Product-type 18 (Insecticide)

Transcription

1 Directive 98/8/EC concerning the placing of biocidal products on the market Inclusion of active substances in Annex I or IA to Directive 98/8/EC Document I Product-type 18 (Insecticide) Annex I - UK Page 1 of 45

2 IMIPROTHRIN (PT18) Document I UK Competent Authority Report CONTENTS 1. STATEMENT OF SUBJECT MATTER AND PURPOSE Introduction OVERALL SUMMARY AND CONCLUSIONS Presentation of the Active Substance Identity, Physico-Chemical Properties & Methods of Analysis Intended Uses and Efficacy Classification and Labelling Summary of the Risk Assessment Human Health Risk Assessment Hazard identification Effects assessment Exposure assessment Risk characterisation Environmental Risk Assessment Fate and distribution in the environment Effects assessment PBT assessment Exposure assessment Risk characterisation List of endpoints DECISION Background to the Decision Decision regarding Inclusion in Annex I Elements to be taken into account by Member States when authorising products Page 2 of 45

3 3.4. Requirement for further information 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 Chapter 6: Other End Points APPENDIX II: LIST OF INTENDED USES Page 3 of 45

4 1. STATEMENT OF SUBJECT MATTER AND PURPOSE 1.1. Introduction This report and the supporting Documents II-A, II-B, II-C, III-A and III-B assess the use of the biocidal active substance, imiprothrin (CAS No ), as an insecticide, according to the procedures of Directive 98/8/EC concerning the placing of biocidal products on the market. The UK Competent Authority (UK CA, the Health & Safety Executive, HSE) proposes the inclusion of imiprothrin as an insecticide on to Annex I of Directive 98/8/EC. This report has not yet been discussed with experts from other Member States and contains only the views of the UK CA. is marketed by Sumitomo Chemical (UK) Plc and they submitted a dossier to the UK CA, including original test reports and study summaries, and this was accepted as complete for evaluation. For the use of imiprothrin as an insecticide (PT 18), the risks to human health and the environment, including any risks from physico-chemical properties and possible unacceptable effects, have been assessed in accordance with the provisions laid down in the Directive. The report will help Member States to make future decisions on individual biocidal products containing imiprothrin, in accordance with the provisions of that Directive, and in particular the provisions of Article 5(1) and the common principles laid down in Annex VI of that Directive. The information in this evaluation report is, at least partly, based on information that is protected under the provisions of Directive 98/8/EC. This evaluation report shall not be used to support any registration outside the context of Directive 98/8/EC, e.g. in other countries, unless the applicant has demonstrated legitimate access to the information on which this evaluation report is based. Page 4 of 45

5 2. OVERALL SUMMARY AND CONCLUSIONS 2.1. Presentation of the Active Substance Identity, Physico-Chemical Properties & Methods of Analysis is the common name for a reaction mass of; 2,5-dioxo-3-prop-2-ynylimidazolidin- 1-ylmethyl (1R)-cis-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylate; 2,5-dioxo- 3-prop-2-ynylimidazolidin-1-ylmethyl (1R)-trans-2,2-dimethyl-3-(2-methylprop-1- enyl)cyclopropanecarboxylate (ca 20:80). is a viscous amber liquid with molecular mass gmol -1. It has a low volatility at room temperature and decomposes at 128 C. It has a water solubility of 93.5 mg/l at 25 C, relative density of 1.12 and vapour pressure 1.86 x 10-6 Pa. The octanol-water partition coefficient (LogP ow 2.9 at 25 C) makes imiprothrin a moderately fat soluble compound. is stable to hydrolysis under acidic conditions, hydrolyses slowly under neutral conditions (t½ = 58.6 days at ph 7) and readily hydrolyses under basic conditions (t½ = 17.9 hours at ph 9) Intended Uses and Efficacy The assessment of the biocidal activity of the active substance demonstrates that it has a sufficient level of efficacy against the target organism(s) and the evaluation of the summary data provided in support of the efficacy of the accompanying product, establishes that the product may be expected to be efficacious. 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 Classification and Labelling Active Substance () Current Classification Classification R-phrases Xn: Harmful N: Dangerous for the environment R22: Harmful if swallowed. R50/53: Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment. Proposed classification based on Directive 67/548/EEC On the basis of a review of the data submitted, the UK CA proposes the following classification for imiprothrin. This proposal should be discussed further at the Risk Assessment Committee at the European Chemicals Agency; therefore there is no guarantee that it will remain unchanged. Page 5 of 45

6 Classification Class of danger R-phrases Proposed classification for imiprothrin following evaluation Xn: Harmful N: Dangerous for the environment R20/22: Harmful by inhalation and if swallowed R50/53: Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment. The Applicant does not agree with the proposal to classify imiprothrin with R20 (harmful by inhalation). A justification for their position is provided in Annex I of Document II-A. Proposed classification based on CLP Regulation SIGNAL WORD Classification H-Statements WARNING Acute Tox 4 Inhalation Acute Tox 4 Oral Aquatic Acute 1 Aquatic Chronic 1 H332: Harmful if inhaled. H302: Harmful if swallowed H400: very toxic to aquatic life H410: very toxic to aquatic life with long lasting effects Biocidal Product (Pralle 0.5 % aerosol) Current Classification The biocidal product is not classified according to Annex I of Council Directive 67/548/EEC. Proposed classification based on Directive 67/548/EEC Based on the proposed classification for imiprothrin, and information available on the coformulants, the classification of the representative product (Pralle 0.5 % aerosol) can be determined. The proposed classification for the product will also be subject to the decision reached at the Risk Assessment Committee at the European Chemicals Agency, regarding imiprothrin; therefore there is no guarantee that it will remain unchanged. Classification Class of danger R-phrases Proposed classification for Pralle 0.5 % aerosol following evaluation F+: Extremely flammable N: Dangerous for the environment R12: Extremely flammable R52/53: Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment. Page 6 of 45

