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405 Similar results were obtained in a more recent study in which three groups of five male and five female Crl:CD®BR rats were given [ 14 C]profenofos (purity, 97.1–98.1%) orally by gavage as a single dose at 1 mg/kg bw or 100 mg/kg bw and another group was pre-treated with 14 consecutive daily oral doses of non-radiolabelled compound at 1 mg/kg bw followed by a single radiolabelled dose at 1 mg/kg bw on day 15. Treated rats were killed 7 days after administration of the r adiolabelled dose. No significant sex-related differences were observed in the elimination and/or distribution of radioactivity. Total radioactivity eliminated via the urine and faeces exceeded 99% of the administered dose for all groups. Most of the administered radioactivity (> 97%) was eliminated via the urine. Elimination was rapid with an average of 95% and 93% of the total radioactivity being excreted in the urine within the first 24 h for the groups at the lower dose and repeated dose, respectively. For the group at the higher dose, 97% of the dose was eliminated in the urine within 48 h. Less than 4% of the radioactivity was excreted in the faeces for all groups. Less than 0.2% of the administered dose was detected in the volatile and CO 2 traps combined. Less than 0.1% of the administered dose was recovered in tissues. At the lower dose, the residues in tissues were less than 0.002 μg equivalent/g, with the exception of the liver, which contained up to 0.02 μg equivalent/g. At the higher dose, residues ranged from not detectable in most tissues to 0.18 μg equivalent/g in the liver (Kennedy & Swain, 1992). Male and female Harlan SD albino rats received single dermal applications of ring-labelled [ 14 C]profenofos at a dose of 0.5 mg/kg bw (specific activity, 9.34 µCi/mg (345.58 kBq/mg) and 10 mg/kg bw (specific activity, 2.6 µCi/mg (96.2 kBq/mg) in a 72-h balance study. Over the 72-h absorption period, the total recoveries of radiolabelled carbon averaged 92–95% of each applied dose in each sex (urine, 80–86%; faeces,, 2.2–3.9%; tissues, 0.09–1.8%; blood, 0.06% or less; treated skin, 3% or less; and cage-washings, 5% or less). Excretion in expired carbon dioxide (CO 2 ) was negligible (less than 0.02%, as determined from a preliminary study using the highest dermal dose). The dermal absorption was approximately 85% of the applied dose in 72 h, which indicated that [ 14 C]profenofos was absorbed at nearly the same rate for males and females regardless of the dose; t1/2 absorption values were 17.9 h and 15.0 h after treatment with the lower dose in males and females, respectively, and 16.7 h and 14.1 h after treatment with the higher dose in males and females, respectively. The calculated 50% excretion rates (urine was the major route of excretion) occurred 18.1 h and 17.4 h after treatment with the lower dose in males and females, respectively, and 23.2 h and 18.7 h after treatment with the higher dose in males and females, respectively. Fifty percent of [ 14 C]profenofos was excreted shortly after 50% had been absorbed, indicating that profenofos and its metabolites were rapidly excreted, i.e. there was no lag-time between absorption and excretion. Levels of radioactivity in selected tissues, organs (liver, kidney) and blood reached a maximum after 2 h, had reached a plateau by 8 h, and declined rapidly by 72 h after application. The total recovery after 72 h averaged 92–95% of the applied dose in males and females, 80–86% in urine and 2–4% in faeces (Williams et al., 1984). 1.2 Biotransformation Urine collected in the 0–24 h after giving RAI rats a single oral dose of profenofos at approximately 4.8 mg/kg bw was analysed by thin-layer chromatography (TLC). Four metabolites were detected and no unchanged profenofos was present, indicating complete degradation of profenofos. The only metabolite identified by TLC was the phosphorous ester cleavage product, 4-bromo-2- chlorophenol. This metabolite did not appear in freshly-obtained urine, indicating that other labile metabolites are cleaved to this phenol (Ifflaender & Mücke, 1974). PROFENOFOS 403–443 JMPR 2007
406 The metabolism of ring-labelled [ 14 C]profenofos (specific activity, 26.2 µCi/mg (969 kBq/mg) was investigated using the urine and faeces collected over a 2-day period after giving eleven male RAI rats a single oral dose at 28.5 mg/kg bw; 90.4% and 3.6% of the administered dose was excreted in urine and faeces within 24 h. The major metabolites detected were CGA 65867 (7%), CGA 47196 (23%), CGA 55163 (26%) and metabolite C (34%). CGA 47197 was present as a minor metabolite (< 0.5%). Neither unchanged profenofos nor its corresponding phenol CGA 55960 was detected in freshly-obtained urine. The faeces contained small amounts of parent profenofos (2%), and CGA 55960 (1%). Additional metabolites were present in minute amounts (0.2% or less) but were not