Chairman: Prof J G Ayres
Members: Prof C Brown; Dr J Cocker; .Mr R Davis; Ms J Dean; Dr M Hare; Mr P Jackson; Prof P Matthiessen; Prof C Ockleford; Dr W Parker; Dr A Povey; Dr H Rees; Prof R Shore; Dr S Waring; Dr S Wilkinson
Assessors: Dr J Hughes (SASA)
Advisers: Mr D Bench (CRD); Dr S Fairhurst (CRD); Dr L Hetherington (HPA); Mr B Maycock (FSA); Miss S Shore (CRD); Dr C Snaith (HSE)
Secretariat: Ms J Wilder (CRD) Secretary; Mr P Fisher (CRD) Secretariat; Miss M Walsh (CRD)Secretariat; Mr C Pidgeon (CRD) Secretariat
Other attendees: Mr P Ashby (CRD); Mr J Dale (CRD); Dr I Dewhurst (CRD); Dr H Gibbons (CRD); Mrs S Godson (CRD); Dr S Green (CRD); Mr M Fryer (CRD); Dr C Stephenson (CRD)
1.1 Apologies were received from: Dr C Harris, Prof G Hawksworth, Dr A Burn (NE), Dr M Camlin (AFBI ), Dr A Davies (Defra ), Dr S Jess (AFBI ), Mr R Mason (CRD), Dr M Taylor (SASA), Mr D Williams (Defra), Mr M Williams (NAWAD),
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 informed members that unfortunately Prof Hawksworth was unable to attend this meeting due to ill health. Members sent their best wishes to her.
2.3 The Chairman welcomed the new members of the ACP, Mr Davis, Dr Hare, Prof Shore and Dr Wilkinson. All present introduced themselves.
2.4 The Chairman noted that this was to be Dr Rees’ last meeting. He expressed thanks to Dr Rees for the valuable inputs he had made to the Committee over the previous 6 years.
3. Agenda item 1:
3.1 a) 350th Meeting: Minutes [ACP 1 (353/2011)]
3.1.1 Agreed as drafted.
3.2 b) 350th Meeting: Detailed record of discussion [ACP 2 (353/2011)]
3.2.1 Agreed as drafted.
4. Agenda item 2: Secretary’s Report [ACP 3 (353/2011)]
4.1 The secretary reported on the recommendations made at previous meetings.
5. Agenda item 3: Matters arising
5.1 a) Trichoderma [ACP 5/1 (352/2011)]
5.1.1 Members recalled that they had identified a need for some additional toxicology data when they had previously considered this application in March. Link to meeting 348. The applicant had now provided further data.
5.1.2 Members agreed that these new data were reassuring. This strain of Trichoderma asperellum was unlikely to produce toxins. Although the temperature range required for growth suggests that the organism could grow at mammalian body temperatures (optimum growth temperatures being ≤36°C), the lack of any raised temperatures in animal experiments suggested that it did not cause an infectious illness.
5.1.3 Members observed that it was unclear why mesenteric lymph nodes had been weighed in the new experiments, as despite a slight increase in weight no further pathology work had been done. However they were content that the weight change was not of significant concern in this case.
5.1.4 Members noted that the product was considered by default to be a potential respiratory sensitiser. They were reassured that in the context of other exposures to similar respiratory sensitisers in every day life such as in compost heaps etc the risk management proposed was satisfactory.
5.1.5 HSE noted that as this substance would come under the remit of COSHH (Control of Substances Hazardous to Health Regulations) by its classification as a biological agent, this would mean there were requirements for health surveillance. HSE had also suggested that consideration be given to a higher grade respiratory protection being required. CRD agreed to discuss these issues with HSE after the meeting and noted that there had been a suggestion that exposure data be collected during use of the product during the earlier discussions.
5.1.6 Members agreed to recommend provisional authorisation for this product as their concerns had been addressed by the further data submitted.
