information gathered from contacts made by medical practitioners with the National Poisons Information Service. The paper was considered to be well laid out with the relevant data readily accessible. This sample reflected incidents that had led people to seek medical advice although the exclusion of NHS direct and NHS 24 was noted to introduce a possible source of bias in the sample, as was the fact that it is only possible to analyse returned questionnaires. Members noted the prevalence of reports of children being exposed to pesticides in the home and garden.
7.3 The PIAP report had not yet been able to incorporate the changes suggested during 2007/08 by the ACP. The Committee remained concerned about the high number of incidents classified as ‘insufficient information’. Further information such as whether the lack of information was related to exposure aspects or to health records would be helpful, particularly where case reports were apparently very similar but differing decisions were recorded about them. Members heard this was possibly a result of initial poor quality data and lack of resource for thorough follow up. Members noted that they had provided some suggestions to improve the quality of initial data and heard that these changes and improved training had been taken forward during 2008. One point that was notable about PIAP reports was the prevalence of incidents involving boom sprayers due to the different types of application reported, in contrast to both NPIS and approval holders information. This suggested reporting-bias to the PIAP scheme. However, it might be of concern because it suggested that the professional sector still had further work to do to improve standards of spray operations. The other two studies provide a clear indication that some incidents are not reported to HSE. Given that the PIAP report covered a small and probably biased sample it was important not to over-analyse the data that were available searching for trends. However members commented that some form of denominator such as usage information to set the reports in context would help readers to understand the context of the reports.
7.4 The survey of approval holders was also likely to be a biased sample as it recorded those people who had contacted the industry for advice. PSD had gathered some data on supply of pesticides to the home garden sector in an attempt to provide a broad indicator for the context of incidents involving home garden products, which accounted for the majority of enquiries reported in this paper. 32 enquiries involved children, but the information available in this report showed that exposure was not certain in some of these cases and not all cases had any health consequences, so it was clear some of the enquiries were precautionary. Members welcomed the additional information on supply of pesticides included in this paper and suggested that despite the uncertainty that remained about usage levels in the home garden, the supply data could be used to help consider trends. They agreed PSD should add a request for these data to the questionnaire for future years. It was noted that the numerator included all incidents reported whereas the denominator included sales data only from those companies who were members of the Crop Protection Association (CPA). It would then have been more appropriate to restrict comparison to the incident data to those reports coming from companies also in the CPA.
7.5 The three papers reported exposures that differed between the reports. Whilst both PIAP and the approval holders data suggested that reports of incidents had remained at broadly similar levels to last year, the null NPIS enquiries had increased. Members suggested that further consideration be given to the possible development of a single system of reports of incidents, and heard that the Veterinary medicines reporting system drew together reports from companies, vets and users into a single system. Members also heard that the HPA had funded work on a computer model on communicable diseases which allowed real time information to be overlaid on geographical systems to assist the work of public health specialists. It was clear that there were technological possibilities that might be able to provide more informative information on pesticide incidents.
7.6 One of the critical issues in allocating resource to monitoring systems would be the severity of incidents. In this respect it was noted that there was limited information on severity in the PIAP report, but all three papers suggested that most of the incidents were very minor, and related to acute exposure. The Hospital Episodes Statistics (HES) analysis published in Clinical Toxicology in 2007 also reported that severe effects were rare. That paper had compared the HES for pesticide incidents with other scenarios also reported in the HES such as falls from ladders to try and set the findings into some form of context.
7.7 Members agreed to ask a group to investigate an integrated system for reporting of pesticide incidents. The group should be either a small working group of the ACP or medical and toxicology panel with appropriate additional advisors such as NPIS, PIAP etc
Action: Secretariat to arrange a working group in discussion with ACP and Med Tox Chairs.
8. Draft Annual Report [ACP 14 (335/2009)]
8.1 Members considered the first draft of the 2008 annual report. As requested they made a number of helpful suggestions to improve the readability of the case histories including the use of boxes away from the main text for the more technical details, use of bullet points at the start of each case history to outline the key messages within the article and flow charts to illustrate the processes followed. The logical ordering that is followed within committee discussions would provide a clear structure for the case histories on active substances.
8.2 As discussion of the replacement to 91/414/EEC had been such a key issue throughout 2008 it was agreed that the Chairman would refer to the Committee discussions on this topic in his forward.
9. WEBFRAM – from Environmental Panel [ACP 6 (335/2009)]
9.1 Members heard that WEBFRAM represents the outcome of several research projects and offers an alternative option for higher tier refinement of bird, mammal and aquatic risk assessment.
9.2 The environmental panel had carefully examined and agreed the underlying data used in this probabilistic model. For regulatory simplicity the median value has been selected for regulatory purposes. The use of this probabilistic approach highlights uncertainties within the risk assessment which are not so transparent in the standard deterministic approach. Whilst there are considerable uncertainties, most are generic and therefore likely to be fairly constant between different assessments. The panel had suggested that WEBFRAM be introduced as an option for applicants to use where their Tier 1 assessment indicated a need for refined risk assessment. The outputs of the model would be compared with calculations based on Tier 1 and initial assessments using WEBFRAM would be considered by environmental members of the ACP to check that the risk assessments remain comparable with the current refinements. A training conference was planned for the spring in which WEBFRAM could be introduced more widely.
