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351 Rats Groups of five male and female Wistar rats were given single oral doses of [phenyl- 3 H]procymidone (radiochemical purity, > 99%; specific activity, 15.8 mCi/mmol (584.6 MBq/mmol) or [carbonyl- 14 C]procymidone (radiochemical purity, > 99%; specific activity, 4.67 mCi/mmol (172.79 MBq/mmol) at 25 mg/kg bw, formulated in 10% Tween 80. A similar group received seven doses of [carbonyl- 14 C]procymidone at 25 mg/kg bw per day. Samples of urine, faeces and carbon dioxide were taken for 7 days after the last dose. A limited number of tissue samples were taken from rats killed at 3, 6, 12, 24, 48 and 168 h after dosing and analysed for 14 C. Radioactivity was rapidly absorbed and eliminated. Almost identical patterns of excretion were found in both sexes and with both labelled forms, primarily in the urine (85–90%). Peak mean concentrations of radioactivity in tissues were reached at 6–12 h after dosing, the highest concentrations being in the kidneys (28 μg equivalent/g) and liver (19 μg equivalent/g) followed by muscle, stomach, lungs, and heart (15, 15, 12 and 12 μg equivalent/g respectively). Fat samples were not taken before 48 h. The tissue concentrations of radioactivity declined rapidly and except for fat (0.3 μg equivalent/g) were < 0.1 μg equivalent/g at 168 h after the last dose. Repeated dosing did not alter the pattern of excretion, but tissue residues were 3–10-fold those seen with a single dose at 168 h after the last dose. This study did not claim to be compliant with GLP (Mikami & Yamamoto, 1976). Excretion and tissue distribution were investigated in groups of five male Sprague-Dawley rats given a single oral dose of [phenyl- 14 C]procymidone (radiochemical purity, > 99%; specific activity, 22.8 mCi/mmol (843.6 MBq/mmol) at a dose of 100 mg/kg bw in corn oil. Urine and faeces were collected from five rats for 7 days after dosing. Tissues were removed from other groups at intervals up to 72 h after dosing. Radioactivity was rapidly and almost completely eliminated in the urine. Fifty-nine per cent of the dose was eliminated on the first day and 96% overall (urine, 84%; and faeces, 13%). The highest concentration of radioactivity was found in fat at 8 h (555 μg equivalent/g), declining to 5 μg equivalent/g at 72 h after dosing. Radioactivity in adrenals, blood, brain, kidneys, liver, prostate, epididymis and testes reached a maximum 8–12 h after dosing (77, 15, 26, 49, 67, 65, 28 and 11 μg equivalent/g, respectively) and subsequently decreased with an overall half-life of 7–12 h. This study did not claim to be compliant with GLP (Kimura et al., 1988). Three groups of five male and five female Crl:CD®(SD)BR rats were given a single oral dose of [phenyl- 14 C]procymidone (radiochemical purity, > 98%; specific activity, 242 μCi/mg (8.95 MBq/mg) at a dose of 1 or 250 mg/kg bw in corn oil. An additional group of rats received 14 consecutive daily doses of unlabelled procymidone at 1 mg/kg bw before being given a single dose of [phenyl- 14 C]procymidone at 1 mg/kg bw. Urine and faeces were collected for 7 days after dosing; the rats were then killed and tissues removed for analysis. After oral administration of procymidone at a dose of 1 mg/kg bw, absorption was rapid and extensive, with approximately 80% of the administered dose being excreted in the urine in 24 h (Table 4). At the higher oral dose of 250 mg/kg bw, the proportion of radioactivity in the urine declined to 63–67% of the administered dose, with a concomitant increase in faecal radioactivity to 24–33% (Table 4). Radioactivity exhaled in the expired air accounted for < 0.03% of the administered dose. There was an indication of more rapid urinary excretion, but no substantial differences in the pattern of excretion for single or multiple lower doses. At either dose, radioactivity retained in the carcass and in the tissues 168 h after dosing accounted for < 0.3% of the dose and ≤ 0.01% of the administered dose respectively, demonstrating almost complete excretion. At 168 h, concentrations of radioactivity in all tissues of rats at 1 mg/kg bw were close to or less than 0.001 μg equivalent/g, except for fat (0.002–0.006 μg equivalent/g) and kidneys (0.001–0.002 μg equivalent/g). Fat also contained the highest concentration of radioactivity (5.0 μg equivalent/g) in rats at 250 mg/kg bw. This study claimed compliance with GLP and US EPA guidelines for studies of metabolism with pesticides (Struble, 1992a). PROCYMIDONE 349–401 JMPR 2007
352 Comparative kinetics between species To further investigate the species differences in findings in studies of developmental and reproductive toxicity, the kinetics and metabolism of procymidone were investigated in female rats, rabbits and monkeys, after single and repeated doses given to non-pregnant animals and to pregnant animals. Single doses Groups of four female Sprague-Dawley Crj:CD(SD)IGS rats were given a single oral dose of [phenyl- 14 C]procymidone (specific activity, 13.7 MBq/mg; purity, > 97.8%) at 37.5, 62.5, 125, 250 or 500 mg/kg bw. Groups of three, female New Zealand White rabbits and female cynomolgus monkeys were given [phenyl- 14 C]procymidone at a dose of 62.5, 125, 250 or 500 mg/kg bw. Corn oil was the vehicle in the studies in rats, while in studesi in rabbits and monkeys the vehicle was 0.5% methylcellulose. It is uncertain what effect the use of different vehicles would have had on the results. Each dose was given to two groups, blood was collected from one group at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 h after dosing and excreta were collected from the other group at 6 (urine only), 24, 48, 72 and 120 h after dosing. The concentration of radioactivity was determined in excreta and plasma. Urine, faeces and plasma were analysed by thin-layer chromatography (TLC) either directly or after solvent extraction and metabolites were identified by co-chromatography with reference compounds. The results (Table 1) showed marked species differences. Absorption in the rabbit was much more rapid than in rats and monkeys. Monkeys had much lower maximum concentration (C ) values were much lower in monkeys than in rabbits and rats, but area under the curve of concentration– max time (AUC) values were relatively low in rabbits given doses of up to 125 mg/kg bw owing to rapid elimination. In monkeys, the predominant compound in plasma was procymidone; in rabbits, acid metabolites and glucuronides of alcohol metabolites were the major components in plasma; in rats, free alcohol metabolites predominated. These results led to a hypothesis that the species differences in developmental effects observed were due to the high concentrations of free alcohol metabolites in rats, which lead to hypospadias (Sugimoto, 2005a, 2005b; Mogi, 2005a). Repeated dosing Groups of four female Sprague-Dawley Crj:CD(SD)IGS rats or groups of three female cynomolgus monkeys received 14 daily doses