5.2 b) Other Matters Arising [ACP 5 (352/2011)]
5.2.1 Members noted progress on the other matters arising. They pointed out that one of the links to the website included in this document seemed to have broken, and the secretary agreed to check this.
6. Application for first inclusion of penthiopyrad (ISO proposed) in Annex I of 91/414/EEC and for UK provisional approval (PPPR), in the product ‘DPX LEM17 20EC’ formulated as an emulsifiable concentrate containing 200 g a.s/L Penthiopyrad [ACP 7 (352/2011)]
6.1 One Member, in written comments, declared a non-specific, non-personal interest.
6.2 Members heard that this evaluation had been an OECD global worksharing project, with CRD working together with colleagues in the USA and Canada. The application for approval in the UK was for the EC formulation to be used on cereals. UK was the EU rapporteur Member State and the documents also included evaluation of the lead product for EU listing.
6.3 Members noted written comments suggested a need for an additional physico-chemical properties study. CRD considered that it was unlikely that repeating this test in a different solvent would provide any additional useful information, and agreed to resolve this issue with the member concerned outside the meeting.
Action: CRD to discuss the need for a data requirement
6.4 Members next considered the toxicology package. They noted there had been some differences of opinion between the work share partners as to the NOAEL in some studies, with CRD proposing a more conservative NOAEL for three studies. Having reviewed the data members agreed that the data in each of these studies were at a balance point. They agreed that CRD had taken the appropriate approach.
6.5 Members observed that the main target organ in the carcinogenicity studies was the liver, and the applicant had provided mechanistic data identifying that the mechanism of this toxicity was a ‘Phenobarbital’-type of toxicity. There was mitogenic stimulation of the liver Kupffer cells, adenoma in the liver and thyroid and liver carcinomas arising by this mechanism that is not of relevance to humans.
6.6 Members agreed that the kidney effects seen were of interest, and that data indicated a slight effect at the lower dose. They agreed that this trend to effect at the lower dose had been correctly identified by CRD in their evaluation, and members concluded that the precautionary principle would direct them to setting the AOEL as proposed by CRD.
6.7 Members then considered the potential toxicity of the metabolite PAM. Modelling suggested that this metabolite could occur in groundwater at significant levels. Members noted that there was a slight positive result in the in vitro mutagenicity data for this metabolite. Members heard that in such circumstances Committee on Mutagenicity advice would be to undertake a multi-tissue COMET assay. The tissues usually considered would be GI tract (looking for DNA reactivity), the liver (for effects on metabolism) and bone marrow (to consider as a mutagen). Members noted that the applicant had just completed a COMET assay and summary results had been tabled for stomach and liver. These indicated a clear negative result in each tissue. Members agreed that the full study would need to be provided and evaluated in due course. Members considered whether a bone marrow study should also be required. CRD commented that there was a negative micronucleus study in bone marrow already available, and asked whether this would support the reasoning for not providing a COMET assay in bone marrow. HPA responded that as there was a slight positive response in clastogenicity the Committee on Mutagenicity’s (COM) recent guidance would suggest a bone marrow study. Members noted there were no obvious haematological effects or suggestions of effects on bone marrow in the dossier. A bone marrow study would therefore be suggested to be consistent with current COM guidelines. CRD added that a further difficulty was that there is no standard OECD guidance on the COMET assay, so it was likely that the applicant had used a standard protocol from elsewhere. Members agreed that the COMET data available would be acceptable for a regulatory decision (provided the full study report was acceptable), and that the applicant be advised that the possible need for further data in bone marrow as a confirmatory study would be referred to EFSA.
Post meeting note: further discussion with COM secretariat confirmed that in this case they would not press for a study in bone marrow as being essential before approval.
6.8 Members then considered whether there was a need for a 28-day neurotoxicity study to refine the ADI for PAM as had been suggested by the HPA. Members noted that some neurotoxic effects had been seen in the studies provided. A further study would help to clarify the mechanism of those effects, but the data available already indicated PAM was of relatively low toxicity and a further study was not likely to make any difference to the ADI selected. For this reason, and to reduce animal testing, members agreed that a further study would not be required for regulatory purposes.