7 Proposed classification based on CLP Regulation: SIGNAL WORD Classification H-Statements DANGER Flam Liq 1 Aquatic Chronic 3 H224: Extremely flammable liquid and vapour H412: Harmful to aquatic life with long lasting effects There is a separate hazard class in CLP for flammable aerosols and also for receptacles containing compressed or liquefied gases. SIGNAL DANGER WORD Classification Aquatic Chronic 3 H222: Extremely flammable aerosol H-Statements H280: Contains gas under pressure ; may explode if heated H412: Harmful to aquatic life with long lasting effects 2.2. Summary of the Risk Assessment Human Health Risk Assessment Hazard identification Toxicology Hazard Summary The toxicity of imiprothrin has been studied in experimental animals; although there are no data available for humans, this is not considered to be a data gap. In rodents, imiprothrin is extensively absorbed following oral and inhalation exposure and it is concluded that absorption values of 100 % are derived for these routes for use in the human health risk characterisation. The only dermal absorption data available are for an aqueous formulation containing 1 % (w/v) imiprothrin for which a value of 5 % was measured for human skin in vitro. Thus, a dermal absorption value of 5 % will be assumed through human skin. Following absorption, extensive metabolism occurs in rodents and imiprothrin and/or its metabolites will be widely distributed. Although there is no specific information to establish whether or not imiprothrin undergoes first pass metabolism, the speed of clearance, the high percentage of metabolites present in the urine, the observation of neurotoxicity after intraperitoneal injection in mice not seen following oral dosing in acute and repeat-dose studies and the fact that toxicity following inhalation exposures occurs at lower dose levels than following oral exposures, indicate that significant first pass metabolism can be assumed. In rodents, elimination is rapid and occurs predominantly via the urine. The ability of imiprothrin to partition into the breast milk and to cross the blood-placenta barrier has not been investigated, but given its relatively high molecular weight it is not considered likely to occur. Page 7 of 45

8 is of moderate acute toxicity in both rats (LD 50 values of 1800 and 900 mg/kg in males and females, respectively) and mice (LD 50 values of 724 and 550 mg/kg reported in males and females, respectively) by the oral route; the mouse appearing to be the more sensitive species. Clinical signs of toxicity suggestive of neurotoxic effects were seen in both species with changes in functional observational battery (FOB) occurring in rats treated with 300 mg/kg in an acute neurotoxicity study. However, no neuropathological changes were seen in the acute and sub-chronic neurotoxicity studies. aerosol is also of moderate toxicity in rats. No mortality was observed at the maximum achievable concentration (by the experimental device) of 1.2 mg/l; however, LC 50 values of mg/l in male and mg/l in female rats were reported for single inhalation exposure to the Manufacturing Use Product aerosol (S MUP). These data suggest classification of S MUP with Xn; R20 is appropriate 1 (Acute Tox 4 Inhalation [H332] under the CLP Regulation). It is noteworthy that these LC 50 values expressed as concentration of imiprothrin in the formulation (i.e. 50 %) would be approximately mg/l and mg/l, respectively. Given that the other component of S MUP (isopropyl myristate) is of low acute inhalation toxicity (LC50 > mg/l), it is considered that classification of imiprothrin as harmful by the inhalation and oral routes (Xn; R20/22 under Directive 67/548/EEC and Acute Tox 4 Inhalation and Oral [H332 and H302] under the CLP Regulation) is appropriate. The available data indicate that imiprothrin is not acutely toxic by the dermal route and no classification is considered appropriate. Pralle 0.5 % aerosol is not acutely toxic by the oral (LD 50 > 5000 mg/kg), inhalation (LC 50 > 0.3 mg/l; the maximum achievable concentration) and dermal (LD 50 > 2000 mg/kg) routes. Overall, no classification of Pralle 0.5 % aerosol for acute toxicity is appropriate. Data from standard studies with imiprothrin showed no skin irritating potential and only slight, transient eye irritation which does not meet the EU criteria for classification. No evidence of irritating effects in the respiratory tract was seen in acute inhalation study with imiprothrin. Although nasal discharge was reported following 28-day inhalation exposure and in the acute study with the manufacturing use product (S MUP), it is predicted that imiprothrin is unlikely to cause respiratory tract irritation. Pralle 0.5 % base liquid was not irritating to the eyes, but caused mild irritating effect on the skin of rabbit which was completely cleared within 7 days. Although there is no specific information on the respiratory tract irritation potential of Pralle 0.5 % aerosol no indication of such an effect was reported in the acute inhalation study. Overall, Pralle 0.5 % aerosol does not meet the EU classification criteria for skin, eye or respiratory tract irritation and hence, no further consideration is given to the irritation end-point in the risk characterisation. In standard skin sensitisation tests (Magnusson & Kligman), neither imiprothrin nor S MUP demonstrated skin sensitising potential and do not require EU classification. No skin 1 The Applicant does not agree with this proposal by the UK CA. The argument of the Applicant is presented in Annex 1 of Document IIA. It is noted that the final decision with regard to this proposal will be made by the Risk Assessment Committee of the European Chemicals Agency Page 8 of 45

