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195 Toxicological evaluation Although increased incidences of liquid faeces were observed in dogs given lambda-cyhalothrin/ cyhalothrin, which may represent a consequence of a local gastrointestinal equivalent of paraesthesia in the skin, the Meeting considered that it was not appropriate to base the ADI and acute reference dose (ARfD) on local effects on the gastrointestinal tract, observed after bolus administration. The most sensitive systemic effect of lambda-cyhalothrin/cyhalothrin was neurotoxicity (decreased motor activity), which was observed in a study of acute toxicity in rats given lambdacyhalothrin orally, with a threshold dose of 0.5 mg/kg bw, and in repeat-dose studies with cyhalothrin and lambda-cyhalothrin in dogs treated orally (ataxia, tremors, occasionally convulsions) with a NOAEL of 0.5 mg/kg bw per day. On the basis of these effects, the Meeting established a group ADI for cyhalothrin and lambda cyhalothrin of 0–0.02 mg/kg bw, using a safety factor of 25. Because lambda-cyhalothrin is relatively rapidly absorbed and excreted and the neurotoxic effects are rapidly reversible and dependent on C max , the Meeting considered it appropriate to adjust the safety factor for the reduced variability in C max compared with AUC. The Meeting considered that the ADI of 0.02 mg/kg bw is adequately protective against the other, non-neurotoxic effects of lambda-cyhalothrin/cyhalothrin observed in short- and long-term studies with repeated doses, and in studies of reproductive and developmental toxicity, where the use of a safety factor of 100 would be appropriate. The Meeting established a group ARfD for cyhalothrin and lambda-cyhalothrin of 0.02 mg/kg bw on the basis of systemic neurotoxicity (decreased motor activity) observed in a study of acute toxicity in rats given lambda-cyhalothrin orally with a threshold dose of 0.5 mg/kg bw per day, and in repeat-dose studies with cyhalothrin and lambda-cyhalothrin in dogs treated orally, in which neurotoxic effects (ataxia, tremors, occasionally convulsions) occurred during the first week, within a few hours after treatment, with an overall NOAEL of 0.5 mg/kg bw per day, and using a safety factor of 25. For the same reasons as described above, the Meeting considered it appropriate to adjust the safety factor for the reduced variability in C max compared with AUC. Levels relevant for risk assessment (a) Cyhalothrin Species Study Effect NOAEL LOAEL Mouse Rat Two-year study of toxicity and carcinogenicity a Toxicity Carcinogenicity Ninety-day study of Toxicity 50 ppm, equal to toxicity a 2.6 mg/kg bw per day Two-year study of toxicity and carcinogenicity a Toxicity Carcinogenicity Two-generation study of Parental toxicity 30 ppm, equivalent to reproductive toxicity a 2.0 mg/kg bw per day Offspring toxicity Reproductive toxicity 20 ppm, equal to 1.8 mg/kg 100 ppm, equal to bw per day 9.2 mg/kg bw per day 500 ppm, equal to — 51 mg/kg bw per day c 250 ppm, equal to 14 mg/kg bw per day 50 ppm, equal to 2.3 mg/kg 250 ppm, equal to bw per day 12 mg/kg bw per day 250 ppm, equal to — 12 mg/kg bw per day c 30 ppm, equivalent to 2.0 mg/kg bw per day 100 ppm, equivalent to — 6.7 mg/kg bw per day c 100 ppm, equivalent to 6.7 mg/kg bw per day d 100 ppm, equivalent to 6.7 mg/kg bw per day d LAMBDA-CYHALOTHRIN 173–200 JMPR 2007
196 15 mg/kg bw per day 30 mg/kg bw per day Developmental toxicity b Maternal toxicity 10 mg/kg bw per day Fetotoxicity 15 mg/kg bw per day c — Rabbit Developmental toxicity b Maternal toxicity 10 mg/kg bw per day Fetotoxicity 30 mg/kg bw per day c — Dog Twenty-six-week study b Toxicity 2.5 mg/kg bw per day 10 mg/kg bw per day a Dietary administration. b Gavage administration. c Highest dose tested. (b) Lambda-cyhalothrin Species Study Effect NOAEL LOAEL Rat Ninety-day study of Toxicity 50 ppm, equivalent to toxicity a 2.5 mg/kg bw per day 250 ppm, equivalent to 12.5 mg/kg bw per day Acute neurotoxicity b Neurotoxicity 0.5 mg/kg bw e 1.3 mg/kg bw f Ninety-day study of Neurotoxicity 150 ppm, equal to — neurotoxicity a 11 mg/kg bwper day c Developmental Maternal toxicity 60 ppm, equal to 4.9 mg/kg neurotoxicity a bw per day Offspring toxicity Developmental (neuro)-toxicity 150 ppm, equal to 11.4 mg/kg bw per day 60 ppm, equivalent to 150 ppm, equivalent to 10.7 mg/kg bw per day d 26.3 mg/kg bw per day d 150 ppm, equivalent to — 11.4 mg/kg bw per day c Dog One-year study b (Neuro)toxicity 0.5 mg/kg bw per day 3.5 mg/kg bw per day a Dietary administration. b Gavage administration. c Highest dose tested. d Based on maternal intake of lambda-cyhalothrin during lactation. e Threshold dose obtained using a nonlinear exponential threshold model. f ED 30 (dose associated with a 30% decrease in motor activity) obtained using a nonlinear exponential threshold model. Estimate of acceptable daily intake for humans 0–0.02 mg/kg bw Estimate of acute reference dose 0.02 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 cyhalothrin/lambda-cyhalothrin Absorption, distribution, excretion and metabolism in animals Rate and extent of absorption Rapid, incomplete absorption (about 40–50% in rats) Distribution Highest concentrations in fat, followed by liver and kidney (rats) Potential for accumulation Low Rate and extent of excretion Rapid (70% in faeces and urine within 24 h in rats) LAMBDA-CYHALOTHRIN 173–200 JMPR 2007
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Pesticide residues in food — 2007
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TABLE OF CONTENTS Page List of part
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Dr Vicki L. Dellarco, Office of Pes