6.9 Members agreed the dermal absorption values had been appropriately derived, that the ADI should be based on the 2 year carcinogenicity study in the rat with the NOAEL as CRD had proposed, that the ARfD should be derived from the developmental toxicity study as CRD proposed. Here members noted that there had been effects on sexual maturation recorded in the study. Observations for this end point had been made daily rather than more frequently and members confirmed it was appropriate to take the more conservative approach as proposed by CRD. Members also agreed the CRD proposals for the AOEL, and the ADI for the metabolite PAM
6.10 Members agreed that estimated exposures would be below the AOEL. They noted that the EC formulation required the risk phrases R43 and R36 and that personal protective equipment (PPE) would be required on mixing, loading and when handling contaminated surfaces on application. Members pointed out a typographical error in the title of estimates 7 and 8 where the title did not match the model presented.
Action: CRD to correct the document
6.11 Members noted that the document included two sets of MRL proposals. One proposal was based on the standard EU approach and was derived from trials compliant with the proposed good agricultural practice (GAP). The other approach was a result of the work sharing arrangements as USA and Canada adopted a slightly different approach. Members noted that written comments highlighted the possibility that if the latter approach were adopted MRLs would not necessarily reflect EU GAP and that this might then result in some difficulties in enforcing such practice. Members agreed that as setting MRLs was a matter for EFSA, this point should be referred to them to consider. They noted that it could be a particular issue for OECD work share projects.
6.12 Members noted that the metabolism data submitted in the residues section had not followed a standard approach. As both moieties of the parent molecule had been labelled in each study it had not been possible to clarify metabolism where the molecule split into the two major parts. CRD had therefore considered all five metabolism studies, and had doubled the estimated quantity of any unknown components as a worst case assumption to ensure that all components had been accounted for. Although there was no precedent for this approach they had discussed it with both USA and Canadian experts and departments in the UK had also indicated their support for this approach to the studies submitted. Members agreed that the approach adopted in evaluating the metabolism work was acceptable but commented that the additional work that had been undertaken by CRD would not have been necessary if the applicant had performed the metabolism studies properly using more appropriate labelling.
6.13 Members agreed that estimates of consumer exposure were all below the relevant reference doses
6.14 In considering the environmental fate data, members commented that again the applicant had submitted a poor data package. Acceptability would depend upon whether the numerical estimates of metabolites in water were critical in the toxicology and ecotoxicology assessments as the values presented had greater than usual uncertainty associated with them
6.15 Members then considered the ecotoxicology assessment. Risk to birds was acceptable. The assessment of risk to mammals from eating earthworms was more problematic, as the extent to which penthiopyrad would accumulate in earthworms was uncertain. There were three different Log Kow values presented. Estimates using one value indicated a clearly unacceptable TER, using the second were marginal and using the third value the estimates TER was acceptable. Members suggested that there were three possible approaches to resolve the uncertainty; a further log Kow study, an earthworm residue study, or further refinement of the estimated dietary intakes. CRD commented that one of the original log Kow values was not acceptable as it had not been obtained for the pure material and it was possible that the buffers used had affected the water solubility. A second study had compared the solubility of pure material in distilled water with the solubility of technical material in octonol, so was also unreliable. They had therefore suggested a further Log Kow study to obtain a reliable figure. Members considered this and agreed that they anticipated the resultant TERs from a further Log Kow study would again be around the trigger value, so in practice they did not consider this approach would resolve the regulatory problem. Members also noted that the predicted environmental concentrations that had been estimated from the environmental fate data had been marginal and they did have concerns as to the reliability of the fate data. They therefore concluded that the best approach to refining the mammalian risk assessment was to obtain some bioconcentration data in earthworms. Members noted that the shrew is the relevant species to consider in the EU evaluation.
