Peer review of the pesticide risk assessment of the active substance captan
2020; Wiley; Volume: 18; Issue: 9 Linguagem: Inglês
10.2903/j.efsa.2020.6230
ISSN1831-4732
AutoresMaria Anastassiadou, Maria Arena, Domenica Auteri, Alba Brancato, László Bura, Luis Carrasco Cabrera, Eugenia Chaideftou, Arianna Chiusolo, Federica Crivellente, Chloé De Lentdecker, Mark Egsmose, Gabriella Fait, Luna Greco, Alessio Ippolito, Frédérique Istace, Samira Jarrah, Dimitra Kardassi, Renata Leuschner, Alfonso Lostia, Christopher Lythgo, Oriol Magrans, Iris Mangas, Ileana Miron, Tünde Molnar, Laura Padovani, Juan Manuel Parra Morte, Ragnor Pedersen, Hermine Reich, Miguel Santos, Rachel Sharp, Juergen Sturma, Csaba Szentes, Andrea Terron, Manuela Tiramani, Bénédicte Vagenende, Laura Villamar‐Bouza,
Tópico(s)Pesticide Exposure and Toxicity
ResumoEFSA JournalVolume 18, Issue 9 e06230 Conclusion on Pesticides Peer ReviewOpen Access Peer review of the pesticide risk assessment of the active substance captan European Food Safety Authority (EFSA), Corresponding Author European Food Safety Authority (EFSA) pesticides.peerrevieew@efsa.europa.eu Correspondence:pesticides.peerrevieew@efsa.europa.euSearch for more papers by this authorMaria Anastassiadou, Maria AnastassiadouSearch for more papers by this authorMaria Arena, Maria ArenaSearch for more papers by this authorDomenica Auteri, Domenica AuteriSearch for more papers by this authorAlba Brancato, Alba BrancatoSearch for more papers by this authorLaszlo Bura, Laszlo BuraSearch for more papers by this authorLuis Carrasco Cabrera, Luis Carrasco CabreraSearch for more papers by this authorEugenia Chaideftou, Eugenia ChaideftouSearch for more papers by this authorArianna Chiusolo, Arianna ChiusoloSearch for more papers by this authorFederica Crivellente, Federica CrivellenteSearch for more papers by this authorChloe De Lentdecker, Chloe De LentdeckerSearch for more papers by this authorMark Egsmose, Mark EgsmoseSearch for more papers by this authorGabriella Fait, Gabriella FaitSearch for more papers by this authorLuna Greco, Luna GrecoSearch for more papers by this authorAlessio Ippolito, Alessio IppolitoSearch for more papers by this authorFrederique Istace, Frederique IstaceSearch for more papers by this authorSamira Jarrah, Samira JarrahSearch for more papers by this authorDimitra Kardassi, Dimitra KardassiSearch for more papers by this authorRenata Leuschner, Renata LeuschnerSearch for more papers by this authorAlfonso Lostia, Alfonso LostiaSearch for more papers by this authorChristopher Lythgo, Christopher LythgoSearch for more papers by this authorOriol Magrans, Oriol MagransSearch for more papers by this authorIris Mangas, Iris MangasSearch for more papers by this authorIleana Miron, Ileana MironSearch for more papers by this authorTunde Molnar, Tunde MolnarSearch for more papers by this authorLaura Padovani, Laura PadovaniSearch for more papers by this authorJuan Manuel Parra Morte, Juan Manuel Parra MorteSearch for more papers by this authorRagnor Pedersen, Ragnor PedersenSearch for more papers by this authorHermine Reich, Hermine ReichSearch for more papers by this authorMiguel Santos, Miguel SantosSearch for more papers by this authorRachel Sharp, Rachel SharpSearch for more papers by this authorJuergen Sturma, Juergen SturmaSearch for more papers by this authorCsaba Szentes, Csaba SzentesSearch for more papers by this authorAndrea Terron, Andrea TerronSearch for more papers by this authorManuela Tiramani, Manuela TiramaniSearch for more papers by this authorBenedicte Vagenende, Benedicte VagenendeSearch for more papers by this authorLaura Villamar-Bouza, Laura Villamar-BouzaSearch for more papers by this author European Food Safety Authority (EFSA), Corresponding Author European Food Safety Authority (EFSA) pesticides.peerrevieew@efsa.europa.eu Correspondence:pesticides.peerrevieew@efsa.europa.euSearch for more papers by this authorMaria Anastassiadou, Maria AnastassiadouSearch for more papers by this authorMaria Arena, Maria ArenaSearch for more papers by this authorDomenica Auteri, Domenica AuteriSearch for more papers by this authorAlba Brancato, Alba BrancatoSearch for more papers by this authorLaszlo Bura, Laszlo BuraSearch for more papers by this authorLuis Carrasco Cabrera, Luis Carrasco CabreraSearch for more papers by this authorEugenia Chaideftou, Eugenia ChaideftouSearch for more papers by this authorArianna Chiusolo, Arianna ChiusoloSearch for more papers by this authorFederica Crivellente, Federica CrivellenteSearch for more papers by this authorChloe De Lentdecker, Chloe De LentdeckerSearch for more papers by this authorMark Egsmose, Mark EgsmoseSearch for more papers by this authorGabriella Fait, Gabriella FaitSearch for more papers by this authorLuna Greco, Luna GrecoSearch for more papers by this authorAlessio Ippolito, Alessio IppolitoSearch for more papers by this authorFrederique