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Abbreviations used 3-MC ACTH ADI ai
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MRL MS MS/MS MTD NMR NOAEC NOAEL NO
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Introduction The toxicological mono
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AMINOPYRALID First draft prepared b
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5 higher renal excretion in the gro
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7 Table 4. Recovery of radioactivit
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9 Table 7. Pharmacokinetic paramete
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11 (c) Exposure by inhalation Five
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13 Table 9. Acute toxicity of amino
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15 The data from urine analysis rev
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17 18, monthly for palpable masses.
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19 Table 12. Body weights of rats f
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21 Table 15. Results of assays for
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23 in both groups, feed consumption
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25 neurotoxicity after 12 months. B
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27 The same five time-mated NZW rab
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29 Mortality was increased in all g
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31 Levels relevant to risk assessme
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33 References Brooks, K.J. (2001a)
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35 Consulting, The Dow Chemical Com
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ATRAZINE First draft prepared by Ru
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39 in the early 1990s; this reflect
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41 Maximum concentrations in the bl
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43 In a study on comparative metabo
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45 Table 1. Metabolism of atrazine
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47 Figure 2. Proposed metabolic pat
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49 to intact skin; and that no read
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51 the highest dose, and food consu
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53 mice (evaluated as roughly equiv
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55 Table 5. Incidence of mammary tu
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57 Table 6. Selected findings from
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59 was decreased when compared with
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61 Table 9. Selected findings of a
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63 proestrus at the expense of days
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65 Table 10. Selected studies of ge
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67 End-point Test object Concentrat
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69 Table 12. Relevant findings in a
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73 respectively) and in males at th
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77 All dams survived until the end
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79 250 and 500 ppm. Body-weight gai
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81 In an assay for reverse mutation
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83 on pubertal development in femal
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85 parameters (decreased pH, specif
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89 0, 75, 150 or 300 mg/kg bw per d
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91 The NOAEL was 25 ppm, equal to 1
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93 In a study on the effect of atra
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95 Delayed parturition was seen at
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97 observed in the pair-fed group.
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99 examined, offspring in the atraz
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101 antagonize E2-induced luciferas
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103 increase in steroidogenesis is
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105 The immune system of adult mice
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107 In a later review of cancer epi
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109 In a 25-day study in rabbits tr
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111 developmental toxicity were 10
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113 regulation in male offspring in
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115 (d) Diaminochlorotriazine (DACT
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117 Developmental target/critical e
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119 • The failure to ovulate resu
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121 The relationship between increa
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123 Table A2. Comparison of paramet
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125 Ballantine, L., Murphy, T. G. &
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127 Dunkelberg, H., Fuchs, J., Heng
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129 Heneweer, M., van den Berg, M.