9.3 Some of the major companies had expressed concerns about data security as the model is run on the web. PSD was currently investigating the possibility of providing a ‘downloadable’ version, but meanwhile noted that actual active substance names do not need to be included in the model runs with the regulatory endpoints from studies – which are themselves published in due course.
9.4 Members noted the importance of calibrating such new approaches to risk assessment against the current methods and suggested that data on some currently approved products be put through the model to check that the same regulatory outcome would be achieved. PSD confirmed that they had already done this as part of the familiarity testing that they had completed.
9.5 Members noted that, although some concerns had been expressed by industry, they thought it might be a useful tool, particularly for consultants, because the model is relatively quick to run. Members also suggested uptake might be improved if companies were offered an incentive to use it. They suggested possible incentives might be a faster processing time if appropriate.
9.6 HSE noted that there were also concerns expressed about the fact that WEBFRAM is a ‘black box’ type of model. PSD explained that there are drop down help menus included in WEBFRAM together with detailed information explaining how the model is set up, and a sensitivity analysis had been added to demonstrate the key drivers for the risk assessments. However, PSD is looking at the possibility of including a tracking module in WEBFRAM which would allow users to see exactly how a particular result had been arrived at.
9.7 Overall members agreed that the suggested implementation would be appropriate and asked to be kept informed as to how the use of WEBFRAM progresses.
10. Conjugated Residue Behaviour: Impact on Human Health Assessment [ACP 13 (335/2009)]
10.1 Dr Harris declared a non-personal non-specific interest in this item as her employer had received funding for work on other compounds for this company.
10.2 Members agreed that this paper reported some very useful projects. The main issue identified was that extraction of conjugated residues did not necessarily reflect their bioavailability. The information presented was fairly compound specific and further work would be required to consider whether bioavailability could be predicted. However the results from these studies indicated that current risk assessment methods were likely to be conservative.
10.3 Members praised the literature survey and asked that the authors be encouraged to publish this work. They drew attention to a typographical error in the units on Page 93 of the paper which would need correction before publication.
10.4 Members made several suggestions for further work, including work on larger molecules and some further in vivo work. It would be important to focus any future work so that it was of most relevance to regulatory decision making. For this reason members suggested that future work should focus on those situations where estimated intakes were within an order of magnitude of possible health effect levels. Members also suggested that the consideration of intestinal uptake be extended to include the pre-closure period in development where transepithelial transport mechanisms differed from those in the adult.
11. Date of the next meeting
11.1 17th March 2009 at Foss House York
12. Any other business
12.1 PSD provided a verbal update for members on progress with the new EU legislation. The European Parliament had voted on both the sustainable use directive and the plant protection product regulation on 13 January. There would now be a second reading in Council at which the UK was expected to support the sustainable use directive but not the regulation because of the introduction of hazard triggers. However it seemed likely that the UK would be out-voted and it was therefore expected that the regulation would be adopted in the summer for implementation in 2010.
12.2 There was now an interim definition of endocrine disruption included for the regulation (see post meeting note) and PSD was currently revising their impact assessment. A derogation where there was overwhelming plant health need had been secured. Candidates for substitution and comparative assessment remained in the regulation and three zones would be introduced to improve harmonisation. UK would be in the central zone, but there were additional safeguards included that would allow refusal of approval if conditions within the zone were considered sufficiently different that mutual recognition would not be appropriate. Safeners adjuvants etc would be included in the scope of the regulation in future and there would be harmonised rules for parallel imports in the regulation.
Post meeting note: The interim arrangements for endocrine disrupters are: ‘ ‘Within four years from the entry into force of this Regulation, the Commission shall present to the Committee referred to in Article 79 (1) a draft of the measures concerning specific scientific criteria for the determination of endocrine disrupting properties to be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 79(4).
Pending the adoption of these criteria, substances, that are or have to be classified, in accordance with the provisions of Directive 67/548/EEC, as carcinogen category 3 and toxic for reproduction category 3, shall be considered to have endocrine disrupting properties’.
12.3 The sustainable use directive provided for greater flexibility in implementation. There would be requirements for National action plans, training, equipment testing, protection of water, and promotion of integrated approaches.
12.4 Members sought clarification as to whether there were provisions for ‘off label’ approvals in the regulation, and this was confirmed. Members noted that ‘negligible exposure’ was required for carcinogens and reproductive toxins. In line with medicines and developing science this should now also include mutagens. Members heard that a deadline had been set for the Commission to provide proposals for how to deal with endocrine disrupters. Members considered this rather optimistic as personal involvement with development of OECD guidelines for fish tests sensitive to endocrine disrupters suggested at least 10 more years work would be required before a full suite of suitable tests was likely to be available.
12.5 Members asked to be alerted when PSD updated the website with their updated impact assessment and further information on the EU legislation.
J G Ayres