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

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535 The Meeting concluded that the existing database on thiacloprid was adequate to characterize the potential hazards to fetuses, infants and children. Toxicological evaluation The Meeting established an ADI of 0–0.01 mg/kg bw based on the NOAEL of 1.2 mg/kg bw per day identified in a 2-year dietary study in rats, and a safety factor of 100. Effects at the lowestobserved-adverse-effect level (LOAEL) of 2.5 mg/kg bw per day included liver toxicity and thyroid changes (follicular epithelial hypertrophy) secondary to liver enzyme induction. The Meeting established an ARfD of 0.03 mg/kg bw based on the NOAEL of 3.1 mg/kg bw identified in a study of acute neurotoxicity in rats, and a safety factor of 100. It was not possible to determine a chemical-specific adjustment factor since it was not confirmed by appropriate toxicokinetic data that the critical effect (decrease in motor and locomotor activity) at the LOAEL of 11 mg/kg bw is dependent on the C max . Levels relevant to risk assessment Species Study Effect NOAEL LOAEL Mouse 14-week study of Toxicity 50 ppm, equal to 250 ppm, equal to toxicity a 19.9 mg/kg bw per day 102.6 mg/kg bw per day Rat Rabbit 2-year study of carcinogenicity a Toxicity 30 ppm, equal to 5.7 mg/kg bw per day Carcinogenicity Females: 30 ppm, equal to 10.9 mg/kg bw per day 13-week study of Toxicity 400 ppm, equal to toxicity a 28.6 mg/kg bw per day 2-year study Toxicity 25 ppm, equal to c arcinogenicity a Carcinogenicity 50 ppm, equal to of t oxicity and 1.2 mg/kg bw per day 2.5 mg/kg bw per day Multigeneration Fertility 600 ppm, equal to — r eproductive toxicity a 43.9 mg/kg bw per day c Parental toxicity Offspring toxicity 50 ppm, equal to 3.5 mg/kg bw per day 50 ppm, equal to 3.5 mg/kg bw per day 1250 ppm, equal to 234.1 mg/kg bw per day Females: 1250 ppm, equal to 475.3 mg/kg bw per day 1600 ppm, equal to 123.2 mg/kg bw per day 50 ppm, equal to 2.5 mg/kg bw per day 500 ppm, equal to 25.2 mg/kg bw per day 300 ppm, equal to 21.7 mg/kg bw per day 300 ppm, equal to 21.7 mg/kg bw per day Developmental Maternal toxicity 10 mg/kg bw per day 50 mg/kg bw per day t oxicity b Embryo- and f etotoxicity 10 mg/kg bw per day 50 mg/kg bw per day Acute neurotoxicity b Neurotoxicity 3.1 mg/kg bw per day 11 mg/kg bw per day Subchronic n eurotoxicity a Neurotoxicity 1600 ppm, equal to 101 mg/kg bw per day c — Developmental n eurotoxicity a Maternal toxicity 50 ppm, equal to 4.4 mg/kg bw per day Offspring toxicity 50 ppm, equal to 4.4 mg/kg bw per day 300 ppm, equal to 25.6 mg/kg bw per day 300 ppm, equal to 25.6 mg/kg bw per day Developmental Maternal toxicity 2 mg/kg bw per day 10 mg/kg bw per day t oxicity b Embryo- and f etotoxicity 2 mg/kg bw per day 10 mg/kg bw per day Toxicity 250 ppm, equal to Dog 1-year study of t oxicity a 8.3 mg/kg bw per day a Dietary administration. b Gavage administration. c Highest dose tested. 1000 ppm, equal to 33.8 mg/kg bw per day THIACLOPRID X-X JMPR 2006
536 Estimate of acceptable daily intake for humans 0–0.01 mg/kg bw Estimate of acute reference dose 0.03 mg/kg bw Information that would be useful for the continued evaluation of the compound Results from epidemiological, occupational health and other such observational studies of human exposures Critical end-points for setting guidance values for exposure to thiacloprid Absorption, distribution, excretion and metabolism in animals Rate and extent of oral absorption Rapid and almost complete, based on oral and intravenous administration of low dose Dermal absorption No data Distribution Widely; highest concentrations in liver, kidneys, lung, adrenals and thyroid Rate and extent of excretion Rapid, > 90% within 48 h; 60–83% in urine, up to 