Istace, Frederique IstaceSearch for more papers by this authorSamira Jarrah, Samira JarrahSearch for more papers by this authorDimitra Kardassi, Dimitra KardassiSearch for more papers by this authorRenata Leuschner, Renata LeuschnerSearch for more papers by this authorAlfonso Lostia, Alfonso LostiaSearch for more papers by this authorChristopher Lythgo, Christopher LythgoSearch for more papers by this authorOriol Magrans, Oriol MagransSearch for more papers by this authorIris Mangas, Iris MangasSearch for more papers by this authorIleana Miron, Ileana MironSearch for more papers by this authorTunde Molnar, Tunde MolnarSearch for more papers by this authorLaura Padovani, Laura PadovaniSearch for more papers by this authorJuan Manuel Parra Morte, Juan Manuel Parra MorteSearch for more papers by this authorRagnor Pedersen, Ragnor PedersenSearch for more papers by this authorHermine Reich, Hermine ReichSearch for more papers by this authorMiguel Santos, Miguel SantosSearch for more papers by this authorRachel Sharp, Rachel SharpSearch for more papers by this authorJuergen Sturma, Juergen SturmaSearch for more papers by this authorCsaba Szentes, Csaba SzentesSearch for more papers by this authorAndrea Terron, Andrea TerronSearch for more papers by this authorManuela Tiramani, Manuela TiramaniSearch for more papers by this authorBenedicte Vagenende, Benedicte VagenendeSearch for more papers by this authorLaura Villamar-Bouza, Laura Villamar-BouzaSearch for more papers by this author First published: 11 September 2020 https://doi.org/10.2903/j.efsa.2020.6230 Requestor: European Commission Question number: EFSA-Q-2016-00185 Acknowledgments: EFSA wishes to thank the rapporteur Member State Austria for the preparatory work on this scientific output. Approved: 24 July 2020 Amended: 8 Dec 2020 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State Austria and co-rapporteur Member State Italy for the pesticide active substance captan are reported and the confirmatory data following the Article 12 of Regulation (EC) No 396/2005 as well. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of captan as a fungicide on pome fruit, peaches and nectarines, plums, cherry, tomato, strawberries (field use) and strawberries (greenhouse application). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified. Summary Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659, lays down the procedure for the renewal of the approval of active substances submitted under Article 14 of Regulation (EC) No 1107/2009. The list of those substances is established in Commission Implementing Regulation (EU) No 686/2012. Captan is one of the active substances listed in Regulation (EU) No 686/2012. In accordance with Article 1 of Regulation (EU) No 844/2012, the rapporteur Member State (RMS), Austria, and co-rapporteur Member State (co-RMS), Italy, received an application from ADAMA Agriculture BV (on behalf of ADAMA Makhteshim Ltd.) and Arysta LifeScience S.A.S. for the renewal of approval of the active substance captan. In addition, the applicant submitted an maximum residue level (MRL) application form for the evaluation of confirmatory data following review according to Article 12 of Regulation (EC) No 396/2005. An initial evaluation of the dossier on captan was provided by the RMS in the renewal assessment report (RAR), and subsequently, a peer review of the pesticide risk assessment on the RMS evaluation was conducted by the European Food Safety Authority (EFSA) in accordance with Article 13 of Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The following conclusions are derived. The uses of captan according to the representative uses as a fungicide on pome fruit, peaches and nectarines, plums, cherries, tomato, strawberries (field use) and strawberries (greenhouse application), as proposed at European Union (EU) level result in a sufficient fungicidal efficacy against the target organisms. Label instructions are needed for the formulations to maintain agitation during mixing, loading and spraying and also mitigation measures for the excess of foaming are required. Data gap was identified for Arysta LifeScience S.A.S. for five-batch data not older than 5 years. For mammalian toxicology, a data gap was identified for information to assess the toxicological relevance of some impurities in the specification from Arysta LifeScience S.A.S., consequently leading to an issue not finalised since it cannot be concluded that the batches used in the toxicity studies are compliant with the technical specification from Arysta LifeScience S.A.S. In the residue section, data gaps were identified for a new tomato metabolism study, processing studies under sterilisation conditions, storage stability data on strawberries and stone fruits as to validate the result from the residue trials and additional Good Agricultural Practice (GAP)-compliant residue trials on