9 sensitisation reactions were seen in a standard study with Pralle 0.5 % base liquid. There are no indications that imiprothrin is a respiratory sensitiser. Based on the known properties of the co-formulants, it is also predicted that respiratory sensitisation would not occur following exposure to Pralle 0.5 % aerosol. Therefore, these endpoints will not be considered further in the risk characterisation. The effects of repeated oral exposure to imiprothrin have been investigated in a range of species and exposure periods (rat: 90 day/2 year dietary; mouse: 90 day/18 month dietary; dog: 90 day/1 year capsule). In addition subacute studies via the dermal (21 day) and inhalation (28 day) routes of exposure have been performed in the rat. The study NOs and LOs are summarised in the following table: Route Duration Species LO (mg/kg/d) NO (mg/kg/d) Reference Oral, diet 90 day Rat Adachi, 1992 Oral, diet 90 day Mouse Yamada, 1992 Oral, capsule 90 day Dog Noda, 1992 Oral, capsule 1 year Dog 50 5 Smith, 1994 Oral, diet 18 month Mouse Nakamura, 1994 Oral, diet 2 year Rat 60 9 Nakamura, 1995 Dermal 21 day Rat : 1000 Local: 500 mg/l LOAEC (mg/m 3 ) : 300 Local: 150 mg/l NOAEC (mg/m 3 ) Moore, 1995 Inhalation 28 day Rat Kawaguchi, 1992 Following oral administration hepatotoxicity and haematotoxicity were reported across all 3 species, the mouse being less sensitive than the rat or dog; in addition, the salivary gland was also a target organ for toxicity in the rat and dog. The effects on the liver increased in severity with dose and were associated with increased ALT activity and decreased AST activity, increased levels of cholesterol and phospholipids and decrease levels of triglycerides. Histopathological changes ranged from mild hepatocyte hypertrophy in the subacute studies to more marked changes in the longer term studies including pitted and altered hepatic foci, centrilobular/portal fibrous tissue and fibrous bridging, dilation of sinusoids, loss of hepatocytes, inflammatory cell infiltration and pigmented centrilobular hepatocytes. Page 9 of 45

10 Haematological changes (decreases in red blood cell count, haemoglobin and haematocrit levels and increased reticulocyte count) were manifest predominantly at higher dose levels in subchronic studies and associated with extramedullary haematopoiesis in the spleen indicating effects are reversible. Indeed, in studies of longer duration, effects on haematological parameters are not as significant. The salivary gland was a target organ for toxicity in dogs and rats. Histopathological examination revealing increased incidences of swelling of acinar cells and proliferation of the serous gland of the submandibular gland. A NO for subchronic exposure of 10 mg/kg/d is identified while for chronic exposures a NO of 5 mg/kg/d is established Following inhalation exposure of rats 4 h/d for 28 days, clinical signs characteristic of neurotoxicity (including decreased spontaneous activity, tiptoe gait, hypersensitivity and tremor) were reported. Effects on the liver were also observed associated with increased cholesterol and decreased triglyceride levels. The salivary gland was also a target for toxicity with an increased incidence of basophilic staining of the acinar cells. Slight indications of haematotoxicity were also noted. A NOAEC of 22 mg/m 3 (equivalent to a systemic dose of 3.6 mg/kg/d) was established. Following dermal exposure of rats to imiprothrin in corn oil 6 h/d for 21 days, the only indication of systemic toxicity was an increase in the absolute weight of the salivary gland at the top dose level. Although this finding was not associated with any histopathological changes, it was considered biologically significant given the effects observed in the oral studies. A systemic NO of 300 mg/kg/d was established from this study. Evidence of slight skin irritation (acanthosis and hyperkeratosis), therefore a local NOAEC of 150 mg/l was also established. In vitro, negative results were reported in a bacterial gene mutation test and a mammalian cell gene mutation assay. However, a positive response was observed with external metabolic activation (+S9) in a chromosome aberration assay. In vivo, negative results were reported in a mouse bone marrow micronucleus test and a rat liver UDS test. Overall, it is considered that imiprothrin does not express mutagenic activity in vivo and that the data on imiprothrin does not meet the EU classification criteria for mutagenicity. Similarly, classification for mutagenicity is not deemed necessary for Pralle 0.5 % aerosol as none of the other coformulants are classified as mutagens. In lifetime dietary studies in the rat at doses up to 219 mg/kg bw/d or the mouse at doses up to 814 mg/kg bw/d, imiprothrin did not exhibit any significant carcinogenic potential. Therefore, classification for carcinogenicity is not considered appropriate for imiprothrin. Pralle 0.5 % aerosol has not been investigated for carcinogenicity. However, given that none of the coformulants are classified for carcinogenicity, it is concluded that Pralle 0.5 % aerosol would not be carcinogenic and no classification is required. Developmental toxicity effects were not seen with imiprothrin at non-maternally toxic dose levels in standard studies in pregnant rats and rabbits. In the rat study, statistically significant Page 10 of 45

