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299 unscheduled DNA synthesis, the test for micronucleus formation in the mouse and did not induce cell transformation in the Syrian hamster cell cultures. On the basis of all these results, the Meeting concluded that dimethomorph is neither mutagenic nor genotoxic. 2.5 Reproductive toxicity (a) Multigeneration studies Rats Groups of 30 male and 30 female Sprague-Dawley rats were fed diets containing dimethomorph (purity, 96.6%) at a concentration of 0, 100, 300 and 1000 ppm for approximately 13 weeks before breeding, and continuing through breeding (3 weeks), gestation and lactation for each of two generations to evaluate the potential for reproductive toxicity and effects on neonatal growth and survival. F 1 consisted of 25 male and 25 female rats. An evaluation of mating performance, conception, gestation, parturition, lactation and weaning, as well as survival, growth and development of the offspring was done. In-life observations, body weights, feed consumption and litter data were recorded. In addition, a gross necropsy of the P and F 1 adults was conducted. The study complied with GLP. Table 32. Compound intake and body-weight developments in female parent rats fed diets containing dimethomorph in a study of reproductive toxicity Parameter Period Time-point Dietary concentration (ppm) 0 100 300 1000 Compound intake (mg/kg bw per day) Premating Weeks 1–15 — 8.0 24.0 79.3 Gestation Days 1–20 — 6.8 20.8 71.4 Lactation Days 1–21 — 13.5 40.7 140.2 Body-weight development (g) Premating Body weight at week 15 292.3 291.2 280.8 267.2 Body-weight gain week 1–15 138.0 137.5 128.3 117.7* Gestation Body weight at day 20 390.9 391.6 384.2 377.0 Body-weight gain day 1–20 108.9 114.2 110 116.3 Lactation Body weight at day 21 320.0 316.0 317.4 310.0 F 1 Compound intake (mg/kg bw per day) Premating Weeks 1–15 — 8.9 27.0 89.2 Gestation Days 1–20 — 7.0 21.5 74.1 Lactation Days 1–21 — 14.6 46.2 151.8 Body-weight development (g) Premating Body weight at week 15 292.4 285.2 281.0 277.4 From Osterburg (1990) * p < 0.05. Body-weight gain weeks 1–15 183.4 178.2 174.4 171.0 Gestation Body weight at day 20 400.5 400.2 388.5 393.5 Body-weight gain day 1–20 117.9 118.8 109.3 116.5 Lactation Body weight at day 21 332.4 327.1 326.1 336.0 DIMETHOMORPH 273–315 JMPR 2007
300 Clinical observations, feed consumption and body weight gain were comparable in all groups in parents of both generations with the exception of the premating period for P, where body weight gain was slightly decreased in the group at 1000 ppm (Table 32). Since the body-weight development thereafter was comparable with that of the other groups and fertility was not affected, this effect was judged not to be of toxicological relevance. There were no treatment-related findings on mating performance, fertility and litter data in P and F 1 . In F 1 , F 2a and F 2b pups at 1000 ppm, there were signs of retarded development indicated by a decreased percentage of pups with erupted incisors when compared with the other groups (Table 34 and Figure 3). However, virtually all pups of the group at the highest dose had incisor eruption within postnatal days 8 and 11–12, as had the pups in the other groups. No other markers for postnatal physical development of the pups (eye opening, hair growth and pinna unfolding) were affected and behaviour was not changed. The NOAEL for maternal toxicity and reproductive performance was 1000 ppm, equal to approximately 80 mg/kg bw per day, the highest dose tested. The NOAEL for pup development was 300 ppm, equal to approximately 20 mg/kg bw per day, on the basis of slight delays in incisor eruption in pups at 1000 ppm (Osterburg, 1990). (b) Developmental toxicity Rats In a dose range-finding study, groups of eight mated female Sprague-Dawley rats received dimethomorph (purity, 98.7%) at a dose of 0, 50, 120, or 300 mg/kg bw per day by oral gavage suspension on days 6 to day 15 of gestation. Clinical examinations were done twice per day and body weights were recorded regularly. On day 20, dams were terminated and the fetuses delivered Table 33. Duration of gestation in a study of reproductive toxicity in rats fed diets containing dimethomorph Generation Duration of gestation (days) Dietary concentration (ppm) 0 100 300 1000 F 1a 22.0 ± 0.3 22.1 ± 0.3 21.9 ± 0.4 21.8 ± 0.4* F 2a 21.9 ± 0.4 21.9 ± 0.3 22.1 ± 0.3 21.7 ± 0.5** F 2b 21.9 ± 0.2 22.2 ± 0.5 21.9 ± 0.3 21.8 ± 0.4 From Osterburg (1990) *Statistically different to group at 100 ppm, p < 0.05. **Statistically different to group at 300 ppm, p < 0.05. Table 34. Incisor eruption in a study of reproductive toxicity in rats fed diets containing dimethomorph Generation Group mean percentage of pups with incisor eruption on postnatal day 10 Dietary concentration (ppm) 0 100 300 1000 F 1a 82.6 ± 30.2 70.3 ± 35.9 63.7 ± 35.0 43.1 ± 37.3 F 2a 79.0 ± 24.0 68.4 ± 28.5 76.2 ± 24.8 48.0 ± 35.9 F 2b 78.8 ± 21.6 77.9 ± 27.8 71.1 ± 36.7 40.3 ± 27.0 From Osterburg (1990) DIMETHOMORPH 273–315 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
