Competent Authority Report
Work Programme for Review of Active Substances in Biocidal Products Pursuant to Council Directive 98/8/EC
Inclusion of active substances in Annex I and 1Ato Directive 98/8/EC
DOCUMENT 1
Diflubenzuron(PT 18)
Applicant: Safepharm Laboratories
RapporteurMemberState: Sweden
Draft November 2007
RMS: SwedenApplicant Safepharm Laboratories / Diflubenzuron PT18 / Doc I
CONTENTS
1.PURPOSE FOR WHICH THE COMPETENT AUTHORITY REPORT WAS PREPARED
1.1.Introduction
1.2.Name and address of applicant
1.3.Manufacturer of the active substance
1.4.Manufacturer of the Product(s)
1.5.Acceptance of the dossier and evaluation work
2.OVERALL SUMMARY AND CONCLUSIONS
2.1.Presentation of the Active Substance
2.1.1.Identity, Physico-Chemical Properties & Methods of Analysis
2.1.2.Intended Uses and Efficacy
2.1.3.Classification and Labelling
2.2.Summary of the Risk Assessment
2.2.1.Human Health Risk Assessment
2.2.2.Environmental Risk Assessment
2.2.3.List of endpoints
3.PROPOSED DECISION
3.1.Background to the proposed decision
3.2.Proposed decision regarding Inclusion in Annex I and Annex 1A
3.3.Elements to be taken into account by Member States when authorising products
3.4.Requirement for further information
3.5.Updating this Assessment Report
Appendix I: List of endpoints
Chapter 1:Identity, Physical and Chemical Properties, Classification and Labelling
Chapter 2:Methods of Analysis
Chapter 3:Impact on Human Health
Chapter 4:Fate and Behaviour in the Environment
Chapter 5:Effects on Non-target Species
Appendix II: List of Intended Uses
Appendix III: List of studies
Appendix IV: List of standard terms and abbreviations
1.PURPOSE FOR WHICH THE COMPETENT AUTHORITY REPORT WAS PREPARED
1.1.Introduction
This competent authority (CA) report and supporting Documents II-A, II-B, II-C, III-A, III-B, and the confidential annex have been prepared for submission to the European Commission to enable a decision to be made on the inclusion of diflubenzuron, as product type 18 (insecticide), in Annex I and Annex 1A of Directive 98/8/EC as a part of the review programme referred to in Article 16(2) of the Directive.
1.2.Name and address of applicant
Safepharm Laboratories
Shardlow business park
London road
Shardlow
Derbyshire
DE72 2GD
1.3.Manufacturer of the active substance
Ensystex
2709 Breezwood Ave.
Fayetteville,
NC 28303
USA
1.4.Manufacturer of the Product(s)
Ensystex
2709 Breezwood Ave.
Fayetteville,
NC 28303
USA
1.5.Acceptance of the dossier and evaluation work
This Evaluation Report was prepared by the Swedish Competent Authority, Swedish Chemicals Agency (KEMI).The dossier, including study reports and summaries, were accepted as complete for evaluation on the 31st October, 2006.
2.OVERALL SUMMARY AND CONCLUSIONS
2.1.Presentation of the Active Substance
2.1.1.Identity, Physico-Chemical PropertiesMethods of Analysis
2.1.1.1.Identity
CAS-No. / 35367-38-5EINECS-No. / 252-529-3
Other No. (CIPAC, ELINCS) / CIPAC-No: 339
IUPAC Name / 1-(4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea
CA Name / N-[[(4-chlorophenyl)amino]carbonyl]-2,6-difluorobenzamide
Common name, synonyms / ISO common name: diflubenzuron
Structural formula /
Molecular formula / C14H9ClF2N2O2
Molecular weight (g/mol) / 310.7
Purity of a.s. / A min. purity of 99.4±0.4% is given by the applicant.
The RMS considers a specified minimum purity of 97.3% to be more appropriate (see further the Confidential Annex)
Impurities / None of the impurities present in technical diflubenzuron are considered relevant. The information on impurities is found in the Confidential Annex.
