Pesticide residues in food â 2006: Toxicological ... - ipcs inchem

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TEMEPHOS First draft prepared by Derek W. Renshaw 1 and Alan Boobis 2 1 Food Standards Agency, London, England; and 2 Experimental Medicine and Toxicology, Division of Medicine, Faculty of Medicine, Imperial College London, London, England Explanation ..................................................................................................... 403 Evaluation for acceptable daily intake ............................................................ 404 1. Biochemical aspects .......................................................................... 404 1.1 Absorption, distribution, excretion and biotransformation ....... 404 2. Toxicological studies ......................................................................... 405 2.1 Acute toxicity ............................................................................. 405 (a) Oral toxicity ........................................................................ 405 (b) Dermal toxicity ................................................................... 407 (c) Inhalation ............................................................................ 408 (d) Dermal irritation ................................................................. 409 (e) Ocular irritation .................................................................. 409 (f) Dermal sensitization ............................................................ 409 2.2 Short-term studies of toxicity ..................................................... 410 (a) Oral toxicity ........................................................................ 410 (b) Dermal toxicity ................................................................... 415 2.3 Long-term studies of toxicity and carcinogenicity ..................... 416 2.4 Genotoxicity ............................................................................... 416 2.5 Reproductive toxicity ................................................................. 417 (a) Multigeneration studies ...................................................... 417 (b) Developmental toxicity ....................................................... 418 2.6 Special studies: neurotoxicity in hens ........................................ 418 3. Observations in humans ..................................................................... 420 3.1 Studies in volunteers .................................................................. 410 3.2 Field studies ............................................................................... 420 3.3 Health monitoring of workers .................................................... 421 Comments ........................................................................................................ 421 References ....................................................................................................... 425 Explanation Temephos (O,O,O’O’-tetramethyl O,O’-thiodi-p-phenylene bis(phosphorothioate)) is an organophosphate insecticide. Temephos is one of the compounds recommended by the World Health Organization (WHO) as a mosquito larvicide treatment for potable water. No acceptable daily intake (ADI) had been established previously. For that reason, the WHO Drinking-water Guidelines TEMEPHOS X-X JMPR 2006
404 programme recommended that temephos be evaluated toxicologically by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR). Temephos has not been previously evaluated by the Meeting. For temephos, the specifications were established by the Joint FAO/WHO Meeting on Pesticide Specifications (JMPS) and published as WHO specifi cations and evaluations for public health pesticides: temephos (WHO, 1999). 1 Several studies with temephos, including studies of acute oral toxicity, dermal toxicity inhalation toxicity, irritancy, skin sensitization, genotoxicity and special studies of neurotoxicity in hens, were certified as being compliant with good laboratory practice (GLP). Other available studies were carried out before the Organisation for Economic Co-operation and Development (OECD) guidelines on GLP were promulgated. The Meeting noted that the reports of some of the critical studies were available only as brief published articles that lacked some of the details normally required for completing an adequate risk assessment. Figure 1. Structural formula of temephos H 3 C O S P S O CH 3 P H 3 C O O S O O CH 3 The specifications for technical temephos (WHO/SIT/19.R4), temephos emulsifiable concentrate (WHO/SIF/31.R4), temephos emulsifiable concentrate for simulium control (WHO/ SIF/34.R3) and temephos sand granules (WHO/SIF/40.R1) were last revised on 10 December 1999. Temephos is a phenyl organothiophosphate insecticide that is mainly used as a larvicide to control mosquitoes, midge, blackfly and other insects. Its toxic action against the target species is by inhibition of cholinesterase in the nervous system. Temephos has been used for the control of mosquito larvae in potable water since the early 1970s (WHO, 1991) and has been recommended for treatment of potable water at a dose not exceeding 1 mg/l (WHO, 1984; Rozendaal, 1997). Evaluation for acceptable daily intake 1. Biochemical aspects 1.1 Absorption, distribution, excretion and biotransformation Rats Groups (number and sex not stated) of Sprague-Dawley rats (body weight, 150–200 g) were given radiolabelled temephos at a dose of 970, 1357, 3164 or 9168 μg (dissolved in acetone and sesame oil) given by oral gavage. The temephos was radiolabelled with tritium at the ortho-position relative to the sulfide linkage on both phenyl rings of the molecule. Samples of urine and faeces were collected for analysis at various times between 7 h and 96 h after dosing. Unspecified numbers of animals from the group at 970 μg were killed at 48 h and rats from the group at 1357 μg were killed at 72 h. Samples of muscle, liver, kidney, stomach, intestines and fat were taken for analysis. The urine for each group at each time was pooled and extracted with chloroform and ethyl ether before analysis 1 Available from: http://www.who.int/whopes/quality/en/temephos.pdf TEMEPHOS X-X JMPR 2006
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Pesticide residues in food — 2006
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TABLE OF CONTENTS Page List of part
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Dr Helen Hakansson, Institute of En
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Abbreviations used ADI ALT APDM ARf
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Introduction The toxicological mono
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BIFENAZATE First draft prepared by
