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ADVICE SUMMARY APPLICATION FOR REGISTRATION OF A CHEMICAL PRODUCT Product name: DIPTEX 150 WP INSECT GROWTH REGULATOR Applicant: AGROCARE PTY. LTD. Product number: 67871 Application number: 57009 Purpose of Application and Description of Use: Registration of a 150 g/kg cyromazine wettable powder product for control of sciarid and phorid fly larvae in mushroom compost. Active Constituent(s): Cyromazine Regulatory Decision: To grant the application subject to the following conditions: Standard Conditions of Registration/Approval 1. Containers must meet AgVet Code Regulation 18 2. Agricultural products must meet Active Constituents Quality Assurance Requirements 3. Label must contain a Date of Manufacture and Batch Number For full conditions, refer to Standard Conditions for Applications on the APVMA website. 57009 Page 1 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007 ADVICE Australian Government Department Of Health And Ageing, Office Of Chemical Safety (OCS) The Acceptable Daily Intake (ADI) for cyromazine is 0.02 mg/kg bw/d, established in 1998 based on a No Observable Effect Level (NOEL) of 1.8mg/kg bw/d from a 2-year rat dietary study. No Acute Reference Dose (ARfD) has been established for cyromazine and no data were submitted to enable an ARfD to be set. Cyromazine is listed in Appendix B of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP), as a substance considered not to require control by scheduling due to its low toxicity. The data package provided in the present submission comprised four acute toxicology studies on the proposed product, Diptex 150 WP Insect Growth Regulator (Diptex 150WP). The toxicology studies submitted have been conducted in accordance with contemporary test guidelines, with the exception of an eye irritation study. The data submitted were considered to be adequate for the assessment of the acute toxicology profile of the proposed product. The data provided in the toxicity studies were relied on by the OCS in considering whether the proposed use of the product would be an undue health hazard to humans. Based on the studies submitted, the formulated product was of low acute oral toxicity, was a slight skin irritant, a moderate eye irritant and is not a skin sensitiser. No acute dermal or inhalational studies were submitted with the product. Based on the acute toxicology profile of the active ingredient and those of the product excipients, it is likely to be of low acute dermal toxicity, however is likely to be a moderate inhalational toxicant. The toxicology data provided and considered in this assessment justify the recommendations in the present evaluation. Furthermore, the proposed use of Diptex 150WP will not be an undue health hazard to humans according to the criteria stipulated in Section 14 of the AgVet Code Act of 1994. 57009 Page 2 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007 Data relied on to provide the advice Data No Data Source* Author(s) Title Date Data Type Data Sub-type Authorising Inherited Party Application No. 73815 S R. Sornat DVM, Inga Mrzyk MSc Report of Toxicological studies - part 2 Acute eye irritation / corrosion study on rabbits June, 2003 Toxicology Acute Eye Irritation Studies, Product Applicant 73816 S Dr Bozena Wiadrowska Acute Oral Toxicity in the Rat for the Product Agrofarm Cyromazyna 150 WP 10 August, 2000 Toxicology Acute Oral Studies, Product Applicant 73817 S R. Sornat DVM, Inga Mrzyk MSc Report of Toxicological studies - part 1 Acute skin irritation / corrosion on rabbits June, 2003 Toxicology Acute Skin Irritation Studies, Product Applicant 73818 S R. Sornat DVM, Inga Mrzyk MSc Agro-Tip 150 WP Report of skin sensitization study on guinea pigs June, 2003 Toxicology Acute Skin Sensitisation Studies, Product Applicant Australian Government Department Of Environment And Heritage (DEH) Agrocare Pty Ltd is seeking registration and label approval for the use of the product Diptex 150 WP Insect Growth Regulator (Diptex 150WP) for control of sciarid and phorid fly larvae in the compost used in mushroom production. The product is a wettable powder containing the active constituent cyromazine (150 g/kg). The use in mushroom production represents the first Australian application of cyromazine in a predominantly non-animal husbandry situation. Cyromazine is currently approved for use in Australia in animal health protection as a feed-through insect growth regulator to control larvae of nuisance flies in poultry manure. A summary of ecotoxicity studies in which fish, daphnia and a green algae were exposed to the formulated material was presented in addition to an expert report of an appraisal of potential risk to bees from use of the product. New environmental fate data were not presented. The environmental risk assessment considered the risks arising from the proposed registration and also from the use of spent mushroom compost added to soil, this latter being the significant route of potential environmental exposure. A public domain document relating to removal of restrictions against use of treated mushroom compost as a fertiliser was provided. DEH concluded that the registration of Diptex 150 WP for control of sciarid and phorid fly larvae in the compost used in mushroom production at 33.3 g/tonne of compost or at spawning or from 270 to 470 g/100 m2 for after casing rates is unlikely to have a harmful environmental effect as such uses are restricted to localised areas where the compost is prepared or within buildings when treatment is at a later stage of the mushroom growing process. These use patterns are expected to give little opportunity for off-site movement and resultant terrestrial or aquatic exposure. 