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Introduction Background to COM review 1. Dichlorvos (O-(2,2-dichlorovinyl)-O,O-dimethylphosphate, DDVP) was first introduced into the UK as an agricultural pesticide in 1962. Non-agricultural uses were first assessed under the voluntary Pesticides Safety Precaution Scheme in 1975-78. A review by the ACP of approvals issued under the Control of Pesticides Regulatory (COPR 1986) was undertaken in 1994. Currently dichlorvos is widely used by amateur and professional users as a public hygiene insecticide (e.g. use of hand held aerosols for surface/space spray and slow release products e.g. strips, cassettes). A relatively small number of products are approved for use in animal husbandry and in agriculture and horticulture on edible crops (e.g. cucumbers) and on non-edible crops (e.g chrysanthemums). Dichlorvos is currently used in a veterinary medicinal product for control of fleas in cats and dogs. The use of dichlorvos in pesticide products and in veterinary medicines is currently being reviewed. 2. The COM considered generic aspects arising from the paper by Sasaki YF et al(1) on the performance of the in-vivo COMET assay with respect to the newly published strategy in the COM guidelance at its 8 February 2001 meeting. The Committee agreed that the positive results reported in the COMET assay using dichlorvos suggested that a full review of all the mutagenicity data was required. COM reviews 3. The toxicokinetics, mutagenicity and carcinogenicity data sections from the draft evaluation prepared by HSE for the Advisory Committee on Pesticides meeting on 5 April 2001 were made available to the COM. The Committee evaluated the data from all of the mutagenicity studies cited in the HSE review.(1-102) The COM also considered additional information and mutagenicity data submitted by industry to HSE prior to the COM meeting on 26 April 2001.(103-107) A further meeting was held on 23 July 2001 to consider additional submitted information and to hear a presentation. from industry. The COM advice was forwarded to the regulatory authorities (the Biocides and Pesticides Authorisation Unit (BPAU) at HSE and the Pesticides Safety Directorate (PSD)) at the end of July 2001 and was subsequently published in December 2001 after a judicial review of the regulatory decisions regarding dichlorvos. An extraordinary meeting of COM was held on 9 January 2002 to consider the new information submitted to the High Court during a judicial review of the regulatory decision on the pesticide products containing dichlorvos and data provided to regulatory authorities up to 4 January 2002 and to decide whether this warranted any revision of the COM statement on dichlorvos. Overall Assessment of In-vitro mutagenicity studies 4. Members agreed that dichlorvos is a weak methylating agent (compared to methyl methanesulphonate; MMS). The Committee concurred with the following assessment of the in-vitro mutagenicity studies.
5. Members agreed that DNA methylation induced by dichlorvos contributed towards the mutagenicity reported in in-vitro test systems but noted that other mechanisms might also be involved. Members considered that the positive results obtained in in-vitro mutagenicity tests with dichlorvos in the presence of an exogenous metabolising fraction and in the assay for single strand breakage of DNA also suggested that dichlorvos and/or its metabolites were genotoxic. This might include dichloroacetaldehyde although the available evidence was insufficient to identify all potential mutagenic metabolites of dichlorvos. 6. The Committee concluded that dichlorvos is an in-vitro mutagen Assessment of in-vivo mutagenicity studies 7. The Committee noted that there were a large number of in-vivo studies available. Dichlorvos was negative in most published in-vivo mutagenicity assays where it was administered as a single dose. These included mouse bone-marrow micronucleus (using i.p route)(70,90,94) and bone-marrow chromosome aberration studies in mice(23,60) and hamsters(22) using oral and, in two studies (mice/hamster) inhalation exposure. Negative results were also reported in SCE in mice(44,53,95) and UDS assays [liver (rats)/forestomach (mice)](9,55,99,101). A negative result was also reported in an adequately conducted bone-marrow chromosome aberration study where mice were given daily oral doses of dichlorvos by gavage for five days.(100) 8. Members also noted that there were a number of positive studies and these are discussed below. 9. The Committee agreed that dichlorvos has been reported to induce micronuclei in keratinocytes in mice following the topical application to skin.(81) Members agreed that the approach used in this study had not been fully validated but agreed the authors had used an appropriate positive control chemical and that the results with dichlorvos were indicative of an in-vivo site-of-contact mutagenic effect. Members also noted a positive response in a nuclear anomaly assay in hair follicles of mice following topical application.75 Although the latter is not considered to be a definitive genotoxicity assay, the results might be indicative of a biological effect in the skin. 10. Members agreed that the positive results reported in an abstract by Majeeth et al in a mouse bone-marrow micronucleus assay could not be interpreted, as insufficient information on the methods and results were available.