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209 of the study were unremarkable. On the basis of these data, difenoconazole was considered to be essentially non-toxic when applied topically under occlusion to intact rabbit skin (Mastrocco et al., 1987a). (c) Inhalation A test for the acute toxicity of difenoconazole technical (batch No. P 012060, purity, 96.2%) was conducted in a group of Tif RAI f (SPF) rats (five of each sex) exposed by inhalation. Exposure was in a head/nose inhalation system for 4 h to a mean analysed atmospheric concentration of 3967/3285 (nominal/gravimetric) mg/m 3 air (technically highest achievable concentration). In order to maintain a constant aerosol concentration with acceptable particle size distribution, it was necessary to blend difenoconazole with 5% Sipernat 50S, an inert silica. The aerosol was generated from the solid test material by means of a brush-feed micronizing jet mill. The aerosol from the dust generator was diluted with filtered humidified air. Owing to the properties of the test material, it was not possible to generate higher concentrations of aerosol. A control group of equal size was exposed to purified air under the same conditions as the test group. The rats were examined for clinical signs of toxicity and mortality during and after exposure and daily thereafter. Individual body weights were recorded immediately before exposure, on day 7 and day 14. The study was terminated 14 days after dosing. Autopsy was performed on all rats. Particular attention was given to the respiratory tract. No rats died during the study. Symptoms observed in rats of both sexes and to a similar extent were dyspnoea during and after exposure and piloerection, hunched posture and reduced locomotion after exposure. Reduced locomotion was not observed after the day of exposure, while hunched posture was also observed on the day after exposure, dyspnoea persisted to include day 4 and piloerection persisted to include day 6. All symptoms disappeared within 7 days. In comparison with rats in the control group, the males showed a lower body-weight gain in the first week and the females showed a higher body-weight gain in the second week after exposure. No treatment-related macroscopic findings were observed. The median lethal concentration (LC 50 ) for difenoconazole suspended in air was > 3300 mg/m 3 (3.3 mg/l) for male and female rats (Hartmann, 1991). (d) Dermal irritation Difenoconazole technical (purity, 91.5%) was evaluated for acute dermal irritation potential in three male and three female Hra:(NZW)SPF rabbits. Difenoconazole (0.5 g) was moistened with 0.9% saline and applied to a 6.25 cm 2 gauze pad that was placed on the shaved dorsal area. The gauze patch was covered with plastic, secured with tape and left for 4 h. Thereafter, patches were removed and the test sites were washed using tap water and paper towels. Adjacent areas of untreated skin of each rabbit served as controls for the test. Signs of skin erythema or oedema were scored after 30 min, 24 h, 48 h, and 72 h after dosing. Dermal irritation was scored and recorded according to the Draize technique One female was found with grade 1 erythema after 30 min. After 24 h, this reaction had cleared. No other skin reactions were noted with any rabbit (Glaza, 1991a). The Meeting concluded that difenocoazole was very slightly and transiently irritating to the skin of rabbits. (e) Ocular irritation Difenoconazole technical (purity, 91.5%) was evaluated for acute eye irritation potential in New Zealand White (Hra:(NZW)SPF) rabbits (initial body weight, 2442–2696 g). Three males and three females in group 1 and two males and one female in group 2 were used. Each rabbit received 0.1 ml of difenoconazole placed into the everted lower lid of the right eye. The upper and lower lids were gently held together for 1 s to prevent loss of material and then released. In group 1 (three males and three females), the eyes of the rabbits were not washed, while in group 2 (two males and one female), the eyes of the rabbits were washed with lukewarm tap water for 60 s starting 30 s after instillation of difenoconazole. The eyes were examined at 1, 24, 48 72 and 96 h after dosing. Eye irritation was scored and recorded according to the Draize technique. DIFENOCONAZOLE 201–272 JMPR 2007
210 Signs of irritation were observed in the cornea, iris and conjunctiva of unwashed eyes (Table 2). All reactions had cleared by day 4 after treatment. Reactions in the washed eye were generally weaker and of shorter duration (Glaza, 1991b). The Meeting concluded that difenoconazole was moderately and transiently irritating to the eyes of rabbits. (f) Sensitization The potential of difenoconazole technical (purity not specified) to produce delayed contact hypersensitivity was evaluated in female Hartley guinea-pigs (initial body weight, 278–385 g) via a modified Buehler method. Ten guinea-pigs were used for each control and treatment group. The positive-control substance was 1-chloro-2,4-dinitrobenzene (DNCB). Difenoconazole was applied undiluted; DNCB was applied as a solution in ethanol/water (20 : 80). On the basis of a preliminary test for irritation it was established that 0.5 g of undiluted difenoconazole and 0.05% DNCB could be applied for topical induction and topical challenge phases of the test. Guinea-pigs in the treatment groups were dosed on test days 1, 3, 6, 8, 10, 13, 15, 17, 20 and 22. Difenoconazole or DNCB were applied to a gauze patch, which was placed on the hair-clipped left flank of the appropriate animals. Patches were secured with occlusive tape and left in place on the guinea-pigs for 6 h on each day. At the end of each exposure period, tape and patch were removed and the test site was wiped with 95% ethanol and water. The guinea-pigs were challenged on test day 36 on the hair-clipped right flank by exposure for 6 h as described for the induction phase. At 24 Table 2. Ocular irritation in rabbits after instillation of difenoconazole