Additives / No additives
Representative biocidal product / Labyrinth ACTM Termite Bait(asolid bait formulation containing 0.25%w/w diflubenzuron to be used in a termite bait station)
2.1.1.2.Physico-Chemical Properties
Diflubenzuron is a white, crystalline solid with a slightly faintodour. Diflubenzuron has a melting point of 228.8°C and it is claimed to decompose upon melting (published data). The relative density has not been determined but it is not considered required for risk characterisation. The solubility of diflubenzuron in water is quite low with a solubility of 0.38mg/l at pH 7.0. No pH effect was shown for the solubility as it was virtually the same at pH4.89 (0.35 mg/l) and pH 9.01 (0.29 mg/l). Hereby, diflubenzuron is considered not to be ionisable within the environmentally relevant pH range. The vapour pressurewas not determined as published data (1.2 x 10-7 Pa) indicates that the vapour pressure is significantly lower than 1 x 10-5 Pa, which is the criterion according to the TNsG. Using the published value for vapour pressure and the experimentally derived water solubility a Henry’s Law Constant of 9.81 x 10-5Pa m3mol-1is obtained which indicates that volatilisation is not expected to significantly contribute to the dissipation of diflubenzuron in the environment. The Log Pow was tested by the HPLC-method (i.e. OECD 117), but the temperature and the pH was not stated.However, the obtained log Pow of 3.73is in good agreement with published data (3.89) and it indicates that diflubenzuron may bioaccumulate. Diflubenzuron is soluble in methanol and less so in hexane. Diflubenzuron is not highly flammable or auto-flammable and based on structural properties and experience in use it is not considered explosive or oxidizing.
2.1.1.3.Analytical methods
The content of diflubenzuron in the technical material was determined by HPLC-UV in accordance with a slightly modified version of the standard method CIPAC 339. The modifications were considered minor and since the provided repeatability data was within the range accepted by the method no further validation data is considered necessary.
A method based on HPLC-UV was provided to address the analysis of diflubenzuron in soil. However, the method was not considered acceptable due to the lack of validation data. No further methods were provided for residue analysis. However, the release of diflubenzuron from the representative biocidal product Labyrinth ACTM Termite Bait to soil, air and water is very limited. Therefore, no monitoring methods for these compartments are considered necessary.
Furthermore, no method is considered necessary for body fluids and tissues as diflubenzuron is not classified as toxic or highly toxic. Moreover, no method has been required for food or feeding stuffs as the intended use will not result in any contact with these matrices.
2.1.2.Intended Uses and Efficacy
The intended uses of the representative biocidal product Labyrinth AC™ is to control termites in house grounds. The product will not be used where rain or any water can reach the product.
Acceptable studies, indicating a high efficacy of Labyrinth AC™ in decreasing the termite activity have been provided. In addition, in order to facilitate the work of Member States in granting or reviewing authorisations, and to apply adequately the provisions of Article 5(1) of Directive 98/8/EC and the common principles laid down in Annex VI of that Directive, the intended uses of the substance, as identified during the evaluation process, are listed in Appendix II.
2.1.3.Classification and Labelling
Classification and labelling of the active ingredient
Risk phrases / R48/20/22 Harmful: Danger of serious damage to health by prolonged exposure through inhalation and if swallowed.R50/53 Very toxic to aquatic organisms. May cause long-term adverse effects in the aquatic environment.
Safety phrases / S2 Keep out of reach of children.
S13 Keep away from food, drink and animal feedingstuffs.
S20/21 When using do not eat, drink or smoke.
S60 This material and/or its container must be disposed of as hazardous waste.
S61 Avoid release to the environment. Refer to special instructions/ safety data sheets.
Proposal for labelling / Xn,N
R48/20/22, R50/53
S2, S13, S20/21, S60, S61
Existing classification and labelling / Diflubenzuron is not classified on Annex 1 of the Dangerous Substances Directive 67/548/EEC
Proposed classification and hazard statement according to GHS:
H373, H410
The current classification has been directly translated into corresponding GHS phrases, using the translation list “Translation between classification in accordance with Directive 67/548/EEC and the new EU C&L Regulation” i.e Annex VII to Proposal for a Regulation of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures, and amending Directive 67/548/EEC and Regulation (EC) No 1907/2006” (COM(2007) 355 final).
Classification and labelling of the formulated product Labyrinth ACTM.
No proposal for product classification was provided by the applicant. According to the criteria in Annex VI to Directive 67/548/EEC, the formulated product should be classified for the environment. Based on a concentration of the active ingredient of 0.25% and an M-factor of 100 (this factor to some extent takes into account uncertainties in the available data for aquatic organisms) the product should be classified as R52/53.
2.2.Summary of the Risk Assessment
2.2.1.Human Health Risk Assessment
2.2.1.1.Human health effects of active substance, diflubenzuron
The critical effect of diflubenzuron is increased formation of Methaemoglobin and sulfhaemoglobin causing anaemia after repeated exposure.