(52) The Committee considered that equivocal evidence of chromosomal aberrations in bone-marrow smears had been reported in a study where hamsters were given a single oral dose of up to half the LD50 of the formulation.(30) 11. The Committee agreed that evidence for the induction of changes in chromosome number had been documented in the bone-marrow of rats following repeated oral dosing with dichlorvos for 6 weeks (5 days/week).(63) Members considered that the methods used were satisfactory and noted that, although the adequacy of reporting was limited, the results indicated a positive effect for the induction of numerical chromosome aberrations. It was noted that a clear dose-response would not be expected in this study as the dose range selected was relatively narrow. 12. Regarding the recently published COMET assay(1), Members considered that the approach adopted by Sasaki and colleagues to the mutagenicity testing of several hundreds of chemicals had a number of drawbacks, for example, limited reporting of signs of toxicity seen in animals. Members considered that the appropriateness of the isolated nuclei method used by Sasaki and colleagues had not been established and noted that there was no cellular measure of cytotoxicity or apoptosis in this study. In respect of the study on dichlorvos, members agreed that the dose level chosen (ca 80% of the LD50) was too high. Members agreed that in view of these limitations, little weight could be placed on this study. The positive data in all tissues examined was unexpected given all the available mutagenicity data on dichlorvos. Members considered that it was not possible to conclude that dichlorvos had mutagenic effects in a wide range of tissues on the basis of these data. Thus, although the authors suggested that dichlorvos had an in-vivo genotoxic effect, the data were uninterpretable. 13. Members considered the in-vivo mutagenicity study in l lacZ transgenic (Muta™ Mouse) undertaken by Plesta and colleagues.(102) The authors had reported a statistically significant (3-fold) increase in mutant frequency in the liver and a slight non-statistically significant increase in mutant frequency in the bone-marrow following repeated dosing with dichlorvos (5 x 11 mg/kg ) given intraperitoneally. Members noted that the dose levels used in this study were high and did induce severe toxicity in the animals. They agreed that although the methods used and standards of reporting used in this study had limitations, the data were indicative of a mutagenic effect of dichlorvos in-vivo at the site-of-contact i.e. the liver. The Committee noted that the authors had failed to identify any O(6) and N-7 methylguanine adducts in tissue DNA from transgenic mice given a single intraperitoneal dose of either 4.4 mg/kg bw or 11 mg/kg dichlorvos bw but agreed that the methods used by the authors were of inadequate sensitivity and it was unlikely that any alkyl adducts could have been detected. In support of this conclusion Members commented that the levels of DNA adducts (O(6) and N-7 methylguanine) in transgenic mice (Muta™ Mouse) following repeated dosing with dimethyl sulphate (10 x 6 mg/kg bw i.p) were only approximately 4-fold higher than the limit of detection. Members considered that evaluation of DNA adducts in dichlorvos treated animals after the repeat dosing regime might have provided valuable information but these analyses had not been undertaken. 14. The Committee concluded that a consistent pattern of mutagenic effects had been documented in the in-vivo studies in which dichlorvos induced mutagenic effects at high doses in the skin following topical application(81), and in the liver following repeated intraperitoneal dosing(102), suggesting a potential site-of-contact effects (i.e. at initial sites of exposure). Additional data submitted by industry: AMVAC (for 26 April 2001) 15. A number of papers had been submitted just prior to the COM meeting. Members agreed that no substantive new mutagenicity data had been submitted.(103-105) The additional data from the mouse lymphoma test undertaken as part of the US NTP assessment of dichlorvos was consistent with other assays and indicated a positive result in this assay. Regarding the specific comments on the most recent in-vivo mutagenicity assays, members agreed with the reservations proposed by industry regarding the interpretation of COMET assay(106) but did not agree with the views expressed regarding the conduct of the mutagenicity study in transgenic animals(107). Members considered that the mutagenicity study in transgenic mice indicated a potential mutagenic hazard at the site-of -contact. 