Draize score Time after patch removal a 1 h 24 h 48 h 72 h 96 h Mean score (24–72 h) Group 1 (eyes unwashed) Cornea opacity 0/0/0/0/0/0 1/1/1/2/0/0 1/0/0/1/0/0 0/0/0/1/0/0 0/0/0/0/0/0 — Mean score 0 0.83 0.33 0.17 0 0.44 Iris lesions 0/1/0/0/1/1 1/1/1/1/1/0 1/1/0/1/0/0 0/0/0/0/0/0 0/0/0/0/0/0 — Mean score 0.5 0.83 0.5 0 0 0.44 Conjunctivae, redness 2/2/2/2/2/2 2/3/3/3/2/2 2/3/2/3/1/2 2/2/1/2/0/1 0/0/0/0/0/0 — Mean score 2.0 2.5 2.16 1.33 0 2.0 Conjunctivae, chemosis 1/1/1/1/1/1 2/1/1/2/1/1 1/1/1/2/0/1 0/0/0/1/0/0 0/0/0/0/0/0 — Mean score 1.0 1.33 1.0 0.17 0 0.83 Group 2 (eyes washed) Cornea opacity 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 — Mean score 0 0 0 0 0 0 Iris lesions 1/0/1 1/0/0 0/0/0 0/0/0 0/0/0 — Mean score 0.67 0.33 0 0 0 0.11 Conjunctivae, redness 2/2/2 2/2/2 1/2/2 1/1/1 0/0/0 — Mean score 2.0 2.0 1.67 1.0 0 1.56 Conjunctivae, chemosis 1/1/1 1/1/0 1/0/0 0/0/0 0/0/0 — Mean score 1.0 0.67 0.33 0 0 0.33 From Glaza (1991b a Numbers are the individual scores for each rabbit tested. 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
Page 174 and 175: 159 reduced motor activity in males
Page 176 and 177: 161 sensitivity with that of labora
Page 178 and 179: 163 measures to prevent worker expo
Page 180 and 181: 165 when brain cholinesterase activ
Page 182 and 183: 167 Critical end-points for setting
Page 184 and 185: 169 Eiben, R., Schmidt, W., & Loese
Page 186 and 187: 171 Myhr, B.C. (1983) Evaluation of
Page 188 and 189: LAMBDA-CYHALOTHRIN First draft prep
Page 190 and 191: 175 Figure 1. Chemical structures o
Page 192 and 193: 177 In a comparative study, the abs
Page 194 and 195: 179 Figure 2. Main pathways of biot
Page 196 and 197: 181 (iv) Dermal sensitization In a
Page 198 and 199: 183 observed in rats at the highest
Page 200 and 201: 185 Mortality was not affected by t
Page 202 and 203: 187 the group at 100 ppm, reduction
Page 204 and 205: 189 and five females per group were
Page 206 and 207: 191 10-12%) than those of controls
Page 208 and 209: 193 Comments Biochemical aspects Or
Page 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 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 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
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259 Ophthalmoscopic examinations pe
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261 the radioactivity was re-elimin
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263 In a single-dose study of neuro
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265 Estimate of acceptable daily in
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267 Clapp, M.J.L., Killick, M.E., H
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269 Herbold, B. (1983c) THS 2212 tr
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271 Pinto, P. (2006b) Difenoconazol
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DIMETHOMORPH First draft prepared b
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275 Five different treatment groups
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277 To investigate the significance
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279 and the E : Z isomer ratio was
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281 Table 10. Tissue distribution o
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283 (e) Dermal sensitization The de
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285 females at the highest dose, to
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287 The NOAEL was 10 mg/kg bw per d
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289 concentrations in females were
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291 health, moribundity and mortali
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293 0-9%, mean, 3.5%; only one out
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Table 26. Organ weights adjusted to
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297 cell hyperplasia. The testes tu
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299 unscheduled DNA synthesis, the
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301 Figure 3. Cumulative percentage
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303 Rabbits In a dose-range finding
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305 (b) Potentiation of hexobarbito
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307 0.2% or less of the administere
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309 eye-opening, pinna unfolding or
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311 Lowest relevant inhalation NOAE
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313 Gardner, J.R. (1989) CME 151 te
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315 van de Waart, E.J. (1991b) Eval
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318 Committee on Pesticide residues
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320 (a) Ocular irritation Rabbits T
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322 weights were decreased in males
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324 toxicity was 5 mg/kg bw per day
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326 respectively; range for histori
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328 Table 4. Incidence of Leydig-ce
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330 and/or bilateral) was noted in
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332 No treatment-related signs of m
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334 Table 6. Incidence of selected
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336 or teratogenic potential at the
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338 and progesterone. The concentra
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340 the doses used in the 1-year st
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342 No neurotoxic effects were seen
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344 Lowest relevant reproductive NO