57009 Page 3 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007 The principal source of environmental exposure is expected to be via the use of spent mushroom compost as a soil fertiliser/amending agent. It is here that any residual cyromazine and melamine, a relatively stable chemical formed by cyromazine degradation, will have the opportunity to enter either the soil or, via runoff, the water compartments. Exposure of birds to residues of both cyromazine and melamine in spent mushroom compost is expected to be negligible and the risk acceptably low. With respect to risk to aquatic species, the spent mushroom compost is a solid material either layered onto, or dug into, the soil; consequently spraydrift is not a route of contamination. While runoff waters from soils treated with spent mushroom compost could carry cyromazine and melamine off-site resulting in potential exposure to aquatic organisms, the risks to these organisms are expected to be acceptable and risk to aquatic species as a result of movement of cyromazine or melamine from spent compost into groundwater was indicated as acceptable. The risk to honey bees from the proposed use of cyromazine in compost preparation is expected to be negligible as the composting sites are not considered likely to contain any significant levels of flowering plants. Bees are not, therefore, likely to be attracted to such areas. Similarly, the spent mushroom compost is considered unlikely to be attractive to bees. Consequently, risk to honey bees and the flying, pollinating insects for which they are surrogates, is expected to be acceptable. Earthworms will be directly exposed to residues of cyromazine and melamine present in spent mushroom compost that is used on soil. The DEH risk assessment showed that the acute and long-term applications of spent mushroom compost that might contain residues of these two chemicals are not expected to result in unacceptable risk to earthworms. Data and information available to the DEH indicated that the proposed use of Agro-Tip 150 WP is unlikely to have adverse effects on soil micro-organisms. Comparison of expected cyromazine soil levels as a result of use of spent mushroom compost with available phytotoxicity endpoints indicated significant adverse phytotoxicity effects are not expected to occur as a result of use of Agro-Tip 150 WP in the mushroom compost’s preparation. The presence of melamine in spent mushroom compost is not expected to result in unacceptable phytotoxicity effects. DEH recommended that the APVMA be satisfied that the proposed registration of use of Diptex 150 WP Insect Growth Regulator for control of sciarid and phorid fly larvae in the compost used in mushroom production would not be likely to have an unintended effect that is harmful to animals, plants, or things or to the environment under s 14(1) of the AgVet Code Act 1994 when the product is used as proposed. 57009 Page 4 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007 Data relied on to provide the advice Data No Data Source* Author(s) Title Date Data Type Data Sub-type Authorising Party 86271 S United State Environmental Protection Agency Removal of Restriction Against Using Treated Mushroom Compost as Fertilizer. Review of Field Accumulation in Rotational Crops Study 27 January 2004 Environment Fate Field Dissipation Soils Public 86278 S Anna Raszka PhD, Ewa Nierzedska MSc, Przemyslaw Fochtman PhD Evaluation of toxicological effects of preparation Agrofarm Cyromazyna 150 WP on aquatic organisms November 2000 Environment Toxicology Aquatic Organisms Other Applicant 86273 S Institute of Environmental Protection Expert opinion on extension of application of AgroTip 150 WP and classification of toxicity for bee 28 April 2008 Environment Toxicology Non-target Invertebrates (terrestrial) Bees Applicant Inherited Application No. APVMA Chemistry And Residues Program, Residues Team Cyromazine is currently approved for use in Australia in animal health protection as a feed-through insect growth regulator to control larvae of nuisance flies in poultry manure. The Applicant has supplied data concerning the metabolism of cyromazine (JMPR summary report, EFSA conclusion report and two academic papers) and information regarding analytical methods. The results of a Good Laboratory Practice (GLP) residues study in mushrooms conducted in Poland were also submitted. A summary of metabolism studies which were conducted on celery, lettuce and tomatoes (representing leafy and fruit crop groups) showed that the common metabolism pathway for the breakdown of cyromazine was to yield the dealkylated product melamine. Parent cyromazine and melamine represented the major part of the TRR, accounting for 37.1%–74.0% and 10.9–45.4% respectively. A summary of five trials conducted on non-radioactive cyromazine showed that residues did not accumulate significantly in mushrooms under normal use conditions when the crop was grown in amended compost. Cyromazine residues were <0.05 mg/kg in mushrooms in all trials/ flushes with the exception of one trial at a target cyromazine concentration in the compost of 10 mg ai/kg. Residues of melamine were in the range 1.5–6.6 mg/kg after application to compost at 5 mg ai/kg. Two papers were submitted which showed the metabolism of radio-labelled cyromazine in greenhouse tomatoes and the fate of cyromazine in plants (bok choy, napa cabbage and Chinese mustard) under environmental conditions. In both studies the only metabolite of cyromazine to be identified was melamine. The current residue definition for cyromazine is cyromazine. The available plant metabolism, analytical methods and toxicological advice support the current residue definition of “cyromazine”. 