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249 can occur in untreated mice, including apoptotic-like bodies, degeneration, depletion and asynchrony of spermatids, and tubular atrophy. Secondary to these testes effects, exfoliated germ cells and debris were found in the epididymides at increased incidences only at the highest doses of 2000 ppm (28- day study) or 6000 ppm (13-week study). The NOAEL for testes effects in mice after 13 weeks of treatment was 1000 ppm, equivalent to 161 mg/kg bw per day. No data were available to directly evaluate the potential for carcinogenicity of 1,2,4-triazole. Available data on mutagenicity data were limited (Salmonella assays and a report of a study of chromosomal aberration in rat bone-marrow cells), but they do not indicate any activity. A large number of parent triazole-derivative pesticides had been classified as carcinogens (most also are non-mutagenic), but the relevance of that finding to expected effects of free triazole may be limited. The types of tumours associated with exposure to the parent chemicals were most commonly hepatocellular adenomas/carcinomas in mice. None of the tumour types were clearly associated with the proportion of free triazole formed in the available studies of metabolism in rats and 1,2,4-triazole showed little or no effects in the livers of rats and mice in short-term studies. In a two-generation study of reproductive toxicity in rats, retardation of body-weight gain was the most sensitive end-point in parent animals. At 250 ppm (equivalent to 16 mg/kg bw per day), body weights of the F1 males were slightly but significantly lower than those of rats in the concurrent control group. In some respects this is in contrast to the results of the two short-term studies of toxicity in rats, where 500 ppm was a clear NOAEL with regard to body-weight reduction in males. In females, body weights were lower only at 3000 ppm. Absolute brain weights were decreased in males and females of the parental generation receiving 3000 ppm. At this dose also, microscopic lesions such as mild to moderate degeneration and necrosis were evident in the cerebellum. The lesions were identical to that observed in the short-term study of combined toxicity and neurotoxicity in rats and are characterized by variable loss of Purkinje cells, white matter degeneration and gliosis. The white matter tract degeneration presented as nerve fibre (axonal) swelling or fragmentation often with digestion chambers containing debris and macrophages. No similar changes were noted in the rats at 500 ppm. In the two-generation study of reproduction, at a feed concentration of 500 ppm, all parameters of reproduction were similar to those of rats in the control group through two generations. Fertility was significantly decreased only at the highest feed concentration of 3000 ppm (equivalent to 218 mg/kg bw per day in females). Two out of 30 females delivered viable offspring (one pup each); there were only three implantation sites compared with 265 in the control group. No effects were observed on the length or the number of the estrous cycles. No treatment-related effects on sperm parameters were observed at any dose, including the males at 3000 ppm. In parental females at 3000 ppm, the number of total corpora lutea and the ovary weights were increased, and a dilatation of uterine horns was found in some rats. Two studies of developmental toxicity in rats (Renhof, 1988a, 1988b) demonstrated maternal toxicity (retarded weight gain) at 100 mg/kg bw or higher, developmental toxicity (increased incidence of runts, lower fetal and placental weights, and a higher incidence of minor skeletal deviations) at 100 mg/kg bw or higher, and an increased incidence of malformations at 200 mg/kg bw. The maternal and the developmental NOAEL in rats was 30 mg/kg bw per day. In the study in rabbits (Hoberman, 2004), lower body-weight gain and clinical signs of systemic toxicity such as excess salivation, hyperpnoea and ptosis were evident at 45 mg/kg bw per day. Five out of 25 dams were sacrificed in a moribund condition at this dose. Developmental effects included lower weights of fetuses at 45 mg/kg bw per day, and there were a few alterations of the urogenital system which occurred in several fetuses at the maternally toxic dose of 45 mg/kg bw per day. Similar to rats, the maternal and the developmental NOAEL was 30 mg/kg bw per day in rabbits. DIFENOCONAZOLE 201–272 JMPR 2007
250 Table 18. Studies of toxicity after repeated doses, reproductive toxicity and genotoxicity with 1,2,4-triazole Study Species or test object Dietary concentration (ppm) Test c oncentration NOAEL (mg/kg per day) Result Adverse effects Reference Short-term studies of toxicity Ninety-day, feeding Ninety-day, feeding, n eurotoxicity Twenty-eightday, feeding, Ninety-day, feeding Genotoxicity Rat 0, 100, 500, 2500 Rat 0, 250, 500, 3000, 1000/4000 Mouse 0, 50, 250, 500, 2000 Mouse 0, 500, 1000, 3000, 6000 Gene mutation S. typhimurium TA98, TA100, TA1535 and TA1537 Gene m utation S. typhimurium TA98, TA100, TA1535 and TA1537 — 10–5000 µg/ plate — 100–7500 µg/plate — 37.9 in males 54.2 in females — 33 in males 41 in females — 90 in males 479 in females — 161 in males 663 in females — Retarded body-weight development (males and females), temporary slight CNS effects, lower erythrocyte parameters (males only), h epatocellular fat accumulation (males only) — Clinical symptoms, body-weight decrease; triglycerides decrease (males), corpora-lutea increase, absolute brain-weight decrease, degenerative effects in brain and peripheral nerves — Testes: increased incidence and severity of background lesions (spermatid degeneration, depletion and asynchrony, tubular atrophy); epididymis: exfoliated germ cells and debris — Males: body-weight decrease, absolute brainweight increase; testes: apoptotic-like bodies increase, spermatid degeneration, depletion and asynchrony, tubular atrophy. Females: clinical symptoms, body-weight decrease; absolute brain-weight decrease; brain/cerebellum: loss of Purkinje cells — Non-mutagenic with and without metabolic activation in all test systems — Non-mutagenic with and without metabolic activation in all test systems Bomhard et al. (1979) Wahle & Sheets (2004) Wahle (2004a) Wahle (2004b) — Poth (1989) — Melly & Lohse (1982) 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
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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
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
Page 260 and 261: 245 physically examined for changes
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
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
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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,
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
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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:
Page 542 and 543:
527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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