peaches/nectarines, plums, strawberries and tomatoes. In view of the data gaps, the consumer risk assessment is considered provisional. The confirmatory data following review according to Article 12 of Regulation (EC) No 396/2005 related to validate analytical methods for the determination of THPI in acidic and high water commodities is fulfilled. The data available on environmental fate and behaviour are sufficient to carry out the required environmental exposure assessments at the EU level. A data gap was identified for information on the effect of water treatment processes on the nature of residues of the active substance and metabolites THPI and THPAM potentially present in surface, when surface water or groundwater are abstracted for drinking water. This gap leads to the fact that the consumer risk assessment from the consumption of drinking water could not be finalised for all the representative uses. High risk was concluded for birds, mammals, aquatic organisms, bees and non-target arthropods other than bees for a number of the representative uses. Low risk was identified for soil dwelling non-target organisms, non-target terrestrial plants and microorganism involved in biological methods for sewage treatment for all the representative uses. Based on the available data and assessment, it is concluded that captan does not meet the criteria for endocrine disruption for both humans and non-target organisms through oestrogen, androgen, thyroid and steroidogenic (EATS)-modalities as set in point 3.6.5. and point 3.8.2 of Annex II to Regulation (EC) No 1107/2009, as amended by Commission Regulation (EU) 2018/605. Background Commission Implementing Regulation (EU) No 844/20121, as amended by Commission Implementing Regulation (EU) No 2018/16592, (hereinafter referred to as ‘the Regulation’), lays down the provisions for the procedure of the renewal of the approval of active substances, submitted under Article 14 of Regulation (EC) No 1107/20093. This regulates for the European Food Safety Authority (EFSA) the procedure for organising the consultation of Member States, the applicant(s) and the public on the initial evaluation provided by the rapporteur Member State (RMS) and/or co-rapporteur Member State (co-RMS) in the renewal assessment report (RAR), and the organisation of an expert consultation where appropriate. In accordance with Article 13 of the Regulation, unless formally informed by the European Commission that a conclusion is not necessary, EFSA is required to adopt a conclusion on whether the active substance can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009 within 5 months from the end of the period provided for the submission of written comments, subject to an extension of an additional 3 months where additional information is required to be submitted by the applicant(s) in accordance with Article 13(3). Furthermore, in accordance with Article 13(3a), where the information available in the dossier is not sufficient to conclude the assessment on whether the approval criteria for endocrine disruption are met, additional information can be requested to be submitted in a period of minimum 3 months, not exceeding 30 months, depending on the type of information requested. In accordance with Article 1 of the Regulation, the RMS Austria and co-RMS Italy received an application from ADAMA Agriculture BV (on behalf of ADAMA Makhteshim Ltd.) and Arysta LifeScience S.A.S. for the renewal of approval of the active substance captan. In addition, the applicant submitted an maximum residue level (MRL) application form for the evaluation of confirmatory data following review according to Article 12 of Regulation (EC) No 396/20054. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicants, the co-RMS (Italy), the European Commission and EFSA about the admissibility. The RMS provided its initial evaluation of the dossier on captan in the RAR, which was received by EFSA on 4 December 2017 (Austria, 2017). In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicants, ADAMA Agriculture BV (on behalf of ADAMA Makhteshim Ltd.) and Arysta LifeScience S.A.S., for consultation and comments on 17 April 2018. EFSA also provided comments. In addition, EFSA conducted a public consultation on the RAR. EFSA collated and forwarded all comments received to the European Commission on 17 June 2018. At the same time, the collated comments were forwarded to the RMS for compilation and evaluation in the format of a reporting table. The applicants were invited to respond to the comments in column 3 of the reporting table. The comments and the applicants’ response were evaluated by the RMS in column 3. The need for expert consultation and the necessity for additional information to be submitted by the applicants in accordance with Article 13(3) of the Regulation were considered in a telephone conference between EFSA and the RMS on 22 October 