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131 Lindsay, L.A., Wimbert, K.V., G
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133 Morseth, S.L. (1996d) Chronic (
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135 Rudzki, M.W., Batastina, G., &
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137 Tennant, A.H., Peng, B. & Klige
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AZINPHOS-METHYL First draft prepare
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141 methylation and oxidation of me
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143 Table 1. Acute oral toxicity of
Page 160 and 161: 145 Table 2. Cholinesterase activit
Page 162 and 163: 147 at the highest dose. In both sp
Page 164 and 165: 149 Table 6. Cholinesterase activit
Page 166 and 167: 151 Table 8. Fertility of F 0 and F
Page 168 and 169: 153 Table 10. Fertility parameters
Page 170 and 171: 155 Groups of 22 mated Sprague-Dawl
Page 172 and 173: 157 after completion of the feeding
Page 174 and 175: 159 reduced motor activity in males
Page 176 and 177: 161 sensitivity with that of labora
Page 178 and 179: 163 measures to prevent worker expo
Page 180 and 181: 165 when brain cholinesterase activ
Page 182 and 183: 167 Critical end-points for setting
Page 184 and 185: 169 Eiben, R., Schmidt, W., & Loese
Page 186 and 187: 171 Myhr, B.C. (1983) Evaluation of
Page 188 and 189: LAMBDA-CYHALOTHRIN First draft prep
Page 190 and 191: 175 Figure 1. Chemical structures o
Page 192 and 193: 177 In a comparative study, the abs
Page 194 and 195: 179 Figure 2. Main pathways of biot
Page 196 and 197: 181 (iv) Dermal sensitization In a
Page 198 and 199: 183 observed in rats at the highest
Page 200 and 201: 185 Mortality was not affected by t
Page 202 and 203: 187 the group at 100 ppm, reduction
Page 204 and 205: 189 and five females per group were
Page 206 and 207: 191 10-12%) than those of controls
Page 208 and 209: 193 Comments Biochemical aspects Or
Page 212 and 213: 197 Metabolism in animals Toxicolog
Page 214 and 215: 199 Harrison, M.P. (1984a) Cyhaloth
Page 216 and 217: DIFENOCONAZOLE First draft prepared
Page 218 and 219: 203 a sex difference nor any marked
Page 220 and 221: 205 demonstrated that the highest t
Page 222 and 223: 207 Figure 3. Proposed metabolic pa
Page 224 and 225: 209 of the study were unremarkable.
Page 226 and 227: 211 Table 3. Results of studies of
Page 228 and 229: 213 The no-observed-adverse-effect
Page 230 and 231: 215 lower than those of rats in the
Page 232 and 233: 217 hepatocellular enlargement. In
Page 234 and 235: 219 i.e. males lost 15.4% and femal
Page 236 and 237: 221 and 357. This reduced food cons
Page 238 and 239: 223 There was very high mortality a
Page 240 and 241: 225 Table 6. Treatment-related hist
Page 242 and 243: 227 Rats Groups of 80 CRL:CD(SD)®
Page 244 and 245: 229 Table 7. Histopathology finding
Page 246 and 247: 231 D. Temporal association. The fe
Page 248 and 249: 233 2.5 Reproductive toxicity (a) M
Page 250 and 251: 235 t estes weights in the males at
Page 252 and 253: 237 continued to be lower than thos
Page 254 and 255: 239 Corpora lutea in each ovary wer
Page 256 and 257: 241 S1 + S2, not ossified — —
Page 258 and 259: 243 in the control group and in the
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245 physically examined for changes
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247 Table 16. Results of studies of
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249 can occur in untreated mice, in
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251 Study of reproductive toxicity
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257 of the test article on microsom
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259 Ophthalmoscopic examinations pe
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261 the radioactivity was re-elimin
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263 In a single-dose study of neuro
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265 Estimate of acceptable daily in
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267 Clapp, M.J.L., Killick, M.E., H
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269 Herbold, B. (1983c) THS 2212 tr
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271 Pinto, P. (2006b) Difenoconazol
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DIMETHOMORPH First draft prepared b
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275 Five different treatment groups
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277 To investigate the significance
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279 and the E : Z isomer ratio was
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281 Table 10. Tissue distribution o
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283 (e) Dermal sensitization The de
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285 females at the highest dose, to
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287 The NOAEL was 10 mg/kg bw per d
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289 concentrations in females were
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291 health, moribundity and mortali
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293 0-9%, mean, 3.5%; only one out
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Table 26. Organ weights adjusted to
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297 cell hyperplasia. The testes tu
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299 unscheduled DNA synthesis, the
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301 Figure 3. Cumulative percentage
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303 Rabbits In a dose-range finding
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305 (b) Potentiation of hexobarbito
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307 0.2% or less of the administere
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309 eye-opening, pinna unfolding or
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311 Lowest relevant inhalation NOAE
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313 Gardner, J.R. (1989) CME 151 te
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315 van de Waart, E.J. (1991b) Eval
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318 Committee on Pesticide residues
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320 (a) Ocular irritation Rabbits T
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322 weights were decreased in males
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324 toxicity was 5 mg/kg bw per day
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326 respectively; range for histori
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328 Table 4. Incidence of Leydig-ce
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330 and/or bilateral) was noted in
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332 No treatment-related signs of m
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334 Table 6. Incidence of selected
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336 or teratogenic potential at the
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338 and progesterone. The concentra
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340 the doses used in the 1-year st
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342 No neurotoxic effects were seen
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344 Lowest relevant reproductive NO
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346 Keller, D.A. (1992c) Oncogenici
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PROCYMIDONE First draft prepared by
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351 Rats Groups of five male and fe