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5 In a series of experiments, group
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7 In a study of the time-course of
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9 the administered dose in males an
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11 limited absorption of parent com
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13 NAME/No. STRUCTURE D1989 OCH 3 D
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15 2.1 Acute toxicity Results of st
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17 (f) Sensitization In a study of
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19 Table 9. Clinical chemistry effe
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21 The degree of this finding was m
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23 On histopathological examination
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25 (equal to 0, 0.9, 10.4 or 25 mg/
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27 Haemoglobin (g/dl): Before treat
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29 weekly. Blood and urine samples
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31 (females) (equal to 0, 1.0, 3.9,
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33 Cytogenetic test Chinese hamster
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35 groups of 30 males and 30 female
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37 and placed in 10% ammonium sulfi
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39 was > 5000 mg/kg bw. The LC 50 i
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41 Multigeneration study of reprodu
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43 Medical data No significant adve
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45 Trutter, J.A. (1997a) 28-Day die
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48 Evaluation for acceptable daily
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50 Table 2. Radioactivity in blood
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52 10 10 0.42 0.0462 0.63 0.0080 8.
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54 Figure 2. Transfer of radioactiv
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56 Skin 33.07 61.59 0.5 17.94 17.29
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58 Table 10. Summary of metabolites
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60 Table 14. Summary of identified
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62 Table 18. Summary of metabolites
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64 Table 19. Structures of identifi
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66 Metabolite Structure O M510F14 N
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68 Metabolite Structure M510F39 N O
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70 2. Toxicological studies 2.1 Acu
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72 1% Tylose CB 30.000. The injecti
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74 the end of dosing. Blood samples
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76 examinations were carried out 8
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78 concentrations were increased at
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80 times were slightly, but signifi
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82 in males and females rats at 250
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84 End-point Test object Dose a (LE
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86 parental rats was not markedly a
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88 groups in conception frequencies
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90 0.7 ± 3.5%, 1.8 ± 4.2%, 2.9 ±
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92 In this study of developmental n
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94 3. Observations in humans In the
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96 was 100 ppm, equal to 10 mg/kg b
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98 Acute toxicity Rat, LD 50 , oral
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100 Mellert, W., Kaufmann, W. & Hil
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CYFLUTHRIN AND BETA-CYFLUTHRIN Firs
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105 Table 1. Diastereoisomer pairs
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107 (i) In vivo Rats Four groups of
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109 2. Toxicological studies 2.1 Ac
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111 Species Strain Sex Route Formul
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113 Rat Groups of 20 male and 20 fe
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115 group and in the groups at the
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117 cyfluthrin (purity, 95.5-95.9%)
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119 In a short-term study of exposu
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121 and dissection. At termination,
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123 2.5 Reproductive toxicity (a) M
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125 gestation. The vehicle was 1% C
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127 females was exposed during days
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129 were not seen in rats in the co
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131 men was exposed for 1 h to actu
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133 40 g/l, in a flowable concentra
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135 were removed from five males an
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137 weights and food consumption we
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139 In females at the highest dose,
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141 The dermal toxicity of cyfluthr
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143 The Meeting concluded that the
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145 Estimate of acute reference dos
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147 Cage, S. (2004) [ 14 C]-beta-cy
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149 Heimann, K.G. (1984c) FCR 4545
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151 Jones, R.D. & Hastings, T.F. (1
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153 Pauluhn, J. & Mohr, U. (1984).
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155 Von Keutz, E. (1987) FCR 4545 -
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158 Zeta-cypermethrin .............
