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229 Table 7. Histopathology findings in the liver in a long-term combined study of toxicity/c arcinogenicity study in rats fed diets containing d ifenoconazole Finding Deaths/ kill Dietary concentration (ppm) Males Females 0 10 20 500 2500 0 10 20 500 2500 N E N E N E N E N E N E N E N E N E N E Hepatocellular hypertrophy Unscheduled 0 30 0 39 0 30 1 27 0 26 0 38 0 35 0 44 3 29 4 32 Interim kill, week 53 0 10 0 10 0 10 0 10 0 10 0 10 0 10 0 10 0 10 0 10 Recovery group, week 57 0 10 — — — — — — 0 10 0 10 — — — — — — 0 10 Terminal kill, week 79–80 7 40 5 31 8 40 28 43 39 44 4 32 0 35 0 26 14 41 32 38 Severity of finding at terminal kill: Minimal 7 4 5 24 7 4 — — 10 18 Slight 0 1 3 3 27 0 — — 4 8 Moderate 0 0 0 1 5 0 — — 0 6 From Cox et al. (1989b) N, No. of rats with finding; E, No. of rats examined. U = unscheduled deaths I = interim kill week 53 R = recovery kill week 57 T = terminal week 79–80 a Only findings seen in more than one rat in any group. DIFENOCONAZOLE 201–272 JMPR 2007
230 (a) Discussion of a possible mode of carcinogenic action of difenoconazole. A. Postulated mode of action. In mice and rats, treatment with difenoconazole caused an increasee in the incidences of hepatocellular adenomas and carcinomas in male and female mice given diets containing difenoconazole at 2500 ppm, equal to 423 and 513 mg/kg bw per day, respectively, for 18 months (Cox et al., 1989a), but not in male or female rats given the same diet, equal to 124 and 170 mg/kg bw per day, respectively, for 24 months (Cox et al., 1989b). Difenoconazole has also been shown to induce various hepatic enzymes of xenobiotic metabolism and it is not genotoxic. These general properties suggest that difenoconazole could have a mode of carcinogenic action (MOA) similar to that of phenobarbital. The generally proposed MOA for phenobarbital is tumour promotion resulting from a long-standing hepatomegaly, hepatocellular hypertrophy and hyperplasia of the liver. Treatment with phenobarbital alone produces hepatocellular adenomas and carcinomas in mice and, when administered after a short treatment with a known liver carcinogen, the incidences of tumours are increased. The potency of CYP induction in mice and rats correlates with the degree of tumour promotion. In addition, phenobarbital has mitogenic effects in liver and has been shown in many studies to inhibit intercellular communication (reviewed in IARC, 2001). Phenobarbital has been studied to a far greater degree than difenoconazole and so it is not expected that there should be complete concordance of the data in order to conclude that the MOAs are most likely the same; however, clear discord should not be demonstrated. B. Key events. Difenoconazole is expected to induce hepatic CYP enzymes. A study on such an effect was performed in male TIF:Magf (SPF) mice given difenoconazole at a dose of 0, 1, 10, 100 or 400 mg/kg bw per day for 14 days. Reversibility was studied in the same experiment in which groups were given difenoconazole at 0 or 400 mg/kg bw per day for 14 days followed by 28 days without treatment. Other groups were given phenobarbital, 3-methylcholanthrene or nafenopin (Thomas, 1992). Difenoconazole increased liver weight, hepatic cytochrome P450 protein and a number of hepatic CYP enzyme and other microsomal (UDP-glucuronosyltranferase, lauric acid 11- and 12-hydroxylase, epoxide hydrolase) enzyme activities, as well as microsomal cytochrome P450-dependent testosterone hydroxylation in a way that was generally very similar to that observed in the same strain of male mouse when phenobarbital was administered. Most effects were observed in only the groups at 100 and 400 mg/kg bw per day, although certain enzyme activities were increased even with difenoconazole at 1 mg/kg bw per day. All effects were dose-dependent and regressed within the 28-day recovery period. Usually, regression was complete. The pattern of enzyme induction by difenoconazole was very similar to that of phenobarbital for 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities in particular. This similarity is important because it is quite different from the induction pattern observed after treatment with either 2-methylcholanthrene or nafenopin. Clearly, other key events must follow, but there was no experimental evidence with d ifenoconazole to support their participation in an MOA. C. Dose–response relationships. All effects on enzyme induction in the 14-day study and the tumour response in the 18-month study were dose-dependent. Liver-weight increases were dose-dependent in a 3-month study in mice. At daily doses of 200 and 2500 ppm, equal to 34 and 440 mg/kg bw in males and 45 and 639 mg/kg bw in females, the absolute liver-weight increases were 9% and 82% in males and 11% and 71% in females. In rats, on the other hand, the responses were less clear. At daily doses of 750, 1500 and 3000 ppm equal to 51, 105 and 214 mg/kg bw in males and 66, 131 and 275 mg/kg bw in females, the absolute liver‐weight increases were 25.7%, 30.9% and 30.2% in males and 24.5%, 26.2% and 40.2% in females. DIFENOCONAZOLE 201–272 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
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145 Table 2. Cholinesterase activit
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147 at the highest dose. In both sp
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149 Table 6. Cholinesterase activit
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151 Table 8. Fertility of F 0 and F
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153 Table 10. Fertility parameters
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155 Groups of 22 mated Sprague-Dawl
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157 after completion of the feeding
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159 reduced motor activity in males
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161 sensitivity with that of labora
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163 measures to prevent worker expo
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165 when brain cholinesterase activ
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167 Critical end-points for setting
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169 Eiben, R., Schmidt, W., & Loese
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171 Myhr, B.C. (1983) Evaluation of
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LAMBDA-CYHALOTHRIN First draft prep
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175 Figure 1. Chemical structures o
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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 210 and 211: 195 Toxicological evaluation Althou
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 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
Page 260 and 261: 245 physically examined for changes
Page 264 and 265: 249 can occur in untreated mice, in
Page 266 and 267: 251 Study of reproductive toxicity
Page 272 and 273: 257 of the test article on microsom
Page 274 and 275: 259 Ophthalmoscopic examinations pe
Page 276 and 277: 261 the radioactivity was re-elimin
Page 278 and 279: 263 In a single-dose study of neuro
Page 280 and 281: 265 Estimate of acceptable daily in
Page 282 and 283: 267 Clapp, M.J.L., Killick, M.E., H
Page 284 and 285: 269 Herbold, B. (1983c) THS 2212 tr
Page 286 and 287: 271 Pinto, P. (2006b) Difenoconazol
Page 288 and 289: DIMETHOMORPH First draft prepared b
Page 290 and 291: 275 Five different treatment groups
Page 292 and 293: 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
Page 516 and 517:
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
Page 532 and 533:
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:
Page 542 and 543:
527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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