of [phenyl- 14 C]procymidone (specific activity, 13.7 MBq/mg; purity, > 98.1%) at 37.5 (rats only), 62.5, 125, 250 or 500 (monkeys only) mg/kg bw per day. Corn oil was the vehicle in the studies in rats, for monkeys the vehicle was 0.5% methylcellulose. Blood was collected 2, 4, 8 and 24 h after the 1st, 3rd, 7th, 10th and 14th dose and additionally 48 and 72 h after the 14th dose. Urine and faeces were collected over a 24-h period after the 1st and 14th dose, at 2-day intervals at other times during the dosing period and at 24–72 h and 72–120 h after the final dose. Plasma, urine and faeces were analysed for radioactivity and for metabolites. The results are summarized in Table 2. These results suggest that a steady state was reached after administration of repeated doses for approximately 3 days in rats, but only after 14 days or longer in monkeys. Although C max and AUC were significantly higher in rats after a single dose, after 14 doses values were similar for rats and monkeys. These findings show that the doses used in the studies of developmental toxicity in cynomolgus monkeys would have produced plasma concentrations of total radioactivity that were similar to those produced in rats at doses resulting in hypospadias, but with different metabolite profiles. In monkeys, most of the radiolabel was unextractable and was not identified. On the data available, the metabolite patterns were similar to those seen with single doses, with unchanged procymidone beng the major component in plasma in monkeys, and alcohol metabolites predominating in rats (Sugimoto, 2005c; Mogi, 2005b). PROCYMIDONE 349–401 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
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
Page 364 and 365: PROCYMIDONE First draft prepared by
Page 368 and 369: 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
Page 386 and 387: 371 at 2000 ppm. Histopathology rev
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
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401 Tarui, H. (2005b) In vitro meta
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404 Explanation Profenofos is the I
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406 The metabolism of ring-labelled
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408 2. Toxicological studies 2.1 Ac
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410 Rabbits Groups of two male and
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412 Groups of five male and five fe
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414 control group and in the test g
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416 of the rabbits at the highest d
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418 The NOAEL for brain acetylcholi
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420 Table 2. Histopathological find
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422 1 out of 70; lowest dose, 3 out
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424 body‐weight gains (3-10% decr
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426 treated groups for body-weight
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428 (b) Short-term studies of neuro
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430 represented as equally as possi
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432 pound and the equitoxic mixture
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434 Inhibition of brain acetylcholi
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436 Toxicological evaluation Erythr
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438 Neurotoxicity/delayed neurotoxi
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440 Harris, S.B. (1982) A teratolog
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442 Puri, E. (1982a) Autoradiograph
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PYRIMETHANIL First draft prepared b
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447 Table 1. Excretion profile in r
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449 Table 3. Half-life of pyrimetha
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451 Table 4. Identification of meta
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453 SN 614 277. The presence of the
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455 2. Toxicological studies 2.1 Ac
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457 treated rabbits showed slight e
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459 still evident in the liver; how
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461 In a 90-day feeding study, grou
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463 per day or 800 mg/kg bw per day
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465 The dosing solutions were prepa
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467 mortality and morbidity. Change
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469 2.4 Genotoxicity Pyrimethanil w
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471 mean body‐weight gains. After
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473 Analysis of dosing solutions in
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475 In a 7-day feeding study, group
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477 at 200 mg/kg bw. These clinical
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479 s ystemic toxicity was 400 ppm
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481 Acute toxicity Rat, LD 50 , ora
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483 Grosshans, F. (2003) Pyrimethan
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485 Markham, L.P. (1989d) Technical
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ZOXAMIDE First draft prepared by I.
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489 The excretion of radioactivity
Page 506 and 507:
491 Table 3. Mean concentration of
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493 Table 4. Distribution of metabo
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495 were also found in the urine, a
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497 owing to the absence of a dose-
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499 The NOAEL was 30 000 ppm, equiv
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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,
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515 Excretion was primarily in the
Page 532 and 533:
517 days 14 to 21. Increased relati
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519 Lowest relevant inhalation NOAE
Page 536 and 537:
521 Morrison, R.D. & Gillette, D.M.
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ANNEX 1 Reports and other documents
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525 31. Pesticide residues in food:
Page 542 and 543:
527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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