The absorption of diflubenzuron is dose-dependant in rat, with approximately 50% being absorbed at 4-5 mg/kg bw and 3-4% at approximately 100 mg/kg bw. Less detailed information from mouse and pig confirm these findings. The half life of radioactivity in rat blood is approximately 14 hours. Detailed tissue distribution studies have not been conducted but in rat excretion was essentially completed after 48 hours. From the summarised studies, the conclusion could be drawn that dermal absorption is limited in both rat (<0.5%) and rabbit (<1%). However, as the RMS has not had the possibility to evaluate these studies we will use the default value of 10% dermal absorption when the risk assessment should be performed.
The acute toxicity is low oral; LD50>4640 mg/kg bw/day, dermal; LD50>2000mg/kg bw/day and LC50>2.49 mg/L. The substance is not skin or eye irritant or corrosive neither is it a sensitising substance. Diflubenzuron is neither mutagenic nor carcinogenic. It is not toxic to reproduction nor considered neurotoxic.
The Acceptable Operator Exposure Level (AOEL) is the lowest sub-chronic NOAEL, in this case the NOAEL for long term toxicity/carcinogenicity (2 mg/kg bw/day), divided by an Assessment Factor of 1000 (x10 for inter-species effects and x10 for inter-individual effects and x10 for the insecurity in data as no original studies was submitted). An oral absorption of approximately 50 % has also to be taken into account. The AOEL is therefore 0.001 mg/kg bw/day. It should be noted that the NOAEL is via the oral route. The major effect observed at the LOAEL was increased methaemoglobin and sulfhaemoglobin together with other effects on blood parameters indicating anaemia.Bystanders will not be exposed to the active substance, diflubenzuron.
2.2.1.2.Human health effect of product
Exposure by oral, inhalation and dermal routes is not expected due to the mode of presentation of the active substance in the product and the use of gloves. Cellulose has been impregnated with the active compound, which is not volatile and the cellulose is non dusty. The piece of cellulose is in a closed cartridge that is placed in a bait station.
2.2.1.3.Human health risk for professional users
Only professional users will be handling the product and that is when the closed cartridges are placed and removed from the bait station. There will be no oral exposure and the dermal and inhalation exposure will be negligible especially as gloves are recommended. Since exposure is considered to be immeasurably low, a margin of safety cannot be calculated.
2.2.1.4.Human health risk for non-professional users
With the suggested use there is no exposure to non-professionals.
2.2.1.5.Human health risk from indirect exposure as result of use
Due to the intended use, were the active substance is in a cartridge in the bait station, there will be no indirect exposure.
2.2.2.Environmental Risk Assessment
2.2.2.1.Fate and distribution in the environment
Due to the recommended use of diflubenzuron in the formulation Labyrinth ACTM, small amounts of the compound will be released to the environment. Due to low potential for volatilisation and mobility in soil, no release is expected to air, surface water or ground water, while release to soil is anticipated mainly via movement of termites that have ingested the formulation.
Diflubenzuron was assessed to be hydrolytically stable at environmentally relevant temperatures and pH conditions. The rate of photolysis was not possible to quantify based on available data, it is however indicated that photolysis may be an important abiotic degradation pathway in the environment.
In studies on aerobic degradation of diflubenzuron in soil, the parent compound was transformed with half-lives from <2 – 2 days at 24°C and 14°C, respectively. Similar half-lives were obtained at anaerobic conditions. Major metabolites formed were CPU and DFBA. As no specific information is available on possible effects from the metabolites, for this risk assessment it is considered more relevant to use a DT50 based on the total extractable fraction (this implies an assumption that the metabolites are of equal toxicity as the parent). From the study by Nimmo et al, 1984, a DT50 based on total extractable radioactivity (parent, CPU and DFBA) could be estimated to 14-28 days at 14°C and ca 7 days at 24°C. As a rough estimate of a reasonable worst case, the DT50 at 20°C (‘standard’ conditions) is considered to be approximately 14 days. This value was identical to that proposed by the applicant in their exposure assessment for the soil compartment in the original dossier.
No reliable DT50 value can be determined for the water/sediment compartment from the available studies. For the recommended use of diflubenzuron in this case, however, it can be expected that negligible amounts will be released to surface water and therefore no further data is needed. The above data on biodegradation is considered to be sufficient for environmental classification purposes. Diflubenzuron can be denoted the risk phrase “R53”; not readily biodegradable.
Diflubenzuron has an estimated half-life of 7.9 hours in air, therefore is predicted to have no effect on stratospheric ozone. It is predicted to not be a potential greenhouse gas.