2018. On the basis of the comments received, the applicants’ response to the comments and the RMS's evaluation thereof, it was concluded that additional information should be requested from the applicants and that EFSA should conduct an expert consultation in the areas of mammalian toxicology, residues, environmental fate and behaviour, and ecotoxicology. The outcome of the telephone conference, together with EFSA's further consideration of the comments, is reflected in the conclusions set out in column 4 of the reporting table. All points that were identified as unresolved at the end of the comment evaluation phase and which required further consideration, including those issues to be considered in an expert consultation, were compiled by EFSA in the format of an evaluation table. The conclusions arising from the consideration by EFSA, and as appropriate by the RMS, of the points identified in the evaluation table, together with the outcome of the expert consultation and the written consultation on the assessment of additional information, where these took place, were reported in the final column of the evaluation table. A final consultation on the conclusions arising from the peer review of the risk assessment and on the confirmatory data following the Article 12 MRL review of Regulation (EC) No 396/2005 took place with Member States via a written procedure in June 2020. This conclusion report summarises the outcome of the peer review of the risk assessment of the active substance and the representative formulation, evaluated on the basis of the representative uses of captan as a fungicide on pome fruit, peaches and nectarines, plums, cherry, tomato, strawberries (field use) and strawberries (greenhouse application), as proposed by the applicants. In accordance with Article 12(2) of Regulation (EC) No 1107/2009, risk mitigation options identified in the RAR and considered during the peer review are presented in the conclusion. A list of the relevant end points for the active substance and the formulation is provided in Appendix A. A key supporting document to this conclusion is the peer review report (EFSA, 2020), which is a compilation of the documentation developed to evaluate and address all issues raised in the peer review, from the initial commenting phase to the conclusion. The peer review report comprises the following documents, in which all views expressed during the course of the peer review, including minority views, where applicable, can be found: the comments received on the RAR; the reporting table (23 October 2018); the evaluation table (29 May 2020); the report(s) of the scientific consultation with Member State experts (where relevant); the comments received on the assessment of the additional information (where relevant); the comments received on the draft EFSA conclusion. Given the importance of the RAR, including its revisions (Austria, 2020), and the peer review report (EFSA, 2020), both documents are considered as background documents to this conclusion and thus are made publicly available. It is recommended that this conclusion and its background documents would not be accepted to support any registration outside the European Union (EU) for which the applicant has not demonstrated that it has regulatory access to the information on which this conclusion report is based. The active substance and the formulated product Captan is the ISO common name for N-[(trichloromethyl)thio]cyclohex-4-ene-1,2-dicarboximide (IUPAC). The representative formulated products for the evaluation were ‘Merpan 80 WDG’ and ‘Captan 80 WG’, water-dispersible granules (WG), both containing 800 g/kg captan. The representative uses evaluated were field spray applications for the control of fungal diseases in pome fruit, plums, cherries in the central and southern European zone, in peaches, nectarines and tomato in the southern european zone, field and greenhouse applications in strawberries in the Central zone and in the EU respectively. Full details of the Good Agricultural Practices (GAPs) can be found in the list of end points in Appendix A. Data were submitted to conclude that the representative uses of captan proposed at EU level result in sufficient fungicidal efficacy against the target organisms, following the guidance document SANCO/2012/11251-rev. 4 (European Commission, 2014b). A data gap has been identified for a search of the scientific peer-reviewed open literature on the active substance and its relevant metabolites, dealing with side effects on non-target species and published within the 10 years before the date of submission of the dossier, to be conducted and reported in accordance with EFSA guidance on the submission of scientific peer-reviewed open literature for the approval of pesticide active substances under Regulation (EC) No 1107/2009 (EFSA, 2011). Conclusions of the evaluation 1 Identity, physical/chemical/technical