11 increased incidence of skeletal variations and visceral anomalies were reported at dose levels causing mortality and significantly reduced bodyweight gain to the dams ( 200 mg/kg/d); and in rabbits, reduction in foetal bodyweight, higher incidence of skeletal variation and an anomaly were reported at 100 mg/kg/d and above, dose levels at which mortality and significantly reduced bodyweight gain were reported in the dams. Based on effects on maternal bodyweights, NOs for maternal toxicity of 50 and 30 mg/kg/d were identified in the rat and rabbit, respectively. Overall, it is concluded that imiprothrin is not a developmental toxicant and no classification is appropriate. Similarly, classification for developmental toxicity is not appropriate for Pralle 0.5 % aerosol as none of the co-formulants in the product are identified as developmental toxicants. showed no adverse effects on reproduction and fertility in a two-generation study in the rat at dietary concentrations of up to 6000 ppm (equivalent to approximately 288 mg/kg/d). The NO for parental toxicity was 200 ppm (11 mg/kg/d) based on increased liver weight (although no pathology is reported this is considered biologically significant given the changes observed in the repeat dose studies) and evidence of blood cell changes (increased incidence of haemosiderin deposits in the spleen) at 2000 ppm (96 mg/kg/d). Overall, classification for fertility is not appropriate. Similarly, no classification for Pralle 0.5 % aerosol is appropriate given that the other co-formulants are not classified as having an adverse effect on fertility. The potential neurotoxicity of imiprothrin was investigated in an acute and a 90-day repeat dose study in rats. No neuropathological changes were detected in either study and in the subchronic study, a NO of 74 mg/kg/d was identified for general toxicity based on decreased bodyweight at the next higher dose of 219 mg/kg/d. Signs of neurotoxicity primarily decreased motor and locomotor activity were observed in the single gavage study at 300 mg/kg; no neurotoxic effects were seen at 100 mg/kg Critical endpoints For risk characterisation, the key health effects to consider for primary exposure scenarios are those arising from acute dermal and inhalation exposures; while following secondary exposure scenarios are those arising from acute (inhalation, dermal and oral) and chronic dermal and oral exposures. Dermal Following 21-day dermal exposure in the rat, the only systemic effect seen was an increase in salivary gland weight (considered biologically relevant as the salivary gland was also a target organ of toxicity following inhalation and oral exposure). A NO of 300 mg/kg/d (assuming 5 % absorption across rat skin, equivalent to systemic dose of 15 mg/kg/d) was identified. There is no information on species differences in susceptibility and the sensitivity or otherwise of humans to these effects. Therefore, the dermal exposure effects are considered potentially relevant to human health. The identified NO of 300 mg/kg/d (assuming 5 % absorption across rat skin, equivalent to systemic dose of 15 mg/kg/d) will be used in the risk characterisation of acute and chronic dermal exposure scenarios. Page 11 of 45

12 Inhalation In a 28-day inhalation study, hepatotoxicity, neurotoxicity, salivary gland toxicity and mild anaemia (characterised as less than 10 % reduction in circulating red cell mass) were seen in rats. A NOAEC of 22 mg/m 3 (equivalent to 3.6 mg/kg/d) has been determined. There are no data available to inform on the sensitivity or susceptibility of humans to these effects, as such they are considered potentially relevant for human health. Consequently, the NOAEC of 22 mg/m 3 (equivalent to systemic dose of 3.6 mg/kg/d) will be used in the risk characterisation of acute inhalation scenarios. Oral Suppression of bodyweight is the most sensitive marker of toxicity following short-term (acute) oral exposure to imiprothrin in a developmental study in the rabbit. A NO of 30 mg/kg/d has been identified. Given the non-availability of data on human susceptibility or sensitivity relative to experimental animals, the effect is considered potentially relevant to human health. Consequently, the NO of 30 mg/kg/d will be used in the risk characterisation of acute oral exposure scenarios. Following longer-term exposures, hepatotoxicity and haematotoxicity were reported across all 3 species, the mouse being less sensitive than the rat or dog; in addition, the salivary gland was also a target organ for toxicity in the rat and dog. No information is available with regards to the sensitivity and susceptibility of humans to imiprothrin-induced hepatoxicity; therefore, the effects are considered potentially relevant for human health. A NO of 5 mg/kg/d was determined in a 1 year dog study for use in the risk characterisation of chronic oral exposure scenarios Uncertainties Dermal Absorption Values Used in the Risk Assessment Data on the dermal absorption of imiprothrin in Pralle 0.5 % aerosol are not available; although, there is an in vitro dermal penetration study conducted with imiprothrin formulated in ethanol (1 % w/v imiprothrin) which showed that its absorption through the skin is slow and minimal. Over 24-hour exposure, the total absorption through the human skin sample was approximately 5 %. However, given that Pralle 0.5 % aerosol formulation is oil-based, increased dermal uptake and consequently greater absorption than that observed in the aforementioned study is expected. The only data that may help inform on the extent of any potential enhancement would be a comparison of similar effects at the LO in the 21 day rat dermal study (using corn oil as the vehicle) and the 28 day rat inhalation study. In both studies an increase in weight of the salivary gland was reported; 15 % following dermal exposure, the only systemic effect identified; and approximately 40 % following inhalation exposure, one of a number of systemic effects reported. Based on these data, it would appear that absorption through rat skin of imiprothrin when administered in corn oil is also low, based on the approximately 30-fold difference in LOs in these studies. Assuming absorption by the inhalation route is 100 %, the UK CA proposes using a dermal absorption value of 5 % through Page 12 of 45

