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57 metabolites found in the urine at up to 2% of the administered dose were formed by conjugation of glucuronide (M510F48) and cysteine (M510F05) at the expense of chlorine in the pyridine moiety. Minor m etabolites identified in urine are identified in Figure 5 and Table 19 as M510F03, M510F04, M510F12, M510F20, and M510F42. Traces of parent substance could be detected. Metabolites found in the group receiving pyridine-labelled boscalid included traces of 2-chloronicotinic acid (M510F47), while 4-chloro-2-aminobiphenyl was not detected in the group receiving diphenyl-labelled boscalid. Individual metabolite recoveries from urine and faeces after dosing with diphenyl-labelled boscalid and pyridyl-labelled boscalid are described in Tables 9–14. In all dose groups and independent of sex and label, the parent substance boscalid was the m ajor component and represented from 57% to 85% of the administered dose in the groups at the h ighest dose and from 30% to 41% in the groups at the lowest dose. The 4’-hydroxyl diphenyl m etabolite (M510F01) and the 2-sulfydryl metabolite (M510F06) derived from the cysteine conjugate of the 2-chloro-pyridine moiety were identified to be predominant metabolites in all dose groups. The m etabolites M510F20 and M510F63 were mainly found in the groups at the lowest dose. As minor metabolites, M510F05, M510F11 and M510F48 were also found in the faeces. Major metabolites in bile were the glucuronyl conjugate of the 4’-hydroxyl diphenyl m etabolite (M510F02) and M510F05 in which cysteine is conjugated with the 2-chloropyridine moiety. As m inor components, the 4’-hydroxyl diphenyl metabolite (M510F01), and the metabolites M510F57 and M510F58 (in which there has been introduction of a hydroxyl group and cysteine into the d iphenyl moiety) were identified. In addition, traces of M510F50 (hydroxyl group on the pyridine moiety) were found. The percentages of these metabolites found in bile are given in Table 15. Table 9. Summary of metabolites identified in urine and faeces of rats given [diphenyl U -14 C]boscalid at a dose of 500 mg/kg bw Metabolite Total excretion (% of administered dose) Urine (0–48 h) Faeces (0–48 h) Male Female Male Female M510F02 1.73 1.60 — — M510F42 0.10 0.03 — — M510F03 — 0.08 — — M510F48 0.37 0.39 1.26 1.05 M510F04 — 0.13 — — M510F05 0.34 0.34 0.64 0.70 M510F01 0.57 2.23 4.32 9.06 M510F20 0.02 0.02 0.80 0.57 Boscalid — — 80.46 64.96 M510F06 — — 6.10 10.29 From Grosshans & Knoell (2001) BOSCALID X-X JMPR 2006
58 Table 10. Summary of metabolites identified in urine and faeces of rats given [pyridine 3- 14 C]boscalid at a dose of 500 mg/kg bw Metabolite Total excretion (% of administered dose) Urine (0–48 h) Faeces (0–48 h) Male Female Male Female M510F47 0.07 0.06 — — M510F02 2.74 2.14 — — M510F42 0.13 0.04 — — M510F03 — 0.13 — — M510F48 0.44 0.33 6.50 0.38 M510F04 — 0.10 — — M510F05 0.40 0.37 4.87 1.52 M510F01 0.51 1.02 8.18 10.54 M510F20 — 0.01 1.05 0.73 Boscalid — — 75.63 56.96 M510F06 — — 1.04 12.24 From Grosshans & Knoell (2001) Table 11. Summary of metabolites identified in urine and faeces of rats given [diphenyl U- 14 C]boscalid at a dose of 50 mg/kg bw Metabolite Total excretion (% of administered dose) Urine (0–48 h) Faeces (0–48 h) Male Female Male Female M510F02 2.95 4.33 — — M510F42 0.18 0.25 — — M510F48 1.10 2.28 — 2.84 M510F04 0.08 0.22 — — M510F05 0.48 0.59 — 1.85 M510F01 9.58 15.79 21.81 18.99 M510F11 — — 2.31 0.53 M510F20 0.57 0.46 6.21 3.79 Boscalid — 0.06 41.00 30.45 M510F06 — — 4.88 7.57 M510F63 — — 0.60 4.01 From Grosshans & Knoell (2001) BOSCALID 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
Page 20 and 21: 7 In a study of the time-course of
Page 22 and 23: 9 the administered dose in males an
Page 24 and 25: 11 limited absorption of parent com
Page 26 and 27: 13 NAME/No. STRUCTURE D1989 OCH 3 D
Page 28 and 29: 15 2.1 Acute toxicity Results of st
Page 30 and 31: 17 (f) Sensitization In a study of
Page 32 and 33: 19 Table 9. Clinical chemistry effe
Page 34 and 35: 21 The degree of this finding was m
Page 36 and 37: 23 On histopathological examination
Page 38 and 39: 25 (equal to 0, 0.9, 10.4 or 25 mg/
Page 40 and 41: 27 Haemoglobin (g/dl): Before treat
Page 42 and 43: 29 weekly. Blood and urine samples
Page 44 and 45: 31 (females) (equal to 0, 1.0, 3.9,
Page 46 and 47: 33 Cytogenetic test Chinese hamster
Page 48 and 49: 35 groups of 30 males and 30 female
Page 50 and 51: 37 and placed in 10% ammonium sulfi
Page 52 and 53: 39 was > 5000 mg/kg bw. The LC 50 i
Page 54 and 55: 41 Multigeneration study of reprodu
Page 56 and 57: 43 Medical data No significant adve
Page 58: 45 Trutter, J.A. (1997a) 28-Day die
Page 61 and 62: 48 Evaluation for acceptable daily
Page 63 and 64: 50 Table 2. Radioactivity in blood
Page 65 and 66: 52 10 10 0.42 0.0462 0.63 0.0080 8.