properties and methods of analysis The following guidance documents were followed in the production of this conclusion: European Commission, 2000a,b, 2010, 2012. The proposed specifications are based on batch data from industrial scale production; however, a data gap was identified for Arysta LifeScience S.A.S. for five-batch data not older than 5 years. The proposed minimum purity is 930 g/kg captan. It should be noted that based on the batch data a higher minimum purity could have been proposed. It is proposed to update the reference specification considering that the original minimum purity was 910 g/kg. Perchloromethylmercaptan (PCMM), carbon tetrachloride and folpet are considered relevant impurities with maximum contents of 5 g/kg, 0.1 g/kg and 10 g/kg, respectively. The minimum purity is meeting the requirements of the FAO specification 40/TC/S (AGP: CP/249, 1990) of minimum 910 g/kg captan and maximum 10 g/kg PCMM, developed under the old procedure. The main data regarding the identity of captan and its physical and chemical properties are given in Appendix A. It should be mentioned that label instructions are needed for the formulations to maintain agitation during mixing, loading and spraying, and also that mitigation measures to reduce excess foaming are required. Adequate methods are available for the generation of pre-approval data required for the risk assessment. Methods of analysis are available for the determination of the active substance and the relevant impurities in the technical material and in the representative formulations. The residue definition for monitoring in plants was defined as captan and THPI, expressed as captan. The compounds of the residue definition can be monitored by gas chromatography–mass spectrometry (GC–MS) with limit of quantification (LOQ) of 0.01 mg/kg for each analyte, in all plant commodity groups. The residue definition in food and feed of animal origin was defined as THPI, 3-OH-THPI and 5-OH-THPI, expressed as captan. The compounds of the residue definition in animal matrices can be monitored by GC–MS with LOQ of 0.01 mg/kg for each analyte in muscle, fat, liver, kidney milk and eggs. The compounds of the residue definition for monitoring in honey (sum of captan and THPI expressed as captan) can be determined by high-resolution GC–MS with LOQ of 0.01 mg/kg for both analytes. The residue definition in the soil was defined as captan. The appropriate GC–MS method exists for monitoring captan in soil with a LOQ of 0.02 mg/kg. An appropriate liquid chromatography with tandem mass spectrometry (LC–MS/MS) method is available for monitoring captan, THPI and THPAM in surface water with LOQ of 0.1 μg/L for all analytes. Captan, THPI and THPAM can be monitored in ground water by GC–MS (captan), GC–MS/MS (THPI) and LC–MS/MS methods (THPAM) with LOQ of 0.1 μg/L for all analytes, however a data gap was identified for additional validation data for the Independent Laboratory Validation (ILV). Residues of captan in air can be determined by GC–MS with a LOQ of 12.8 μg/m3. The residue definition for monitoring in body fluids and tissues was defined as THPI, 3-OH-THPI and 5-OH-THPI. Methods exist for the determination of THPI, 3-OH-THPI and 5-OH-THPI in tissues with LOQs of 0.01 mg/kg and for the determination of THPI in body fluids by GC–MS with LOQs of 0.03 mg/L. As a consequence, a data gap was identified for a monitoring method for the determination 3-OH-THPI and 5-OH-THPI in body fluids. 2 Mammalian toxicity The following guidance documents were followed in the production of this conclusion (European Commission, 2003, 2012; EFSA, 2014b; EFSA PPR Panel, 2012; ECHA, 2017). Captan was discussed at the Pesticides Peer Review Experts’ Meeting 13 in September 2019. The proposed specification from ADAMA is supported by the batches which were used in toxicological studies. At the levels specified in the proposed technical specifications, the toxicologically relevant impurities, PCMM, carbon tetrachloride and folpet, do not pose a toxicological concern. Pending on further assessment of the toxicological relevance of the impurities in the specification from Arysta LifeScience S.A.S. (data gap), it cannot be concluded that the batches used in the toxicity studies are compliant with the technical specification from Arysta LifeScience S.A.S (issue not finalised). Captan is rapidly and extensively absorbed and excreted following oral administration to rats. Ring-labelled captan is excreted mainly via urine, while trichloromethyl-labelled captan is also excreted via pulmonary route. Captan is widely distributed but tissue residues were negligible due to rapid excretion. Captan is extensively metabolised at low dose, while incompletely metabolised at high dose. This is due to the fact that biotransformation of captan occurs in the gastrointestinal tract and at low doses a high proportion is extensively