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191 10-12%) than those of controls
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193 Comments Biochemical aspects Or
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195 Toxicological evaluation Althou
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197 Metabolism in animals Toxicolog
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199 Harrison, M.P. (1984a) Cyhaloth
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DIFENOCONAZOLE First draft prepared
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203 a sex difference nor any marked
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205 demonstrated that the highest t
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207 Figure 3. Proposed metabolic pa
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209 of the study were unremarkable.
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211 Table 3. Results of studies of
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213 The no-observed-adverse-effect
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215 lower than those of rats in the
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217 hepatocellular enlargement. In
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219 i.e. males lost 15.4% and femal
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221 and 357. This reduced food cons
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223 There was very high mortality a
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225 Table 6. Treatment-related hist
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227 Rats Groups of 80 CRL:CD(SD)®
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229 Table 7. Histopathology finding
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231 D. Temporal association. The fe
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233 2.5 Reproductive toxicity (a) M
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235 t estes weights in the males at
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237 continued to be lower than thos
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239 Corpora lutea in each ovary wer
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241 S1 + S2, not ossified — —
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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
Page 264 and 265: 249 can occur in untreated mice, in
Page 266 and 267: 251 Study of reproductive toxicity
Page 268 and 269: 253 Table 19. Results of studies of
Page 270 and 271: 255 Table 21. Results of studies of
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
Page 306 and 307: 291 health, moribundity and mortali
Page 308 and 309: 293 0-9%, mean, 3.5%; only one out
Page 310 and 311: Table 26. Organ weights adjusted to
Page 312 and 313: 297 cell hyperplasia. The testes tu
Page 316 and 317: 301 Figure 3. Cumulative percentage
Page 318 and 319: 303 Rabbits In a dose-range finding
Page 320 and 321: 305 (b) Potentiation of hexobarbito
Page 322 and 323: 307 0.2% or less of the administere
Page 324 and 325: 309 eye-opening, pinna unfolding or
Page 326 and 327: 311 Lowest relevant inhalation NOAE
Page 328 and 329: 313 Gardner, J.R. (1989) CME 151 te
Page 330: 315 van de Waart, E.J. (1991b) Eval
Page 333 and 334: 318 Committee on Pesticide residues
Page 335 and 336: 320 (a) Ocular irritation Rabbits T
Page 337 and 338: 322 weights were decreased in males
Page 339 and 340: 324 toxicity was 5 mg/kg bw per day
Page 341 and 342: 326 respectively; range for histori
Page 343 and 344: 328 Table 4. Incidence of Leydig-ce
Page 345 and 346: 330 and/or bilateral) was noted in
Page 347 and 348: 332 No treatment-related signs of m
Page 349 and 350: 334 Table 6. Incidence of selected
Page 351 and 352: 336 or teratogenic potential at the
Page 353 and 354: 338 and progesterone. The concentra
Page 355 and 356: 340 the doses used in the 1-year st
Page 357 and 358: 342 No neurotoxic effects were seen
Page 359 and 360: 344 Lowest relevant reproductive NO
Page 361 and 362: 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,
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:
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527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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