13 rat skin to establish a systemic dose. In the absence of data to establish a dermal absorption value for imiprothrin across human skin, the UK CA has adopted a highly conservative approach and uses a value of 100 % in the risk characterisation (it should be noted that it is likely that the true dermal absorption value of imiprothrin as formulated in Pralle 0.5 % aerosol will be considerably less than this). Inter- and Intra-species Variability Oral Following acute oral exposure to imiprothrin, signs of neurotoxicity were the most profound effect described; occurring at 100 mg/kg/d in a rat acute neurotoxicity study. However, in the developmental toxicity study in rabbits decrease in bodyweight gain were observed at 100 mg/kg/d and based on this effect, a NO of 30 mg/kg/d was determined. It is also noted that suppression of bodyweight was observed following single oral dosing in rats (at 2000 mg/kg and above) and mice (> 1000 mg/kg/d). It is therefore concluded that changes in the bodyweight is the most sensitive effect of acute exposure to imiprothrin. Following repeated oral exposure to imiprothrin, hepatotoxicity was observed in rats, mice and dogs with slight changes reported in haematological parameters (reduction in circulating red cell mass). Indications of toxic effects on the salivary glands were also observed in the rat and the dog. Following both single and repeated exposure to imiprothrin, there is no definitive information on the mechanism of toxicity. The relative sensitivity of humans to imiprothrin toxicity as compared to the experimental animals is unknown and it is not possible to identify from the available data the potential inter-individual variability in susceptibility to these effects. In the absence of sufficient specific data on the kinetics of imiprothrin in experimental animals as compared to humans, and to account for the uncertainties in extrapolation of animal data to humans, a standard default factor of 10 for inter-species variation (animal to human) and 10 for intra-species variability (human to human) will be applied in the risk characterisation for these effects. Inhalation Following inhalation exposure, hepatic effects and mild haematological effects (less than 10 % reduction in circulating red cell mass) are observed in rats. There is no information available to identify the relative sensitivities of humans as compared to experimental animals to the imiprothrin-induced effects. Similarly, there are no data to reliably inform on the potential for inter-individual variability in susceptibility. Given these uncertainties, the standard default factors of 10 for potential inter-species (animals to humans) and 10 for intra-species (human to human) variability will be applied in the risk characterisation. Dermal Local effects (acanthosis and hyperkeratosis) and increased in salivary gland weight were observed in rats following dermal application of imiprothrin. The relative sensitivity of humans compared to experimental animals to imiprothrin toxicity is unknown and there is no definitive data to inform on the potential inter-individual variability in susceptibility to its effects. Consequently, to account for these uncertainties, the default factor of 10 for inter-species (animals to humans) and 10 for intra-species (human to human) variability will be applied in the risk characterisation. Page 13 of 45

14 Route to Route Extrapolation undergoes first pass metabolism following oral exposure; therefore, it is considered not appropriate to extrapolate from oral to dermal and inhalation exposures scenarios for systemic effects. However, there are repeated exposure studies available for both the dermal (rat, 21-day) and inhalation (rat, 28-day) routes. Dose-response/severity of key health effect There are 5 key studies that can be used in the risk characterisation. A developmental toxicity study in the rabbit for acute exposure scenarios, a 90-day dog study for medium term oral exposure scenarios, a 1-year dog study for long-term oral exposure scenarios, a 28-day rat inhalation study for inhalation exposure scenarios and a 21-day rat dermal study for dermal exposure scenarios. The dose-response characteristics of each study are briefly described below. In the developmental toxicity study in the rabbit, a significant decrease in bodyweight gain of dams was observed at 100 mg/kg/d and based on this effect, a NO of 30 mg/kg/d was determined. Based on these data no additional assessment factors are considered appropriate for acute oral exposure scenarios. Thus, an overall assessment factor of 100 is proposed, equivalent to an Acceptable Exposure Level () of 0.3 mg/kg/d for acute exposure scenarios. Ninety day studies are available in the rat, dog and mouse. The lowest NO derived from these studies was 5.9 mg/kg/d in the rat study with the LO being 179 mg/kg/d. The NO derived from the dog study was 10 mg/kg/d with a LO of 100 mg/kg/d. Given the large dose spacing in the rat study, the NO from the dog study is considered the most appropriate for use in medium-term oral exposure scenarios. In this study, liver enlargement accompanied by changes in enzyme activity, salivary gland effects and mild anaemia were reported at 1000 mg/kg/d but none of these effects were evident in recovery animals six weeks post-exposure. At the mid-dose of 100 mg/kg/d, signs of toxicity (transient salivation and increased incidence of loose and watery faeces) and increase in weights of the salivary gland (8-18 %) and the liver (relative, %) were described. No effects were reported at 10 mg/kg/d, identified as the NO. It is worth noting that in equivalent studies in the rat at dose level of 179 mg/kg/d the only effects observed were decreased in food consumption, increased reticulocyte number and increased swelling of the salivary gland cells (graded as minimal in severity). Based on these data no additional assessment factors are considered appropriate for medium-term oral exposure scenarios. Thus, an overall assessment factor of 100 is proposed, equivalent to an Acceptable Exposure Level () of 0.1 mg/kg/d for medium-term exposure scenarios. Although a lifetime exposure study in rats is available from which a NO of 9 mg/kg/d is derived, the NO of 5 mg/kg/d from the 1-year study in dogs will be used for long term oral exposure scenarios as this represents the more conservative approach. In this study, increased incidence of dark liver was found in all animals treated with 500 mg/kg/d (the highest dose Page 14 of 45