6.16 Turning to the aquatic risk assessment, members noted that there were good data on fish bioconcentration. As it was relatively unlikely that the bioconcentration in earthworms would be anticipated to be significantly different this supported the additional data requirement to resolve the mammalian risk assessment. Members noted that there had been problems with the aquatic risk of the SC formulation proposed for use in the EU. Of the Daphnia studies provided for this formulation the acute study by Gallagher et al 2007 was the sole reliable study. This indicated an EC50 value of 56.9µg/l active equivalent. The applicant had argued that the Gallagher 2009a study was valid and that the geometric mean value should be used in the risk assessment. Members agreed that if the 2009a study had been acceptable a geometric mean would have been an appropriate value. However there were effects seen at the lowest tested concentration and there were test organisms trapped in the surface film in the 2009a study, meaning members did not accept this as a reliable study
6.17 The applicant had also presented a risk assessment following the recent EFSA opinion where a data package included data on more than one aquatic invertebrate species. The EFSA opinion indicated the assessment should use the geometric mean of the study results and then divide by the assessment factor. Members noted that the opinion made several assumptions about the data to be used in that approach which were not the case in this package. One study was a mysid shrimp study where precipitation of test material meant the results were unreliable in the Committee’s opinion. A mayfly study had 20% mortality in the control. There are no current guidelines for a mayfly study, but from personal experience of mayfly tests members commented that this was actually quite good for this species. Members suggested this study was acceptable. Several of the endpoints for aquatic invertebrates were ‘greater than’ values rather than absolute values, so were too uncertain to use in the EFSA approach. The EFSA opinion assumes that the log of species sensitivities are normally distributed. The Daphnia data in this package do not fit that assumption. Members therefore concluded that the aquatic risk assessment should be based on the acceptable Daphnia study resulting in the need for the larger buffer zone for the EU uses. The acute Daphnia data were supported by the chronic data for the SC formulation
6.18 Members noted that the EC formulation proposed for use in the UK was less toxic in the aquatic environment and that the risk assessment presented was acceptable.
6.19 Members noted typographical errors in the units on page 58
6.20 Returning to consider the environmental fate data members commented that there were problems caused by the quality of the data. The laboratory data indicated a half life for the parent in soil of about 100 days. The parent compound was also found to be susceptible to photolytic degradation. However the field dissipation study had applied the compound to bare soil with no incorporation. This meant there had been initial photolysis, combined with a dark phase metabolism. This complicated interpretation of the data. The study was likely to be adequate for consideration of parent material, but could not be relied upon for assessing metabolites. As an example, for metabolite PAM the X2 errors were all more than 20%, so fitting was unacceptable. If it is essential to refine estimated exposures to PAM or other metabolites, then an additional laboratory study based on adding the metabolite directly to soil would be required. This would give much greater confidence in the rate of degradation derived from the study
6.21 The sorption study was also weak as there had been a poor selection of soils used. The soils were high in clay and high in organic carbon. There was also evidence of sorption to the tubes. Members also asked CRD to check the Freundlich coefficient used. It looked most likely that the correct value was 0.95%.
Post meeting note: a value of 0.95% was confirmed
6.22 Members observed that the environmental fate data suggested that metabolite PAM would reach ground water at sufficient levels to require further consideration. Due to the problems outlined in the data package it was not possible to be confident of the values derived. This was not of concern as the metabolite had been concluded by toxicologists not to be a relevant metabolite based on the toxicology data (including the tabled COMET assay). Members asked that the applicant be informed as to the poor quality of their data package and noted that it was possible the field dissipation study would be found to be unacceptable by EFSA. If that happened, it was possible EFSA would conclude there was not a complete dataset available.
6.23 Members next considered the efficacy package. They agreed with CRD’s conclusions including the recommendations for ‘moderate control’ for some diseases due to the variability of response. They noted the on-going monitoring of resistance in Septoria. CRD explained that the resistance to azoles in UK Septoria populations was still evolving. There were currently about 7 known CYP51 gene mutations which can occur in multiple combinations resulting in different phenotypes. There was a research project ongoing considering SDHI and azole resistance. Members observed that the company approach to this product had exposed a potential problem in the currently accepted UK extrapolations between major and minor crops in an EU wide context.