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353 Table 1. Pharmacokinetic parame
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355 Seven doses C max (µg equivale
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357 Three groups of five male and f
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359 The excretion of radioactivity
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361 Figure 1. Proposed metabolic pa
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363 water consumption were determin
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365 finding. Histopathology reveale
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367 The NOAEL was 500 ppm, equivale
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369 The NOAEL was 100 mg/kg bw per
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371 at 2000 ppm. Histopathology rev
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373 b Each test was conducted in tr
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375 experimental period. Rats were
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377 hypospadias, testicular atrophy
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379 a single dose, which produced o
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381 The anti-androgenic activities
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383 but only at 6000 ppm after 13 w
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385 The results are summarized in T
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387 males (all litters) in the grou
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389 procymidone (18-27% of the admi
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391 Procymidone induced liver tumou
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393 The Meeting concluded that the
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395 Toxicologically significant com
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397 Harada, T. (1983) A review on m
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399 Murakami, M., Yoshitake, A. & H
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401 Tarui, H. (2005b) In vitro meta
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404 Explanation Profenofos is the I
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406 The metabolism of ring-labelled
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408 2. Toxicological studies 2.1 Ac
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410 Rabbits Groups of two male and
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412 Groups of five male and five fe
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414 control group and in the test g
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416 of the rabbits at the highest d
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418 The NOAEL for brain acetylcholi
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420 Table 2. Histopathological find
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422 1 out of 70; lowest dose, 3 out
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424 body‐weight gains (3-10% decr
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426 treated groups for body-weight
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428 (b) Short-term studies of neuro
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430 represented as equally as possi
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432 pound and the equitoxic mixture
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434 Inhibition of brain acetylcholi
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436 Toxicological evaluation Erythr
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438 Neurotoxicity/delayed neurotoxi
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440 Harris, S.B. (1982) A teratolog
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442 Puri, E. (1982a) Autoradiograph
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PYRIMETHANIL First draft prepared b
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447 Table 1. Excretion profile in r
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449 Table 3. Half-life of pyrimetha
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451 Table 4. Identification of meta
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453 SN 614 277. The presence of the
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455 2. Toxicological studies 2.1 Ac
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457 treated rabbits showed slight e
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459 still evident in the liver; how
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461 In a 90-day feeding study, grou
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463 per day or 800 mg/kg bw per day
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465 The dosing solutions were prepa
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467 mortality and morbidity. Change
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469 2.4 Genotoxicity Pyrimethanil w
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471 mean body‐weight gains. After
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473 Analysis of dosing solutions in
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475 In a 7-day feeding study, group
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477 at 200 mg/kg bw. These clinical
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479 s ystemic toxicity was 400 ppm
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481 Acute toxicity Rat, LD 50 , ora
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483 Grosshans, F. (2003) Pyrimethan
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485 Markham, L.P. (1989d) Technical
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ZOXAMIDE First draft prepared by I.
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489 The excretion of radioactivity
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491 Table 3. Mean concentration of
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493 Table 4. Distribution of metabo
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495 were also found in the urine, a
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497 owing to the absence of a dose-
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499 The NOAEL was 30 000 ppm, equiv
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501 Table 9. Haematological finding
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503 Table 11. Body weight, food con
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505 daily for signs of moribundity,
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507 Table 14 Results of studies of
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509 phase. The study was certified
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511 Table 16. Spleen weights and hi
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513 FOB/motor activity assessment,
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515 Excretion was primarily in the
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517 days 14 to 21. Increased relati
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519 Lowest relevant inhalation NOAE
Page 536 and 537:
521 Morrison, R.D. & Gillette, D.M.
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ANNEX 1 Reports and other documents
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525 31. Pesticide residues in food:
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527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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