15 tested) and one female at 50 mg/kg/d. Microscopic findings in the centrilobular section characterised as hepatic fibrosis, dilation of sinusoids, loss of hepatocytes, inflammatory cell infiltration and an increase in pigmented centrilobular hepatocytes were described at 50 and 500 mg/kg/d with the incidence and severity increasing with dose. These changes were associated with increase in liver weight in 500 mg/kg/d male only (24 %) and ALT activity (by 11 % and 28 % at 50 and 500 mg/kg/d, respectively). Reduction in haematological parameters (Hb level, RBC count and PCV), bodyweight gain and changes in other organs weight (salivary gland, testes, prostate and uterus) were also reported at this dose. There were no adverse effects observed at 5 mg/kg/d. Based on these data no additional assessment factors are considered appropriate for long term oral exposure scenarios. Thus, an overall assessment factor of 100 is proposed, equivalent to an Acceptable Exposure Level () of 0.05 mg/kg/d for long-term exposure scenarios. Dermal In the 21-day dermal study, increased in salivary gland weight and local effects (acanthosis and hyperkeratosis) were observed at the highest dose of 1000 mg/kg/d (500 mg/l). No toxic effects were seen at 300 and 100 mg/kg/d. Therefore, 300 mg/kg/d (150 mg/l) is identified as the NO for dermal exposure scenarios. Given that dermal absorption through rat skin is considered to be 5 %, a systemic NO of 15 mg/kg/d is taken forward to the risk characterisation. Based on these data no additional assessment factor is considered appropriate for acute dermal exposure scenarios. Thus, an overall assessment factor of 100 is proposed, equivalent to an value of 0.15 mg/kg/d. For medium and long term dermal exposure scenarios, additional assessment factors of 3 and 6, respectively, are considered appropriate (to account for extrapolation from a subacute study to subchronic and chronic studies, respectively; as described in the TGD on risk characterisation). Thus, for medium term dermal exposure scenarios, an overall assessment factor of 300 is proposed, equivalent to an value of 0.05 mg/kg/d; while for long term inhalation exposure scenarios, an overall assessment factor of 600 is proposed, equivalent to an value of mg/kg/d. Inhalation In the 28-day inhalation study, only two dose levels (22 and 186 mg/m 3 ) were investigated. Increased incidence of dark livers was observed in 40 % of animals exposed to 186 mg/m 3 and the relative weights of several organs including the liver (11-21 %) were significantly increased. Mild anaemia (less than 10 % reduction in circulating red cell mass) which appears to be regenerative in nature was also observed. There were no toxic responses observed at 22 mg/m 3 equivalent to systemic dose levels of 3.6 and 3.9 mg/kg/d in males and females, respectively. Thus, 3.6 mg/kg/d is identified as the NO for inhalation exposure scenarios. However, it is worth noting that there is a 9-fold difference between this and the next dose level investigated, it is therefore probable that the actual NO might be higher. Based on these data no additional assessment factor is considered appropriate for acute inhalation exposure scenarios. Thus, an overall assessment factor of 100 is proposed, equivalent to an value of mg/kg/d. For medium and long term inhalation exposure scenarios additional assessment factors of 3 and 6, respectively, are considered appropriate (to account for extrapolation from a subacute study to subchronic and chronic studies, respectively; as described in the TGD on risk characterisation). Thus, for medium term inhalation exposure scenarios, an overall assessment Page 15 of 45

16 factor of 300 is proposed, equivalent to an value of mg/kg/d; while for long term inhalation exposure scenarios, an overall assessment factor of 600 is proposed, equivalent to an value of mg/kg/d Effects assessment The modelling of exposures, and risk assessment/risk characterisation during production and formulation of imiprothrin should be addressed under other EU legislation (e.g. Directive 98/24/EC) and not repeated under Directive 98/8/EC (agreed at Biocides Technical Meeting TMI06). It was agreed at TM II 2006 (Arona, June 2006) that these data should not routinely be considered as core data requirement for the purposes of Annex I inclusion, although Competent Authorities may require these for specific products and/or use scenarios for the risk assessment. These data will normally only be required for post authorisation control and monitoring purposes by individual Member States. Failure to produce these data at the completeness stage or during the evaluation should not therefore preclude entry onto Annex I. The manufacture of imiprothrin takes place outside the EU. When considering formulation of the Pralle 0.5 % aerosol, the UK CA has taken into consideration the Framework Directive (89/391/EC) Introduction of measures to encourage improvements in the safety and health of workers at work and its daughter directive (98/24/EC) Protection of the health and safety of workers from the risks related to chemical agents at work. It is assumed that activities during the formulation of Pralle 0.5 % aerosol are carried out in accordance with the requirements for worker protection laid out in these directives Application of product The Pralle 0.5 % aerosol product is intended to be supplied to the non-professional users market only. Alternative products are available to professional pest control offices seeking to control crawling insects indoors. On this basis, it is assumed that professional operators will not use the Pralle 0.5 % aerosol and hence exposures to professional users have not been assessed. Pralle 0.5 % aerosol is a ready for use product and is intended to be used as a surface spray for spot, crack and crevice treatments indoors to control crawling insects. It is to be marketed solely for non-professional use. The directions state that it should be used for no more than 15 minutes spraying, using short bursts of 1-2 seconds with a total spray time of around seconds. Primary exposure Exposure assessment Although it is intended that adults will carry out treatments with this product, it is foreseeable that a child who has caring responsibilities for a parent may also carry out treatments. Exposures have therefore been assessed for an adult and for a 10-year old child. During normal use, exposure may occur via the inhalation and dermal routes. Oral exposure as a result of Page 16 of 45

