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517 days 14 to 21. Increased relative liver weight was noted at doses of 5000 ppm and greater in males and females, and in absolute liver weight only in males at 20 000 ppm. The changes in liver weight were not associated with any histopathological or clinical chemistry change and were not considered to be adverse. There was no evidence of toxicity in the studies of prenatal developmental toxicity in rats or rabbits. The NOAEL in both studies was 1000 mg/kg bw per day on the basis of absence of toxicity to dams or fetuses at the highest dose tested. Zoxamide was not teratogenic in rats or rabbits. Zoxamide was not neurotoxic in a study of acute neurotoxicity at doses of up to 2000 mg/kg bw. No adverse effects were seen during neurological and behavioural examinations performed during routine repeat-dose studies with zoxamide. Studies on two plant metabolites of zoxamide—RH-141,452 (3,5-dichloro-4-hydroxymethyl benzoic acid) RH-141,455 (3,5-dichloro-1,4-benzene-dicarboxylic acid)—formed to a limited extent in rats, showed them to be rapidly absorbed and rapidly excreted, essentially unchanged; to have low acute oral toxicities to mice (LD 50 s, > 5000 mg/kg bw), and to give negative results in assays for gene mutation with strains of Salmonella typhimurium. There were two reports of mild adverse effects after exposure to a diluted formulation containing zoxamide and mancozeb. In one case there was a report of skin irritation, in the other “flu-like” symptoms were reported. The Meeting considered it to be unlikely that these effects were related directly to exposure to zoxamide. Toxicological evaluation An acceptable daily intake (ADI) of 0–0.5 mg/kg bw was established for zoxamide based on the NOAEL of 48 mg/kg bw per day in the 1-year study in dogs, on the basis of reduced body-weight gain in females at 255 mg/kg bw per day. An acute reference dose (ARfD) was considered to be unnecessary for zoxamide as zoxamide is of low acute toxicity, did not produce developmental effects and did not produce any other significant effects after acute exposures. Levels relevant to risk assessment Species Study Effect NOAEL LOAEL Mouse Rat Two-year studies of toxicity Toxicity 7000 ppm, equal to — and carcinogenicity a 1021 mg/kg bw per day c Carcinogenicity 7000 ppm, equal to 1021 mg/kg bw per day c — Two-year studies of toxicity Toxicity 20 000 ppm, equal to — and carcinogenicity a 1058 mg/kg bw per day c Carcinogenicity 20 000 ppm, equal to — 1058 mg/kg bw per day c Multigeneration study of Reproductive toxicity 30 000 ppm, equal to — reproductive toxicity a 1474 mg/kg bw per day c Parental toxicity 30 000 ppm, equal to — 1474 mg/kg bw per day c Offspring toxicity 30 000 ppm, equal to — 1474 mg/kg bw per day c Developmental toxicity b Maternal toxicity 1000 mg/kg bw per day c — Embryo/fetotoxicity 1000 mg/kg bw per day c — ZOXAMIDE 487–522 JMPR 2007
518 Acute neurotoxicity b 2000 mg/kg bw per day c — Rabbit Developmental toxicity a Maternal toxicity 1000 mg/kg bw per day c — Embryo/fetotoxicity 1000 mg/kg bw per day c — Dog One-year study of toxicity a Reduced body-weight gain 1500 ppm, equal to 48 mg/kg bw per day a Dietary administration. b Gavage administration. c Highest dose tested. 7500 ppm, equal to 255 mg/kg bw per day Estimate of acceptable daily intake for humans 0–0.5 mg/kg bw Estimate of acute reference dose Unnecessary Studies that would be useful for the continued evaluation of the compound Results from epidemiological, occupational health and other such observational studies of human exposure Critical end-points for setting guidance values for exposure to zoxamide Absorption, distribution, excretion and metabolism in mammals Rate and extent of oral absorption Moderate (C max , 8 h); approximately 60% absorbed at 10 mg/kg bw Dermal absorption Approximately 1% from concentrate; 6% from dilution Distribution Extensive. Highest levels in liver. Potential for accumulation Low Rate and extent of excretion > 85% in 48 h. Urine (approximately 10–20%); bile (approximately 45%); faeces (approximately 50–80%). Metabolism in animals Extensive. Primarily via hydrolysis, dehalogenation, oxidation and conjugation. Toxicologically significant compounds in animals, Zoxamide. plants and the environment Acute toxicity Rat, LD 50 , oral Rat, LD 50 , dermal Rat, LC 50 , inhalation Rabbit, skin irritation Rabbit, eye irritation Guinea-pig, skin sensitization (test method used) Short-term studies of toxicity Target/critical effect Lowest relevant oral NOAEL Lowest relevant dermal NOAEL > 5000 mg/kg bw > 2000 mg/kg bw > 5.3 mg/l Not irritating Slight transient irritant A skin sensitizer (Buehler; Magnusson & Kligman) Body-weight gain 1500 ppm (48 mg/kg bw per day) in a 1-year study in dogs < 107 mg/kg bw for local effects; 714 mg/kg bw per day for systemic effects. ZOXAMIDE 487–522 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
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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
Page 482 and 483: 467 mortality and morbidity. Change
Page 484 and 485: 469 2.4 Genotoxicity Pyrimethanil w
Page 486 and 487: 471 mean body‐weight gains. After
Page 488 and 489: 473 Analysis of dosing solutions in
Page 490 and 491: 475 In a 7-day feeding study, group
Page 492 and 493: 477 at 200 mg/kg bw. These clinical
Page 494 and 495: 479 s ystemic toxicity was 400 ppm
Page 496 and 497: 481 Acute toxicity Rat, LD 50 , ora
Page 498 and 499: 483 Grosshans, F. (2003) Pyrimethan
Page 500 and 501: 485 Markham, L.P. (1989d) Technical
Page 502 and 503: ZOXAMIDE First draft prepared by I.
Page 504 and 505: 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
Page 512 and 513: 497 owing to the absence of a dose-
Page 514 and 515: 499 The NOAEL was 30 000 ppm, equiv
Page 516 and 517: 501 Table 9. Haematological finding
Page 518 and 519: 503 Table 11. Body weight, food con
Page 520 and 521: 505 daily for signs of moribundity,
Page 522 and 523: 507 Table 14 Results of studies of
Page 524 and 525: 509 phase. The study was certified
Page 526 and 527: 511 Table 16. Spleen weights and hi
Page 528 and 529: 513 FOB/motor activity assessment,
Page 530 and 531: 515 Excretion was primarily in the
Page 534 and 535: 519 Lowest relevant inhalation NOAE
Page 536 and 537: 521 Morrison, R.D. & Gillette, D.M.
Page 538 and 539: ANNEX 1 Reports and other documents
Page 540 and 541: 525 31. Pesticide residues in food:
Page 542 and 543: 527 67. Pesticide residues in food
Page 544: 529 101. Pesticide residues in food
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