6.24 Members agreed the resistance strategy was acceptable and in line with current FRAC requirements. They observed that, in the context of the sustainable use directive, it was perhaps a bit counter-intuitive to propose the routine use of two fungicides at full dose, as this could be conceived as unnecessary use. In this case it was agreed to be appropriate for resistance management. It was noted that it was common practice for users to tank-mix fungicides but these were usually applied at reduced doses. It was also noted that whilst there were lots of data included in the efficacy package but again they had been poorly presented.
6.25 Members commented that it was good to see the globally harmonised system used in the classification and labelling proposed for the active substance. The draft labelling proposed for the UK product did not yet include the globally harmonised approach. Members also noted that the draft label included the phrase ‘if swallowed seek medical advice’ which would not usually be required for products classified as this one
6.26 Members noted that the UK label advice included the lowest volume of 200l/Ha. They asked whether it would be possible to use this at reduced volume. The secretary advised that reduced volume spraying was usually possible if compliant with the guidance in the code of practice. CRD noted that in this case the product is classified as a sensitiser, and asked whether there was a need to propose a minimum dilution as a statutory control. Members noted that although there was a local lymph node assay, this was again of inadequate quality and could not be used to determine a trigger concentration for sensitisation. CRD noted that this raised a generic issue about the use of reduced volumes where a product was classified as a sensitiser and in this case they would need to review the issue with both the applicant and relevant committee members.
6.27 Members agreed that they could not recommend approval at present, primarily due to the incomplete risk assessment for earthworm-eating mammals, but noted that the outstanding matters could probably be resolved by email if necessary. They also asked that their concerns about the lack of scientific rigour in several areas of this data package be drawn to the applicants’ attention.
7. The Open Meeting [ACP 8 (352/2011)
7.1 The committee expressed their thanks to the CRD staff who had done such a fantastic job in helping the open meeting 2011 to go so well.
7.2 Members commented that the meeting had successfully handled a number of contentious issues in open discussion resulting in some meaningful ways forward. They agreed that the structure of the meeting and questions for the small groups had been essential to achieving the insightful discussions, and recommended this approach was adopted for future ACP open meetings
7.3 Members noted the good range of people attending from individual members of the public, NGOs researchers and the chemical industry. Several points in discussion suggested there was a need to update the ACP short guide to the regulatory process and consideration could be given to getting the message out in the public domain more visibly. There had been particular interest in understanding how individuals could engage in the regulatory process, and how packages are updated to reflect changing regulatory requirements. Members had also received a suggestion that a list of participants and their affiliation would be useful to have available at the meeting as well as posted on the web with the proceedings
7.4 Members agreed that all the presentations, a note of the discussion and a list of participants would be added to the website. Members agreed to review the short note of the meeting by email. They agreed that the PAHES draft report would be added to the website for the next week to enable any further written comments to be considered. The Chairman would take account of the comments made in both PAHES groups and any subsequent comments received in writing in revising the draft report. This would be circulated electronically to ACP members and advisors before being finalised and sent to Ministers
7.5 The Secretary would produce a draft note drawing out the findings of the bees group to be passed to EFSA. Similarly, in the light of discussions at the Open Meeting, the Chairman would send a supplementary note to the summer letter sent to DH on climate change.
8. COT and COC Statements on Paraoccupational Exposure to Pesticides [ACP 19 (352/2011)
8.1 Members heard that the government response to the Royal Commission on Environmental Pollution report ‘Crop spraying and the health of residents and bystanders’ had agreed to undertake a focused review of the literature. The Chairman indicated that he had been working in a team considering a systematic review of respiratory impacts. These statements from the Committee on Toxicity and the Committee on Carcinogenicity drew together the findings of their reviews of the literature. Members’ comments were sought
8.2 Members agreed that both reports were well argued and were very good reviews. The database was limited with very little replication. The committees had therefore adopted a narrative review approach. The classification and regression tree approach provided a rational approach to the data. Members noted that, as always, a key problem in reviewing these studies was obtaining really good data on the extent and duration of exposure. Some studies did have positive ‘odds ratios’ with confidence intervals exceeding unity.