17 deposition around the mouth and from hand-to-mouth contact may also occur, however, it is expected that the person carrying out the treatment will wash exposed skin immediately after treatment thereby minimising exposure by this route. The TNsG indicates that products of this type may be used an average of 9 times per year (TNsG, Part 2, page 245), hence this will be assessed as a series of short-term exposures. Quantification of potential primary exposure during the use of Pralle 0.5 % aerosol has been presented within Section 3 of Document II-B. The exposure assessment has been conducted using guidance provided in the Technical Notes for Guidance, TNsG document (European Commission, 2002). The predicted primary exposures to imiprothrin from the use of Pralle 0.5 % aerosol are summarised in Tables 2.4 and 2.7. Table 2.1: Summary of risk characterisation for primary dermal exposure (adult) Scenario NO [mg/kg/d] [mg/kg/d] dose [mg/kg/d] Exposure Tier 1: Entire canister used during a single treatment, 120 seconds spray time x Tier 2: Canister used according to manufacturer s instructions x Tier 3: Exposure based on data from Matoba et al x Table 2.2: Summary of risk characterisation for primary inhalation exposure (adult) Scenario NO [mg/kg/d] [mg/kg/d] dose [mg/kg/d] Exposure Tier 1: Entire canister used during a single treatment, 120 seconds spray time. Tier 2: Canister used according to manufacturer s instructions. Tier 3: Exposure based on data from Matoba et al x x x Page 17 of 45

18 Table 2.3: Summary of risk characterisation for primary dermal exposure (10-year old child) Scenario NO [mg/kg/d] [mg/kg/d] dose [mg/kg/d] Exposure Tier 1: Entire canister used during a single treatment, 120 seconds spray time. Tier 2: Canister used according to manufacturer s instructions. Tier 3: Exposure based on data from Matoba et al x x x Table 2.4: Summary of risk characterisation for primary inhalation exposure (10-year old child) Scenario NO [mg/kg/d] [mg/kg/d] dose [mg/kg/d] Exposure Tier 1: Entire canister used during a single treatment, 120 seconds spray time. Tier 2: Canister used according to manufacturer s instructions. Tier 3: Exposure based on data from Matoba et al x x x The highest exposure is expected when a 10-year old (or child) uses the entire canister in one single application. In this case the lowest of 366 and of 0.27 were derived. The is greater than 100 indicating that the risks posed to amateurs from the use of Pralle 0.5 % aerosol following the procedures specified by the applicant are acceptable. Secondary exposure Secondary exposure of adults, children and infants to imiprothrin as a result of the use of Pralle 0.5 % aerosol may occur by inhalation and skin contact. Secondary exposure of infants may also occur by ingestion (hand-to-mouth). The following potential exposure scenarios are considered possible: Acute inhalation of airborne material and acute skin contact with settled residues away from the treated area (including hand-to-mouth contact for infants). Page 18 of 45

19 Acute hand contact with surface residues at the treated site (including hand-to-mouth contact for infants). Chronic dermal exposure with settled residues away from the treated area (including hand-to-mouth contact for infants). Acute exposure Two acute exposure scenarios are envisaged and it is possible that both short-term scenarios may apply to an individual following treatment. For example, an infant who is present in a treated room and therefore exposed to airborne imiprothrin and surface residues away from the treated site may also accidentally touch the treated site with their hand and may subsequently ingest residues from the contaminated hand. The following combinations have therefore been considered to estimate potential systemic exposure: Tier 1 assessment Inhalation exposure and skin contact away from the treated site has been assessed on the assumption that an entire canister has been used for a single treatment. Skin contact with residues at the treated site has been assessed assuming a surface distribution for imiprothrin of mg/cm 2. This value represents the amount deposited from a 2 second release at a rate of 9.65 mg imiprothrin/second from a height of 25 cm, depositing over an area of 150 cm 2. These are worst case estimates based on release rate data for a similar imiprothrin based aerosol product manufactured by the applicant (see Document II-B, Section 3). Tier 2 assessment Inhalation exposure and skin contact away from the treated site has been assessed on the assumption that the treatment has been carried out according to the manufacturer s instructions. Skin contact with residues at the treated site has been assessed using surface distribution data from the study by Matoba et al (1995) in which a representative treatment with a similar imiprothrin-based product was carried out in an experimental room. Tier 3 assessment The assessment is based on data from the study by Matoba et al (1995). Chronic exposure Skin contact with settled residues away from the treated area (including hand-to-mouth contact for infants) is the only anticipated source of chronic exposure. As a general rule, a substance is considered volatile only if it has a vapour pressure > 10 x 10-3 Pa at 20 o C (Curry et al., 1995). The vapour pressure of imiprothrin is 1.86 x 10-6 Pa at 25 o C and so it should not volatilise from treated surfaces under normal conditions of use. Chronic inhalation exposure has, therefore, not been considered. There is also the potential for dermal contact with residues on surfaces away from the treated site. It is unlikely that there will be longer-term skin contact with residues at the treated site because treatments will tend to be carried out behind appliances etc and will therefore be in areas that are not accessed routinely during normal daily life. The dermal exposure assessment is based on surface residue data from the study by Matoba et al (1995). This assessment does not take account of the decline in surface residues over time due to domestic activities such as cleaning or removal as a result of previous contact. Hence, assuming that there is no decline over time will substantially overestimate exposure. Page 19 of 45