The available adsorption/desorption data indicate that diflubenzuron is rapidly and relatively strongly adsorbed to soil. The compound is expected to have a moderate potential for mobility in the soil profile.
None of the available studies were conducted in accordance with standard test protocols for bioconcentration tests or to GLP standards and no quantitative estimations could be made from the results. Due to the limited exposure of the aquatic and terrestrial environment at the recommended use of the present formulation, however, it is still considered to give sufficient indications of acceptable levels of bioconcentration. In conclusion, though diflubenzuron appears to be absorbed quite readily it also seems to be depurated rapidly, and hence bioaccumulation is not thought to be of concern.
2.2.2.2.Effects assessment
The studies on aquatic organisms were generally of insufficient quality (for various reasons, see Doc IIIA) to establish reliable endpoints for a risk assessment. For the proposed use of diflubenzuron in this case, however, the exposure of surface water is considered to be negligible. Hence, the data only need to fulfil the requirements for an environmental classification of the compound. From available studies, it is clear that the criteria for R50 are fulfilled due to the high toxicity to aquatic invertebrates.
Overall, the studies on terrestrial organisms submitted in the original dossier were insufficient (see Doc IIIA) to establish reliable endpoints for a risk assessment. Furthermore, based on the mode of action of diflubenzuron, the tested organisms most likely did not belong to the most sensitive groups of species. Therefore, the applicant was asked to provide additional studies on soil dwelling arthropods. The applicant submitted a number of studies from published literature.
In one study, larvae of Diaprepes abbreviatus (sugar-cane rootstalk borer weevil) were exposed to diflubenzuron via different routes (contact with treated soil, contact with solution, or ingestion of treated diet). This species does most likely belong to the most sensitive group. No clear dose-response curve could be derived from the study (mortality was 56.5, 73.9, 65.2 and 65.2% at dietary concentrations of 10, 100, 500 and 1000 ppm diflubenzuron, respectively, and no data was reported for the control and lower test concentrations), therefore no reliable LC50 value can be derived from this study. It was shown however that only exposure via ingestion resulted in mortality of more than 50% after 4 months. This was supported also by studies on other species. Further, the additional data showed that adult life stages of soil arthropods are not affected by diflubenzuron.
No data are available on the effects of the metabolites CPU and DFBA formed in aerobic soil degradation studies. For the risk assessment, it is assumed that the metabolites are of equal toxicity as the parent compound. This may, however need to be discussed.
2.2.2.3.PBT assessment
Diflubenzuron is assessed to not fulfil the criteria for PBT substances.
2.2.2.4.Exposure assessment
Due to the low solubility and its mode of use, it is expected that no release to surface water, ground water or sediment will occur.Diflubenzuron has low volatility and emissions to the air compartment are expected to be negligible from the recommended use of the product.
In the applicant’s proposal, the fraction of active ingredient directly released to soil resulting from spill during application, re-fill and disposal of the bait station was included in the exposure estimation. These stages of the use of biocidal products, however, are normally not taken into account in the risk assessment at the EU level. To be consistent with assessments for similar products, therefore only the indirect release via movement of the termites should be considered.
The applicant proposed that a fraction of 10% of the active ingredient would be released via indirect exposure (from termites). This figure was not supported by data and is therefore not considered to be relevant for this assessment. In the study by Nimocks et al 2006, however, analyses of soil samples around a bait station during a period of 50 days showed that <16% (LOQ of the analytical method) of the amounts of diflubenzuron in the bait was released to the surrounding soil.
There is at present no Emission Scenario Document available for this type of products.Based on discussions during a workshop concerning Product Type 18 held in Brussels in December 2007, a 'standard' soil compartment for this type of products was recommended to have a radius of 50 cm and a depth of 10 cm where the compound is assumed to be evenly mixed intothe soil (total volume 0.0785 m3). Assuming a soil density of 1700 kg/m3, this corresponds to133.45 kg soil. Considering that <16% of the amount of active ingredient used in a control campaign (3 x 0.820 g) will be indirectly released via the movement of termites, an interval of 30 days between each re-fill and a degradation half-life of 14 days would result in a PECsoil for diflubenzuron of <1.255 mg/kg directly after the last re-fill after 60 days. This value may be used as a starting point in the risk assessment for soil dwelling organisms.
Factors to consider qualitatively:
The calculations above are based on “non-measured” concentrations in the soil around a bait station (<LOQ) from the study by Nimocks et al (2006) in the absence of better methods of analyses.