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160 Evaluation for acceptable daily
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162 polar metabolites, which are fu
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164 for up to 70 days. Signs typica
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166 rapidly metabolized by cleavage
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170 Table 2. Effect of cis : trans
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172 Table 3. Significant haematolog
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174 Rabbits Occluded dermal applica
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176 1100 ppm in weeks 1-6, with inc
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178 Wistar-derived (Alderley Park)
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180 At 1500 ppm, liver APDM activit
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182 for premature deaths, 10 male a
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184 by gavage for days 7 to 19 of g
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186 observed at the intermediate an
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188 The females recovered from this
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190 tibial nerve (SPTN), trigeminal
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194 for 5 weeks. Observations inclu
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196 caused obvious irritation and r
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198 days 6-15 of gestation. After m
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200 was observed in two males at 72
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202 control and other treated group
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204 Table 14. Results of studies of
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206 (b) Developmental toxicity Rats
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208 mild and temporary paraesthesia
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210 range appeared to exist for the
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212 for which the LD 50 was > 2000
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214 substances. Since conventional
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216 Critical end-points relevant fo
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218 Butterworth, S.T.G. & Clark, D.
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220 East Millstone, New Jersey, USA
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222 Jersey, USA. Submitted to WHO b
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224 Toxicology Laboratory (Tunstall
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226 Ullrich, B. (2003) Report on a
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228 Cyromazine was first evaluated
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230 were taken for the measurement
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232 highest dose, rather than indic
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234 Tissue residues: Tissues a < 0.
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236 Because of the low total recove
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238 Name Description Compound found
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240 After each dose of [U- 14 C tri
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242 In male and female monkeys give
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244 stress and discomfort during th
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246 Table 18. Dermal absorption of
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248 rate under steady-state conditi
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252 the test substance. The method
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254 taken for haematological and bi
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256 not differ appreciably from pre
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258 Analysis of the diets showed th
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260 considered to be biologically s
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262 observed incidence probably rel
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264 c Cyromazine was assayed twice
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268 either sporadic or as a consequ
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270 fetuses were removed, weighed a
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272 The NOAEL for maternal toxicity
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274 In New Zealand White rabbits, c
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276 and litters with malformations.
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278 of melamine powder into the rab
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280 reduction in the survival of ma
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282 There is significantly less ris
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284 Toxicological data Cyromazine h
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286 Toxicological evaluation The Me
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288 Other toxicological studies Tox
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290 IARC (1999a) Some chemicals tha
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292 Simoneaux, B. & Marco, G. (1984
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294 Declaration of Helsinki (Cristi
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296 lowered arousal level at doses
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298 Cerebellum 3 1 51** 76** 80** 7
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300 Table 4. Maximum inhibition of
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302 auditory/physical examination w
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304 • • • • • Home-cage o
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306 Dogs Groups of four male and fo
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308 capsules. Some volunteers recei
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310 Blood was taken for measurement
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312 Human a Dietary administration
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314 Piccirillo, V.J. (1978) Acute o
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316 Haloxyfop (racemic), its sodium
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318 Recovery of radioactivity in ur
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320 skin of nine male and nine fema
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322 1.2 Biotransformation Mice In a
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326 96%) at a concentration designe
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328 was centrilobular hepatocellula
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330 The treatment had no effect on
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332 All dogs were killed for autops
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334 with that of controls (but no s
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336 Table 4. Results of studies of
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338 doses of up to 1.0 mg/kg bw per
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340 delayed ossification in the hyo
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342 Mice In a GLP-compliant study,
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344 and in females at the highest d
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346 Between January 1999 and Januar
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348 The Meeting concluded that halo
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350 Critical end-points for setting
Page 365 and 366: 352 Elcombe, B.M. (2002a) Effects o
Page 367 and 368: 354 Scortichini, B.H., Bohl, R.W. &