20 Combined exposure Since this product is intended for non-professional use indoors it is likely that the person carrying out the treatment will also receive secondary exposures as a result of the treatment. This combined exposure is only relevant for the day of treatment (i.e. acute exposure scenarios). Combined exposures have been considered for both an adult and a 10-year old child. The following assessments have been considered. Tier 1 assessment Primary and secondary exposures (inhalation and skin contact away from the treated site) have been assessed on the assumption that an entire canister has been used for a single treatment. Skin contact with residues at the treated site has been assessed assuming a surface distribution for imiprothrin of mg/cm 2. Tier 2 assessment Primary and secondary exposures (inhalation and skin contact away from the treated site) have been assessed on the assumption that the treatment has been carried out according to the manufacturer s instructions. Skin contact with residues at the treated site has been assessed using surface distribution data from the study by Matoba et al (1995) in which a representative treatment with a similar imiprothrin based product was carried out in an experimental room. Tier 3 assessment The assessment is based on data from the study by Matoba et al (1995). Primary exposure Risk characterisation is produced outside the EU, therefore; no human health exposure scenarios have been assessed for the manufacture of the active substance. Formulation of Pralle 0.5 % aerosol takes place in the EU. The UK CA has taken into consideration the Framework Directive (89/391/EC) and its daughter directive (98/24/EC) which laid out the protection of the health and safety of workers from the risks related to chemical agents at work. As such, it is assumed that activities during the formulation of Pralle 0.5 % aerosol are carried out in accordance with the requirements for worker protection. The risks to the non-professional user from inhalation and dermal exposure following application of Pralle 0.5 % aerosol are of low concern as demonstrated by the large s obtained with even the worst case estimates (adults: values of 639 and 3992 following dermal and inhalation exposure, respectively; child: values of 366 and 2381, respectively) which assumes the spraying of an entire canister. Secondary exposure The UK CA considers the risks to infants, children and adults following acute and long-term secondary dermal exposure to imiprothrin through the use of Pralle 0.5 % aerosol to be low. Although potential risks were identified in Tier 1 for the acute dermal exposure scenario in which an entire can is sprayed in an entire application (s of 63, 37 and 41 for adult, child, infant respectively), acceptable s were obtained in Tier 2 where treatment is carried out according to the manufacturer s instructions (354, 204 and 226). Further assurance that Page 20 of 45

21 exposure by the dermal route would be low is demonstrated by the large s obtained from measured data mimicking the possible real life situation (i.e. Tier 3). For long-term dermal exposure scenarios, potential risks were identified for an adult, child and infant (s of 507, 291 and 324 respectively). However, given that the product is a spot, crack and crevice treatment and thus adults, children and infants are not expected to routinely gain access to the exposed areas, an acute (as opposed to chronic) endpoint is considered most appropriate to assess such exposures against and so the s can be considered a gross overestimate. In addition, the dermal exposure assessment based on surface residue data from the study by Matoba et al (1995) substantially overestimates exposure since it does not take into account the decline in surface residues over time due to domestic activities such as cleaning or removal as a result of previous contact. The conservative dermal absorption value that has been used (100 %) will also overestimate exposure. The UK CA considers the risks to infants, children and adults following acute secondary inhalation exposure to imiprothrin through the use of Pralle 0.5 % aerosol to be low. This is based on using the product in accordance with the manufacturer s instructions (Tier 2) and the identification of acceptable values of 235, 146 and 132 (for adults, children and infants, respectively). The UK CA considers the risks to infants following acute and long-term secondary oral exposure to imiprothrin through the use of Pralle 0.5 % aerosol to be low. The only relevant oral exposure scenario is considered to be following hand-to-mouth contact by an infant. Following acute secondary oral exposure, an acceptable of 464 is identified in the worst case, Tier 1 scenario; while following long-term secondary oral exposure an acceptable of 1080 is identified. Combined exposure If applied according to the manufacturer s instructions (i.e. Tier 2), acceptable s (> 100) are identified for adults and older children following combined dermal or inhalation exposures to imiprothrin following application of Pralle 0.5 % aerosol. Further assurance that the risk of combined exposure would be low is demonstrated by the large s obtained from measured data mimicking the possible real life situation (i.e. Tier 3). Overall, the UK CA concluded that the risk of combined exposure to imiprothrin through the use of Pralle 0.5 % aerosol to be low. Conclusion Overall, the UK CA considers that the application of imiprothrin via Pralle 0.5 % aerosol is unlikely to present an unacceptable risk to infants, older children and adults and accepts that the precautionary phrases on the product label proposed by the applicant are adequate to mitigate any residual risk: DO NOT BREATHE SPRAY MIST USE ONLY IN WELL-VENTILATED AREAS Page 21 of 45