16. The Committee commented on the "Blue-Ribbon" evaluation of dichlorvos completed in July 1998(105) and noted that differences in the rate of methylation compared to the rate of phosphorylation could not be used to discount a potential in-vivo mutagenic hazard of dichlorvos. Additionally the role of phosphorylation in the induction of genotoxic effects could not be discounted. COM review of submission from industry (23 July 2001) 17. A further meeting of the Committee was held on the 23 July 2001 to consider a presentation from industry on the mutagenicity of dichlorvos. This consisted mainly of a critique of the four positive in-vivo studies underpinning the COM statement (referred to in paragraphs 9-13 above), and of the Committee's approach to weight-of-evidence considerations. No additional information was provided to support the reference submitted by industry to the Committee on the possibility of oxidative damage (108) as a mechanism for the induction of mutations seen in the Muta™ mouse study. COM consideration of additional information (9 January 2002) 18. The COM considered the new information submitted to the High Court during a judicial review of the regulatory decision on the pesticide products containing dichlorvos (held between 5-9 November 2001) and additional data provided to regulatory authorities up to 4 January 2002 to see if any revision of the COM statement on dichlorvos was warranted. 19. The COM considered the documents listed under reference 111 of this statement. Members only considered the information relating to the scientific assessment of dichlorvos and did not consider information of a legal nature. There were a number of topics raised in the documents. 20. Members agreed that mutagenicity studies that had not been subject to full international validation could be used to inform hazard assessment and regulatory decision making, This was particularly relevant when considering in-vivo activity at sites of initial contact for compounds shown to be direct acting mutagens in-vitro. The COM guidance (published in December 2000; See http://www.doh.gov.uk/com/guidance.pdf) recognised that such situations needed to be approached on a case-by-case basis. The current COM guidance listed a number of non-standard test methods which could be used including the use of transgenic animal models. Members concluded that the information available to the Committee to assess the potential for site-of-contact mutagenicity for dichlorvos was very limited, namely in-vivo skin micronucleus test, the intraperitoneal Muta™ Mouse study and forestomach UDS assay. The design of all these studies had limitations which had been noted by the COM. However in the absence of more definitive data, the results of these tests can be used to provide a provisional hazard assessment and could not be dismissed. Members considered the comments put forward on the conduct of the Muta™ Mouse study undertaken by Plesta and colleagues and reaffirmed that this study was acceptable for hazard identification and had given a positive result. 21. A number of the documents commented on the possibility that a threshold existed for the mutagenic efects of dichlorvos. Members reaffirmed their view (see COM statement COM/01/S3 published June 2001 http://www.doh.gov.uk/comivm.htm) that in the absence of specific investigations concerning mechanisms and possible thresholds, the prudent assumption was that there was no threshold for in-vivo mutagens. Members recalled that sufficient data had been provided to determine the existence of a threshold for aneugens that acted by inhibition of the mitotic spindle and also in the case of rapid detoxification of hydroquinone after oral administration; however this was not the case with dichlorvos. 22. COC Members attending the COM meet of 9 January 2002 reviewed the available information from the carcinogenicity bioassays reviewed in the HSE review (submitted to ACP in April 2001) and in the documents submitted to the court and most recently to the regulatory authorities as part of the data call in up to 4 January 2002. COC members considered that it was extremely difficult to assess the extent of exposure from the available information. However the evidence suggested that some exposure of the skin would have occurred during the inhalation study undertaken by Blair et al in 1974. Regarding the other studies in rats, COC members considered there were limitations in all of the studies (e.g age of study, numbers of animals used, extent of pathology investigations) and that, apart from evidence of mononuclear cell leukaemia in F344 male rats in two studies, there was no evidence for a carcinogenic effect in rats. It was noted that a Pathology Working Group (PWG) had subsequently discounted the finding of mononuclear cell leukaemia in the NTP bioassay in rats, but the report presenting the basis for this decision was not available to COC members. Regarding other studies in mice, COC members considered that there were limitations in the conduct of these studies similar to those undertaken in the rat. Members considered that it was not possible to undertake a comparison of the studies in mice where dichlorvos had been administered in corn oil and those where dichlorvos had been administered in the drinking water or as an aqueous solution by gavage. COC members reaffirmed, however that when the NCI and NTP bioassays in mice were considered together there was limited evidence for an effect on squamous epithelium of the forestomach and oesophagus in mice. However the latter study should be viewed in in terms of its age and small number of oesophageal tumours. On considering the overall package of carcinogenicity bioassays COC members felt that there was no consistent evidence for a genotoxic carcinogenic effect. COC members noted that there was no agreed mechanism for the forestomach tumours. COM Discussion 23. The Committee agreed that there is clear unequivocal evidence that dichlorvos can induce DNA damage, chromosomal breakage and mutations in mammalian cells from in-vitro studies. The