identified (Ifflaender & Mücke, 1976). A small amount (approximately 7%) of CGA 55960 was found in the urine of male rats (Tif:RAI-f strain) dosed orally with single doses of ring-labelled [ 14 C]profenofos at 0.19 or 1.80 mg/ kg bw. The main urinary metabolites identified in this study were similar to those reported previously by Mücke and colleagues (Mücke, 1986). The pattern of metabolites was investigated in urine and faeces of groups of five male and five female Crl:CD®BR rats given [ 14 C]profenofos as a single dose at 1 or 100 mg/kg bw, or [ 14 C] profenofos as a single dose at 1 mg/kg bw after 14 consecutive daily oral doses of non-radiolabelled profenofos at 1 mg/kg bw. The metabolites identified in the urine were metabolite C – the sulfated phenol (37–48%), CGA 55163 (22–27%), CGA 47196 (14–25%), CGA 65867 (5–16%), and CGA 55960 (0.1–1.7%). Major faecal components consisted of small amounts of profenofos (< 0.1–1.3%) and CGA 55960 (0.7–1.9%) for all groups. The minor amounts of faecal radioactivity (combined, 0.2–1.3%) contained partially or all of the urinary metabolites (Kennedy & Swain, 1992). An overview of the proposed metabolic pathways of profenofos in rats is given in Figure 2. Figure 2. Proposed metabolic pathways of profenofos in the rat Cl O OC 2 H 5 Br O P SC 3 H 7 CGA 15'324 Cl O OC 2 H 5 Br O P SH CGA 65'867 Cl O OH Br O P SC 3 H 7 CGA 47'197 1 Cl O OC 2 H 5 Br O P OH CGA 47'196 Cl Br OH Cl CGA 55'960 Cl CO 2 H Br Metabolite C OSO 3 H Br O HO O OH OH OH CGA 55'163 PROFENOFOS 403–443 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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249 can occur in untreated mice, in
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251 Study of reproductive toxicity
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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
Page 370 and 371: 355 Seven doses C max (µg equivale
Page 372 and 373: 357 Three groups of five male and f
Page 374 and 375: 359 The excretion of radioactivity
Page 376 and 377: 361 Figure 1. Proposed metabolic pa
Page 378 and 379: 363 water consumption were determin
Page 380 and 381: 365 finding. Histopathology reveale
Page 382 and 383: 367 The NOAEL was 500 ppm, equivale
Page 384 and 385: 369 The NOAEL was 100 mg/kg bw per
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Page 388 and 389: 373 b Each test was conducted in tr
Page 390 and 391: 375 experimental period. Rats were
Page 392 and 393: 377 hypospadias, testicular atrophy
Page 394 and 395: 379 a single dose, which produced o
Page 396 and 397: 381 The anti-androgenic activities
Page 398 and 399: 383 but only at 6000 ppm after 13 w
Page 400 and 401: 385 The results are summarized in T
Page 402 and 403: 387 males (all litters) in the grou
Page 404 and 405: 389 procymidone (18-27% of the admi
Page 406 and 407: 391 Procymidone induced liver tumou
Page 408 and 409: 393 The Meeting concluded that the
Page 410 and 411: 395 Toxicologically significant com
Page 412 and 413: 397 Harada, T. (1983) A review on m
Page 414 and 415: 399 Murakami, M., Yoshitake, A. & H
Page 416: 401 Tarui, H. (2005b) In vitro meta
Page 419: 404 Explanation Profenofos is the I
Page 423 and 424: 408 2. Toxicological studies 2.1 Ac
Page 425 and 426: 410 Rabbits Groups of two male and
Page 427 and 428: 412 Groups of five male and five fe
Page 429 and 430: 414 control group and in the test g
Page 431 and 432: 416 of the rabbits at the highest d
Page 433 and 434: 418 The NOAEL for brain acetylcholi
Page 435 and 436: 420 Table 2. Histopathological find
Page 437 and 438: 422 1 out of 70; lowest dose, 3 out
Page 439 and 440: 424 body‐weight gains (3-10% decr
Page 441 and 442: 426 treated groups for body-weight
Page 443 and 444: 428 (b) Short-term studies of neuro
Page 445 and 446: 430 represented as equally as possi
Page 447 and 448: 432 pound and the equitoxic mixture
Page 449 and 450: 434 Inhibition of brain acetylcholi
Page 451 and 452: 436 Toxicological evaluation Erythr
Page 453 and 454: 438 Neurotoxicity/delayed neurotoxi
Page 455 and 456: 440 Harris, S.B. (1982) A teratolog
Page 457 and 458: 442 Puri, E. (1982a) Autoradiograph
Page 460 and 461: PYRIMETHANIL First draft prepared b
Page 462 and 463: 447 Table 1. Excretion profile in r
Page 464 and 465: 449 Table 3. Half-life of pyrimetha
Page 466 and 467: 451 Table 4. Identification of meta
Page 468 and 469: 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,
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507 Table 14 Results of studies of
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509 phase. The study was certified
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511 Table 16. Spleen weights and hi
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513 FOB/motor activity assessment,
Page 530 and 531:
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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