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346 Keller, D.A. (1992c) Oncogenici
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PROCYMIDONE First draft prepared by
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351 Rats Groups of five male and fe
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353 Table 1. Pharmacokinetic parame
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355 Seven doses C max (µg equivale
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357 Three groups of five male and f
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359 The excretion of radioactivity
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361 Figure 1. Proposed metabolic pa
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363 water consumption were determin
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365 finding. Histopathology reveale
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367 The NOAEL was 500 ppm, equivale
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369 The NOAEL was 100 mg/kg bw per
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371 at 2000 ppm. Histopathology rev
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373 b Each test was conducted in tr
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375 experimental period. Rats were
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377 hypospadias, testicular atrophy
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379 a single dose, which produced o
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381 The anti-androgenic activities
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383 but only at 6000 ppm after 13 w
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385 The results are summarized in T
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387 males (all litters) in the grou
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389 procymidone (18-27% of the admi
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391 Procymidone induced liver tumou
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393 The Meeting concluded that the
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395 Toxicologically significant com
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397 Harada, T. (1983) A review on m
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399 Murakami, M., Yoshitake, A. & H
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401 Tarui, H. (2005b) In vitro meta
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404 Explanation Profenofos is the I
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406 The metabolism of ring-labelled
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408 2. Toxicological studies 2.1 Ac
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410 Rabbits Groups of two male and
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412 Groups of five male and five fe
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414 control group and in the test g
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416 of the rabbits at the highest d
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418 The NOAEL for brain acetylcholi
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420 Table 2. Histopathological find
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422 1 out of 70; lowest dose, 3 out
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424 body‐weight gains (3-10% decr
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426 treated groups for body-weight
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428 (b) Short-term studies of neuro
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430 represented as equally as possi
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432 pound and the equitoxic mixture
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434 Inhibition of brain acetylcholi
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436 Toxicological evaluation Erythr
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438 Neurotoxicity/delayed neurotoxi
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440 Harris, S.B. (1982) A teratolog
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442 Puri, E. (1982a) Autoradiograph
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PYRIMETHANIL First draft prepared b
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447 Table 1. Excretion profile in r
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449 Table 3. Half-life of pyrimetha
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451 Table 4. Identification of meta
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453 SN 614 277. The presence of the
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455 2. Toxicological studies 2.1 Ac
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457 treated rabbits showed slight e
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459 still evident in the liver; how
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461 In a 90-day feeding study, grou
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463 per day or 800 mg/kg bw per day
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465 The dosing solutions were prepa
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467 mortality and morbidity. Change
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469 2.4 Genotoxicity Pyrimethanil w
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471 mean body‐weight gains. After
Page 488 and 489:
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
Page 498 and 499:
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
Page 508 and 509:
493 Table 4. Distribution of metabo
Page 510 and 511:
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,
Page 530 and 531:
515 Excretion was primarily in the
Page 532 and 533:
517 days 14 to 21. Increased relati
Page 534 and 535:
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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