compound has been shown to interact with DNA via methylation, however several other mechanisms are theoretically possible. In-vivo dichlorvos can be rapidly detoxified by hydrolysis before it reaches the systemic circulation. Members noted from the HSE review that retention of 14C-vinyl-labelled dichlorvos in skin was recorded in a study where radiolabelled dichlorvos was applied to the skin on the backs of male rats. Several non-standard in-vivo mutagenicity assays have indicated that dichlorvos can induce genetic damage when systemic detoxification mechanisms are bypassed, e.g. following exposure to the skin and exposure to the liver following intraperitoneal dosing. The COM agreed that there was a potential risk of mutagenicity at site of contact tissues, i.e. at the initial sites of exposure. The COM felt there was no evidence for systemic mutagenic effects. The Committee agreed that until evidence was provided to the contrary and in the absence of appropriate mechanistic data, a precautionary approach should be adopted and no threshold could be assumed for the mutagenic activity of dichlorvos. 24. Members were aware that there was some limited evidence for a carcinogenic effect in mice from standard bioassays.(109,110) This related to an increase in squamous cell papillomas of the forestomach in mice and carcinomas of the forestomach in female mice given gavage doses of dichlorvos(110) together with the finding of squamous cell papilloma and carcinoma of the oesophagus in a small number of mice.109 Members noted there was no evidence for carcinogenicity from a number of other carcinogenicity bioassays including an inhalation bioassay in the rat, although there were limitations with all of these studies. 25. Members noted that negative results had been obtained with dichlorvos in a single dose UDS assay in the forestomach of mice using gavage dosing.(9,99,101) An increase in replicative DNA synthesis had been reported in this study. Members noted that there were a number of proposals regarding the mechanism of dichlorvos tumourigenicity in the mouse forestomach including localised irritancy of dichlorvos in corn oil. The Committee agreed that this proposal had not been proven and considered that it was not possible to exclude a genotoxic effect from these data given the relative insensitivity of the method used as indicated by the response with the positive control chemical; they felt that repeat dosing would most likely be required to identify any mutagenic effect of dichlorvos in this assay. Conclusion 26. The Committee concluded that dichlorvos should be regarded as an in-vivo mutagen at the site-of-contact (ie at the initial sites of exposure. The COM felt there was no evidence for systemic mutagenic effects.) High doses of dichlorvos induced mutagenic effects in the skin following topical application and in the liver following intraperitoneal dosing. The Committee noted the limited evidence for a carcinogenic effect of dichlorvos. This related to tumours of the forestomach in mice after gavage dosing and also the oesophageal tumours seen after dietary administration. There was no satisfactory explanation proven for the mechanisms of these tumours and the Committee felt, given the available mutagenicity data on dichlorvos, that it would be prudent to assume a genotoxic mechanism. The Committee agreed that in the absence of appropriate mechanistic data a precautionary approach should be adopted and no threshold could be assumed for the mutagenic and carcinogenic effects of dichlorvos. References 1. Sasaki YF, Sekihashi K, Izumiyama F, Nishidate E, Saga A, Ishida K, tsuda S. (2000). 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NTP Technical Report on the toxicology and carcinogenesis studies of dichlorvos (CAS 62-73-7) in F344/N rats and B6C3F1 mice (gavage studies). NTP Program PO Box 12233, Research Triangle Park, NC 27709, USA. NTP TR 342, NIH Publication 89-2598. 111. Additional information submitted to high court during judicial review (5-9 November) and to BPAU/PSD up to 4 January 2002. New Documents (AMVAC) 1. Cancer summary - 'Dichlorvos: An Assessment of Carcinogenic Potential'. 2. Letter to Ian Chart from J A MacGregor dated 7 December 2001. 3. Letter from Dr. Ward Richter, Director of Pathology Southern Research Laboratory, dated 4 December 2001 New Documents (Other data holders) 1. Submission from Denka 2. Submission from Product Safety Assessment Ltd Documents previously submitted during the Judicial Review proceedings 1. Written Comments submitted on 11 May 2001 to COM following the first draft COM Statement (F3 920-942). 2. Written summary submitted on 28 June 2001 prior to presentation to the 23 July 2001 COM Meeting (D1 86-93). 3. Written comments submitted on 26 July 2001 following the second draft COM statement (D1 98 - 104). 4. Expert opinion of David Brusick August 2001 (D1 117-122). 5. Expert opinion of John Ishmael August 2001 (D1 147 - 157). 6. Expert opinion of Karel de Raat August 2001 (D1 167-180). 7. Expert opinion of John Mennear August 2001 (D1 184-197). 8. First witness statement of J. A. MacGregor August 2001 (D1 217-243). 9. Second witness statement of J. A. MacGregor August 2001 (D1 312-326), 10. Third witness statement of J A MacGregor (D2 674-677). 11. Affidavit of Anju Sanehi (D1 1-7 paragraphs 13-18).
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