34% in faeces (largely due to biliary excretion) Potential for accumulation No evidence of accumulation Metabolism in mammals Extensive; C- and N-hydroxylation, S-oxidation and methylation, oxidativering cleavage and methylene-bridge cleavage, conjugation Toxicologically significant compounds Parent compound (animals, plants and the environment) Acute toxicity Rat, LD 50 , oral 396–836 mg/kg bw Rat, LD 50 , dermal > 2000 mg/kg bw Rat, LC 50 inhalation 1.233 to > 2.535 mg/l air (4-h, nose-only exposure) Rabbit, skin irritation Not irritant Rabbit, eye irritation Slightly irritant Guinea-pig, skin sensitization Not sensitizing (maximization) (test method) Short-term studies of toxicity Target/critical effect Liver (histopathological changes), thyroid (hormonal and h istopathological changes), adrenals (X-zone: histopathological changes) Lowest relevant oral NOAEL 8.3 mg/kg bw per day (1-year study in dogs) Lowest relevant dermal NOAEL 300 mg/kg bw per day (4-week study in rats) Lowest relevant inhalation NOAEC 0.002 mg/l air (4-week study in rats) Genotoxicity Not genotoxic in vitro or in vivo Long-term studies of toxicity and carcinogenicity Target/critical effect Liver (histopathological changes), thyroid (hormonal and h istopathological changes), adrenals (X-zone: histopathological changes) Lowest relevant NOAEL 1.2 mg/kg bw per day (2-year study in rats) Carcinogenicity Thyroid adenomas in male rats, uterine adenocarcinoma in rats, ovarian luteomas in mice THIACLOPRID 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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266 2.5 Reproductive toxicity (a) M
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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
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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
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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
Page 497 and 498: 484 No gross findings were observed
Page 499 and 500: 486 received a macroscopic examinat
Page 501 and 502: 488 Although decreased concentratio
Page 503 and 504: 490 Sciatic nerve; No. examined 50
Page 505 and 506: 492 are caused by the higher incide
Page 507 and 508: 494 2.5 Reproductive toxicity (a) M
Page 509 and 510: 496 In a two-generation study of re
Page 511 and 512: 498 In dams that died or were sacri
Page 513 and 514: 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
Page 523 and 524: 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
Page 533 and 534: 520 at 2500 ppm. The administration
Page 535 and 536: 522 No macroscopic changes were det
Page 537 and 538: 524 The following procedures were p
Page 539 and 540: 526 litter for the group at 1000 pp
Page 541 and 542: 528 Hepatic enzyme activities in th
Page 543 and 544: 530 subtypes 1A1, 2B1, 2D1 and othe
Page 545 and 546: 532 Long-term studies of toxicity a
Page 547: 534 The Meeting concluded that ther
Page 551 and 552: 538 dated 27 July, from Bayer AG, W
Page 553 and 554: 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
Page 563 and 564: 550 Table A3. NOAELs and LOAELs for
Page 565 and 566: 552 Appendix 2 Table B1. List of an
Page 567 and 568: 554 Metabolite Structure / trivial
Page 569 and 570: 556 Metabolite Structure / trivial
Page 571 and 572: 558 Evaluation for acute reference
Page 573 and 574: 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
Page 579 and 580: 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
Page 585 and 586: 572 In a short-term study of neurot
Page 588 and 589: ANNEX 1 Reports and other documents
Page 590 and 591: 577 31. Pesticide residues in food:
Page 592 and 593: 579 66. Pesticide residues in food
Page 594: 581 100. Pesticide residues in food
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