8.3 Members observed that there were a number of neuro-behavioural studies indicating health effects, some of which included some measure of exposure. However the studies might best be described as a ‘fishing expedition’, and in one case one of the measures was potentially associated with pesticides, but members commented that there were a number of other equally plausible alternatives
8.4 Members also heard that one of the group discussions at the open meeting had suggested that manufacturers might hold some relevant data, and in some cases it might be possible to obtain data relating to manufacturing exposure to a limited range of pesticides
8.5 Overall members concluded that these reports reflected good reviews using the appropriate narrative methodology. There were three outcomes that could form the basis for further targeted research. These were: exposure to fungicides and spontaneous abortion; haemopoietic cancers and allergic response in children. The ACP recommended that these be specifically included in the search terms used for the annual literature review. The conclusions would be communicated to HSE as it was possible the pesticides users cohort study could consider these endpoints. It was also possible the MRC might be interested in sponsoring further research such as a prospective study in children.
Action: Chairman to write to COT and CoC chairs; and to HSE drawing attention to these findings.
9. The Annual Report 2011 [ACP 18 (352/2011)
9.1 Members considered possible topics for the 2011 annual report. These included using the climate change work as an example of ACP ways of working; the processes and range of emergency approvals; a comparative overview of common issues with a new class of chemicals; an update on bees. The reports from the two working groups were likely to be taken forward into next year so may form topics for the 2012 report. Members agreed to consider suggestions and reach agreement by email.
Action: secretary to email suggestions
10. Environmental Panel
10.1 Members heard a verbal report of a special environmental panel meeting which considered recent research on mesocosm studies. There had been two recent research projects considering the extent to which mesocosm studies represented ‘real world’ aquatic ecosystems. Particular issues discussed included the impact of seasonal changes and the relevance of ‘pristine’ ecological experimental systems to real systems found in agricultural areas. There was a lively scientific discussion and further analysis was being undertaken. Following this it was anticipated there would be further discussion at the March meeting of the environmental panel.
11. Medical & Toxicology Panel
11.1 The Chairman provided a short verbal report explaining that the main issue considered at the medical and toxicology panel had been the annual review of the literature
12. Bystander Risk Assessment (BRAWG) Working Group
12.1 The Chairman explained that the group hoped to have a draft report available soon. They were planning an open meeting to be held on 7 December in London. At present it seemed likely the group would recommend following an approach broadly in line with that advised by the EFSA scientific panel.
13. Date of the next meeting
13.1 ACP 353 is to be held on Tuesday 24 January 2012
14. Any other business
14.1 Members’ attention was drawn to the new code of conduct. The cabinet office code of practice was still awaited
14.2 CRD explained that the Public Bodies Bill which set the scene to enable the change in status of the ACP and several other public bodies had reached its 3rd commons reading. There had been a lot of amendments and changes so it was possible there would be delays before the parliamentary process was complete. Although one of the changes had been to remove the schedule listing candidate public bodies it was understood that there was no change in the intentions for the ACP. Once the Bill had completed its parliamentary progress, there would be further implementing legislation required so it was now likely the ACP change in status would not take place until about October next year. CRD explained that Defra values the work delivered by the ACP in both advising on authorisations and in the wider work they undertake. It was expected that the need for this work would continue
14.3 The Chairman informed members that he was to meet with Prof Watson, Defra’s chief scientist, in December
14.4 CRD commented that this was the last meeting of the ACP to be chaired by Prof Ayres. Members and officials all thanked the Chairman and congratulated him on his excellent chairing of these meetings over the previous 6 years
15. Information Papers
15.1 Members considered a number of information papers.
J G Ayres
26 June 2012