metabolised prior absorption, while at higher doses captan is incompletely metabolised and a proportion is excreted unchanged. In the gastrointestinal tract, the metabolic cleavage of nitrogen–sulfur bond results in thiophosgene and 4,5-cyclohexene-1,2-dicarboximide (THPI, major urinary rat metabolite). Hydroxylation of THPI results in 3-hydroxy-4,5-cyclohexene-1,2-dicarboximide (3-OH-THPI, major urinary rat metabolite) or 5-hydroxy-4,5-cyclohexene-1,2-dicarboximide (5-OH-THPI), or metabolism of THPI to THPI-epoxide (and further to the diol) or 1-amido-2-carboxy-4,5-cyclohexene (THPAM, major urinary rat metabolite). No unique human metabolite is found from the in vitro intraspecies comparative metabolism study. THPI, 3-OH-THPI and 5-OH-THPI are proposed for monitoring purposes in body fluids and tissues. Captan is of low acute toxicity by the oral and dermal routes. However, captan is toxic by inhalation (Acute toxicity Category 3, H331 (‘Toxic if inhaled’)). Captan is not irritating to the skin but induces irreversible effects in the eyes (Serious eye damage Category 1, H318 (‘Causes serious eye damage’)). Furthermore, the peer review considered that the criteria for the sub-category 1A of the classification Skin sensitisation (H317, ‘May cause an allergic skin reaction’) according to Regulation (EC) No 1272/20085 may be met based on the skin reaction in the maximisation study in the guinea pig. In addition, captan was not phototoxic in the OECD 3T3 NRU-PT test. The overall short-term oral toxicity no observed adverse effect level (NOAEL) is 60 mg/kg body weight (bw) per day based on a statistical significant increase in relative liver weight in males and a statistically significant decrease in total plasma protein and albumin in males, and a slightly higher incidence of emesis and soft/mucoid stool observed in the 1-year dog study. The short-term inhalation toxicity no observed adverse effect concentration (NOAEC) for systemic effects is 0.60 μg/L and the peer review considered that the criteria for classification according to Regulation (EC) No 1272/20086 may be met for STOT RE 1 – H372 (‘Causes damage to organs through prolonged or repeated exposure if inhaled’) based on significant toxic effects (mortality) observed at 12.98 μg/L in the 90-day rat study. Based on the available data package, including three new in vitro studies with the test material having a fully characterised impurity profile, captan is likely to be genotoxic in vitro. However, there is overwhelming evidence, including a transgenic rodent assay and an in vivo mouse micronucleus assay with proof of bone marrow exposure, that the genotoxic potential of the substance is not expressed in vivo. Overall, based on a weight of evidence, the majority of the experts agreed that captan is unlikely to be genotoxic.6 In rat, the long-term toxicity, NOAEL is 25 mg/kg bw per day based on reduced body weight gain observed in the 2-year studies, while the carcinogenicity NOAEL is 250 mg/kg bw per day (highest tested dose). In the 22-month mouse study, the long-term toxicity NOAEL is 60.9 mg/kg bw per day, based on macroscopic and microscopic lesions in the small intestine observed in females, while the carcinogenicity NOAEL of 60.9 mg/kg bw per day is based on duodenal tumours at 122.8 mg/kg bw per day and above. Harmonised classification for captan includes Carcinogenicity Category 2, H351 (‘Suspected of causing cancer’), based on a non-genotoxic mode of action, that is associated with the irritant nature of captan, as agreed by the majority of experts.7 In the three-generation rat study, the reproductive toxicity NOAEL is 500 mg/kg bw per day (highest tested dose), the overall parental NOAEL is 25 mg/kg bw per day based on decrease in body weight, in males and the NOAEL for pup toxicity is 25 mg/kg bw per day based on significant reductions in pup body weight. In the rat teratogenicity study, the developmental effects included reduced fetal weight and increase in minor skeletal variations while the maternal effects were reduced food consumption and body weight at 450 mg/kg bw per day. The resulting developmental and maternal NOAEL is 90 mg/kg bw per day. In the rabbit teratogenicity study, the developmental toxicity NOAEL is 20 mg/kg bw per day based on a reduced fetal weight, an increased early resorptions and post implantation loss and an increased incidence of major abnormalities observed in the presence of maternal toxicity. The maternal lowest observable adverse effect level (LOAEL) is 10 mg/kg bw per day due to a decrease in food intake and body weight (gain) observed at this dose. The rabbit studies were considered by the experts as not appropriate for human risk assessment due to the strong antimicrobial activity of captan, which is associated with secondary effects unique to the physiology of the rab
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