57009 Page 5 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007 A GLP residue study involving residue trials conducted on champignons has been provided in support of the application. The trials were conducted in Poland during 2010. The highest cyromazine residues observed in champignons were 1.36 mg/kg. In additional summary data from JMPR, in which application was made to casing layer/ compost at 2.0–8.0 kg ai/ha, residues at PHIs ranging from 13–57 days ranged from 0.19–4.2 mg/kg. On the basis of the supplied data a Maximum Residue Limit (MRL) in mushrooms is proposed at 10 mg/kg. A Withholding period (WHP) “DO NOT HARVEST FOR 21 DAYS AFTER APPLICATION” is supported when Diptex 150 WP Insect Growth Regulator is used as proposed. Data relied on to provide the advice Data No Data Source* Author(s) Title Date Data Type Data Sub-type Authorising Inherited Party Application No. 73822 S D.S. Root, T. Hongtrakul and W.C. Dauterman Studies on the Absorption, Residues and Metabolism of Cyromazine in Tomatoes 22 January 1996 Residues Crop Residues Human Consumption Public 73823 S Lori O. Lim, Susan J. Scherer, Kenneth D. Shuler, and John P. Toth Disposition of Cyromazine in Plants under Environmental Conditions 1990 Residues Crop Residues Human Consumption Public 73821 S FAO (Food and Agriculture Organization of the United Nations) Cyromazine. In: Pesticide residues in food - 2007. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues 2007 Residues Crop Residues Human Consumption Public 73812 S Edyta Mincewicz MSc Determination of Residues of Cyromazine in Champignons after Application of Agro-Tip 150 WP Formulation May, 2011 Residues Crop Residues Human Consumption Applicant 73814 S European Food Safety Authority Review of the existing maximum residue levels (MRLs) for cyromazine according to Article 12 of Regulation (EC) No 396/2005 2011 Residues Crop Residues Human Consumption Public 73819 S Assoc. Prof.Czeslaw Slusarski, PhD, Robert Wrzodak, MSc, Maria Rogowska, PhD Sampling Report. Sampling of mushrooms for residue testing. Report Number: AGMS-A December 2010 Residues Crop Residues Human Consumption Applicant 73820 S J. Smith and T. Boone Determination of Cyromazine and Melamine Residues in Crops 15 July 1983 Residues Crop Residues Human Consumption Public 57009 Page 6 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007 External Efficacy Reviewer Two studies conducted in mushroom-growing facilities in Europe, with white button mushrooms, Agaricus biosporus were provided. The methods, study designs and formulations were appropriate. These studies were designed to meet the guidelines of the European & Mediterranean Plant Protection Organisation (EPPO). The applicant provided detailed reports of the two studies, which were executed in Skierniewice and Warsaw, Poland. Mushrooms were grown in plastic boxes in controlled growing conditions in mushroom growing rooms. Diptex 150WP was either mixed with the compost (growing medium) or sprayed onto the surface of the growing medium. The efficacy of Diptex 150WP was assessed by counting the number of Sciaridae & Phoridae flies that emerged from the compost and were captured on sticky plates in the mushroom growing rooms. There was 80 to 100% control of flies in the boxes treated with Diptex 150WP and this was statistically significant. Diptex 150WP did not have an adverse effect on the mushroom fruit-bodies (crop). The data from these reports demonstrate that Diptex 150WP effectively controls Megaselia halterata (Phoridae) and Lycoriella solani (Sciaridae) under commercial growing conditions during the cultivation of white button mushrooms. The methodology and results of these trials is considered representative of commercial mushroom growing conditions in Australia and demonstrates that AGRO-TIP 150WP should be effective as claimed on the label, when used according to the proposed label instructions. The APVMA accepts the advice provided in regard to the efficacy criteria. Data relied on to provide the advice Data No Data Source* Author(s) Title Date Data Type Data Sub-type Authorising Inherited Party Application No. 73810 S Maria Rogowska PhD, Assoc Prof Czeslaw Slusarski PhD, Robert Wrzodak MSc Evaluation of the biological efficacy of the plant protection product Agro-Tip 150 WP, applied to the casing or compost, in the control of larvae of Sciaridae Lycoriella ingenua and larvae of Megaselia halterata occuring in mushroom culture 2010 Efficacy and Safety Efficacy Applicant 73809 S Prof. Jerzy Szwejda, Prof. Stanislaw Ignatowicz, Krystian Szudyga PhD The Assesment of Biological Effectiveness Agro-Tip 150 WP Preparation Against Megaselia Haltertata Meig. (Diptera Phoridae) and Lycoriella Solani Winn. (Diptera: Sciaridae) in the Growing of White button mushroom (Agaricus biosporus) 2010 Efficacy and Safety Efficacy Applicant Other Details About The APVMA’s Decision To Grant The Application Based on other information available to the APVMA the APVMA was able to be satisfied on all criteria under the AgVet Codes. * S = Data submitted with the application I = Data inherited (that is, referenced) from another application 57009 Page 7 of 7 KP25S_F39 Version: 2 Issued: 14/08/2007