Page 67 and 68: 54 Figure 2. Transfer of radioactiv
Page 69: 56 Skin 33.07 61.59 0.5 17.94 17.29
Page 73 and 74: 60 Table 14. Summary of identified
Page 75 and 76: 62 Table 18. Summary of metabolites
Page 77 and 78: 64 Table 19. Structures of identifi
Page 79 and 80: 66 Metabolite Structure O M510F14 N
Page 81 and 82: 68 Metabolite Structure M510F39 N O
Page 83 and 84: 70 2. Toxicological studies 2.1 Acu
Page 85 and 86: 72 1% Tylose CB 30.000. The injecti
Page 87 and 88: 74 the end of dosing. Blood samples
Page 89 and 90: 76 examinations were carried out 8
Page 91 and 92: 78 concentrations were increased at
Page 93 and 94: 80 times were slightly, but signifi
Page 95 and 96: 82 in males and females rats at 250
Page 97 and 98: 84 End-point Test object Dose a (LE
Page 99 and 100: 86 parental rats was not markedly a
Page 101 and 102: 88 groups in conception frequencies
Page 103 and 104: 90 0.7 ± 3.5%, 1.8 ± 4.2%, 2.9 ±
Page 105 and 106: 92 In this study of developmental n
Page 107 and 108: 94 3. Observations in humans In the
Page 109 and 110: 96 was 100 ppm, equal to 10 mg/kg b
Page 111 and 112: 98 Acute toxicity Rat, LD 50 , oral
Page 113 and 114: 100 Mellert, W., Kaufmann, W. & Hil
Page 116 and 117: CYFLUTHRIN AND BETA-CYFLUTHRIN Firs
Page 118 and 119: 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
Page 327 and 328:
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
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352 Elcombe, B.M. (2002a) Effects o
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354 Scortichini, B.H., Bohl, R.W. &
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356 Economic Co-operation and Devel
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358 There were no treatment-related
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360 comparable to control levels. A
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362 Groups of 17 male and 17 female
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364 No compound-related effects wer
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366 Berry, D. & Gore, C.W. (1975) P
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368 Quinoxyfen has not been evaluat
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370 In the main study, which compli
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372 Concentrations of total radioac
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374 several hydroxy-quinoxyfen meta
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376 There were no mortalities or ad
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378 at doses of ≥ 100 mg/kg bw pe
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380 In a GLP-compliant study to det
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382 control group. This was observe
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384 The homogeneity and stability o
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386 Testes weight (g) at 24 months
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388 slight (3 out of 30) hepatocell
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390 marked inanition, decreased fae
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392 Females Relative liver weightt
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394 were patch-tested specifically
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396 In studies of developmental tox
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398 Rat, LC 50 , inhalation Rabbit,
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400 Gollapudi, B.B. & Lick, S.J. (1
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TEMEPHOS First draft prepared by De
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405 by thin-layer chromatography (T
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407 In a special study to investiga
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409 concluded that temephos was of
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411 Table 3. Effects on mean erythr
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413 Females 0 1.091 1.224 1.324 1.3
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415 of up to 18 ppm. In the group a
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417 Chromosomal aberration DNA repa
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419 of the birds treated with temep
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421 concentration of 1 ppm. Only on
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423 being appreciably less than thi
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425 Lowest relevant developmental N
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427 WHO (1991) Safe use of pesticid
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430 All new studies with thiabendaz
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432 use of this dose form was consi
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434 At 1000 mg/kg bw, qualitative e
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436 At 100 mg/kg bw, slightly decre
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438 There were no treatment-related
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440 Table 6. Incidence of malformat
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442 Dose (mg/kg bw) (grouped by exp
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444 1157 12/21 (57.1)*** 27.2 ± 33
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446 versus placebo): increased appe
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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
Page 489 and 490:
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
Page 501 and 502:
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
Page 515 and 516:
502 Table 33. Selected variations a
Page 517 and 518:
504 Days 16-21 73.3 78.7 62.5 44.3*
Page 519 and 520:
506 Thiacloprid was not teratogenic
Page 521 and 522:
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
Page 527 and 528:
514 plate incorporation procedure,
Page 529 and 530:
516 (iv) Comparative study on liver
Page 531 and 532:
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
Page 541 and 542:
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
Page 551 and 552:
538 dated 27 July, from Bayer AG, W
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540 Kroetlinger, F. (1995a) YRC 289
Page 555 and 556:
542 Wetzig, H. & Geiss, V. (1998b)
Page 557 and 558:
544 Table A1. NOAELs and LOAELs for
Page 559 and 560:
546 2.2 Postulated mode of action (
Page 561 and 562:
548 • • • Chromosomal aberrat
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550 Table A3. NOAELs and LOAELs for
Page 565 and 566:
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
Page 575 and 576:
562 Table 4. Results of bone-marrow
Page 577 and 578:
564 malformations between the contr
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566 In a study of prenatal developm
Page 581 and 582:
568 combination of heparin and an a
Page 583 and 584:
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:
Page 592 and 593:
579 66. Pesticide residues in food
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581 100. Pesticide residues in food
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