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241 S1 + S2, not ossified — — — — — — — — 1 1 1 4 — — — — — — — — S1 + S2, incompletely. ossified 3** 2 3 12 — — — — — — — — — — — — — — — — Forelimb Polydactyly 1 1 1 4 — — — — — — — — — — — — — — — — Pelvis/pubes Not ossified — — — — — — — — 2 1 2 8 — — — — 1 1 1 4 Incompletely ossified 8** 4 6 24 4 2 3 12 4 2 2 8 1 1 1 4 1 1 1 4 Pelvis/ischia Incompletely ossified 6** 3 4 16 — — — — — — — — — — — — — — — — From Lochry (1987) ** p ≤ 0.01, binomial test. DIFENOCONAZOLE 201–272 JMPR 2007
242 Analyses of the sites of fetal ossification revealed a significant increase in the average number of ribs in the fetuses from the dams at 200 mg/kg bw, with a related significant increase in the number of thoracic vertebrae and decrease in the average number of lumbar vertebrae. Increases in the average number of ossified hyoid and caudal vertebrae and decreases in the average number of sternal centres and hind-paw phalanges also occurred for fetuses at 200 mg/kg bw. All other incidences were within the expected range for fetuses of this strain and age and were not significantly different among the groups. The differences in skeletal observations that were recorded as statistically significant are summarized in Table 14. As may be seen, the changes were extremely small and unlikely to have produced any deleterious effects. TheNOAEL for maternal toxicity was 20 mg/kg bw per day on the basis of reduced body-weight gain at 100 mg/kg bw per day. The NOAEL for fetal toxicity was 100 mg/kg bw per day on the basis of a low incidence of minor deviations in skeletal ossification found at 200 mg/kg bw per day. There were no indications of embryotoxicity or teratogenicity at any dose up to 200 mg/kg bw (Lochry, 1987). Rabbit In a study of developmental toxicity, groups of 20 artificially inseminated New Zealand White rabbits were given difenoconazole technical (purity, 95.7%) at a dose of 0, 1, 25 or 75 mg/kg bw per day in an aqueous vehicle (3% aqueous corn starch containing 1.0% Tween 80) administered by stomach tube on days 7–19 after insemination. A standard dose volume of 5 ml/kg bw was used. The control group was dosed with the vehicle only. Food consumption and body weights were recorded regularly throughout the study period. The state of health of the rabbits was checked each day. Eye examinations were performed before dosing and at the end of the dosing period on all rabbits. On day 29 after insemination, all surviving females were killed and assessed by gross pathology (including weights of the unopened uterus and the placentae). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for any external, soft tissue and skeletal findings. The stability of the test substance was proven by reanalysis. The stability and homogeneity of the test substance preparation was analytically verified over at least a 21-day period. The correctness of the concentrations was analytically demonstrated to be 96%, 96% and 97% of the target concentrations of 1, 25 and 75 mg/kg bw. Premature mortality occurred in three study groups: one control doe and one doe at 1 mg/kg bw per day were found dead on days 15 and 16, respectively, apparently due to dosing accidents and one doe at 75 mg/kg bw per day was found dead on day 18, after a period of apparently treatmentrelated anorexia. Clinical observations possibly related to treatment included stool variations in 7 out of 19 and 12 out of 19 of the groups of does at 25 and 75 mg/kg bw per day, respectively, compared with two or three in the groups at 0 and 1 mg/kg bw per day, although this was thought to be secondary to variations in food consumption. There were two abortions in the group at 75 mg/kg bw per day, which were attributed to treatment. Other signs, including alopecia, anogenital stains and blood in pan were considered incidental. All does at 75 mg/kg bw per day lost body weight during the first few days of treatment and body-weight gains of the does at 75 mg/kg bw per day were significantly lower than rabbits in the control group for most of the dosing period. This effect of treatment was consistent with reduced food consumption and indicative of toxicity. Body-weight gains of the does at 25 mg/kg bw per day were also somewhat lower than those of the controls, but not significantly so. Body-weight gains of the does at 1 mg/kg bw per day were not affected by treatment. Body-weight changes over the full duration of the study (and including uterus and its contents) were 0.61, 0.54, 0.48 and 0.40 kg in the groups at 0, 1, 25 and 75 mg/kg bw per day, respectively. Relative to the control group, food consumption was significantly reduced in the group at 75 mg/kg bw per day during the treatment period (days 7–19), with mean values being about 50% lower than those for the controls during the first week of dosing. Food consumption increased in all groups during the second week of dosing, most prominently among the rabbits at 75 mg/kg bw per day. Food consumption by the does 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
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179 Figure 2. Main pathways of biot
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181 (iv) Dermal sensitization In a
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183 observed in rats at the highest
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185 Mortality was not affected by t
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187 the group at 100 ppm, reduction
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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 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 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
Page 294 and 295: 279 and the E : Z isomer ratio was
Page 296 and 297: 281 Table 10. Tissue distribution o
Page 298 and 299: 283 (e) Dermal sensitization The de
Page 300 and 301: 285 females at the highest dose, to
Page 302 and 303: 287 The NOAEL was 10 mg/kg bw per d
Page 304 and 305: 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
Page 506 and 507:
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,
Page 522 and 523:
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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