Page 369 and 370: 356 Economic Co-operation and Devel
Page 371 and 372: 358 There were no treatment-related
Page 373 and 374: 360 comparable to control levels. A
Page 375 and 376: 362 Groups of 17 male and 17 female
Page 377 and 378: 364 No compound-related effects wer
Page 379 and 380: 366 Berry, D. & Gore, C.W. (1975) P
Page 381 and 382: 368 Quinoxyfen has not been evaluat
Page 383 and 384: 370 In the main study, which compli
Page 385 and 386: 372 Concentrations of total radioac
Page 387 and 388: 374 several hydroxy-quinoxyfen meta
Page 389 and 390: 376 There were no mortalities or ad
Page 391 and 392: 378 at doses of ≥ 100 mg/kg bw pe
Page 393 and 394: 380 In a GLP-compliant study to det
Page 395 and 396: 382 control group. This was observe
Page 397 and 398: 384 The homogeneity and stability o
Page 399 and 400: 386 Testes weight (g) at 24 months
Page 401 and 402: 388 slight (3 out of 30) hepatocell
Page 403 and 404: 390 marked inanition, decreased fae
Page 405 and 406: 392 Females Relative liver weightt
Page 407 and 408: 394 were patch-tested specifically
Page 409 and 410: 396 In studies of developmental tox
Page 411 and 412: 398 Rat, LC 50 , inhalation Rabbit,
Page 413 and 414: 400 Gollapudi, B.B. & Lick, S.J. (1
Page 418 and 419: 405 by thin-layer chromatography (T
Page 420 and 421: 407 In a special study to investiga
Page 422 and 423: 409 concluded that temephos was of
Page 424 and 425: 411 Table 3. Effects on mean erythr
Page 426 and 427: 413 Females 0 1.091 1.224 1.324 1.3
Page 428 and 429: 415 of up to 18 ppm. In the group a
Page 430 and 431: 417 Chromosomal aberration DNA repa
Page 432 and 433: 419 of the birds treated with temep
Page 434 and 435: 421 concentration of 1 ppm. Only on
Page 436 and 437: 423 being appreciably less than thi
Page 438 and 439: 425 Lowest relevant developmental N
Page 440: 427 WHO (1991) Safe use of pesticid
Page 443 and 444: 430 All new studies with thiabendaz
Page 445 and 446: 432 use of this dose form was consi
Page 447 and 448: 434 At 1000 mg/kg bw, qualitative e
Page 449 and 450: 436 At 100 mg/kg bw, slightly decre
Page 451 and 452: 438 There were no treatment-related
Page 453 and 454: 440 Table 6. Incidence of malformat
Page 455 and 456: 442 Dose (mg/kg bw) (grouped by exp
Page 457 and 458: 444 1157 12/21 (57.1)*** 27.2 ± 33
Page 459 and 460: 446 versus placebo): increased appe
Page 461 and 462: 448 activity, tiptoe gait, landing
Page 463 and 464: 450 Noakes, J.P. (2005a) Thianendaz
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452 tests normally performed and th
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454 Radiolabel was excreted primari
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456 the excretory organs, was the r
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458 Table 6. Excretion of radioacti
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460 of unchanged parent compound we
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462 M10 (KNO 1891) + M11 (KNO 1893)
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464 on body weights. Exposure at 15
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466 The no-observed-adverse-effect
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468 Hepatocytes, hypertrophy 0 2 6
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470 they may also be related to var
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472 weights of males were approxima
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474 Thyroid weight (mg): Week 12 6
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476 Table 17. Relevant findings in
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478 Dogs In a dose range-finding st
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480 Prostate / uterine weight (g) 2
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482 the treatment groups receiving
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484 No gross findings were observed
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486 received a macroscopic examinat
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488 Although decreased concentratio
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490 Sciatic nerve; No. examined 50
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492 are caused by the higher incide
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496 In a two-generation study of re
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498 In dams that died or were sacri
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500 No clinical signs or increased
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502 Table 33. Selected variations a
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504 Days 16-21 73.3 78.7 62.5 44.3*
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506 Thiacloprid was not teratogenic
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508 Table 37. Motor and locomotor a
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510 Day 91 19.78 20.00 19.58 18.22*
Page 525 and 526:
512 Table 40. Selected findings in
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514 plate incorporation procedure,
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516 (iv) Comparative study on liver
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518 and relative liver weight in an
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520 at 2500 ppm. The administration
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522 No macroscopic changes were det
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524 The following procedures were p
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526 litter for the group at 1000 pp
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528 Hepatic enzyme activities in th
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530 subtypes 1A1, 2B1, 2D1 and othe
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532 Long-term studies of toxicity a
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534 The Meeting concluded that ther
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536 Estimate of acceptable daily in
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538 dated 27 July, from Bayer AG, W
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540 Kroetlinger, F. (1995a) YRC 289
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542 Wetzig, H. & Geiss, V. (1998b)
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544 Table A1. NOAELs and LOAELs for
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546 2.2 Postulated mode of action (
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548 • • • Chromosomal aberrat
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550 Table A3. NOAELs and LOAELs for
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552 Appendix 2 Table B1. List of an
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554 Metabolite Structure / trivial
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556 Metabolite Structure / trivial
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558 Evaluation for acute reference
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560 increased thyroid weights in th
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562 Table 4. Results of bone-marrow
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564 malformations between the contr
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566 In a study of prenatal developm
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568 combination of heparin and an a
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570 Table 10. Selected findings fro
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572 In a short-term study of neurot
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ANNEX 1 Reports and other documents
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577 31. Pesticide residues in food:
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579 66. Pesticide residues in food
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581 100. Pesticide residues in food
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