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115 (d) Diaminochlorotriazine (DACT) Species Study Effect NOAEL LOAEL Rat Thirteen-week study of toxicity a Endocrine disrup-tion (estrous cycle) 100 ppm, equal to 7.6 mg/kg bw per day 250 ppm, equal to 19.7 mg/kg bw per day Developmental toxicity b Maternal toxicity 2.5 mg/kg bw per day 25 mg/kg bw per day Special study, 29/52 weeks a Embryo/fetotoxicity 2.5 mg/kg bw per day 25 mg/kg bw per day Endocrine disruption (LH surge) 48 ppm, equal to 3.4 mg/kg bw per day 270 ppm, equal to 18.8 mg/kg bw per day Special 19-day study b Female pubertal delay 25 mg/kg bw per day c 50 mg/kg bw per day c Special 30-day study b Male pubertal delay 6.25 mg/kg bw per day c 12.5 mg/kg bw per day c Dog Thirteen-/52-week study of Toxicity 100 ppm, equal to toxicity a 3.5 mg/kg bw per day 1500/750 ppm, equal to 23.8 mg/kg bw per day LH, luteinizing hormone. a Dietary administration. b Gavage administration. c Atrazine molar equivalent dose. (e) Hydroxyatrazine Species Study Effect NOAEL LOAEL Rat Dog Thirteen-week study of Toxicity 100 ppm, equal to toxicity a 6.3 mg/kg bw per day Two-year study of toxicity and carcinogenicity a (Sprague-Dawley rats) Toxicity Carcinogenicity 25 ppm, equal to 1.0 mg/ kg bw per day 400 ppm, equal to — 17.4 mg/kg bw per day c 300 ppm, equal to 18.9 mg/kg bw per day 200 ppm, equal to 7.8 mg/kg bw per day Developmental toxicity b Maternal toxicity 25 mg/kg bw per day 125 mg/kg bw per day Embryo/fetotoxicity 25 mg/kg bw per day 125 mg/kg bw per day Special 19-day study b Female pubertal delay 200 mg/kg bw per day c,d — Thirteen-/52-week study of Toxicity 150 ppm, equal to toxicity a 5.8 mg/kg bw per day 1500 ppm, equal to 59.6 mg/kg bw per day a Dietary administration. b Gavage administration. c Highest dose tested. d Atrazine molar equivalent dose. Estimate of acceptable daily intake for humans Group ADI for atrazine, deethyl-atrazine (DEA), deisopropyl-atrazine (DIA) and diaminochlorotriazine (DACT) 0–0.02 mg/kg bw Hydroxyatrazine 0–0.04 mg/kg bw Estimate of acute reference dose ATRAZINE 37–138 JMPR 2007
116 Group ARfD for atrazine, deethyl-atrazine(DEA), deisopropyl-atrazine (DIA) and diaminochlorotriazine (DACT) 0.1 mg/kg bw Hydroxyatrazine Unnecessary Information that would be useful for the continued evaluation of the compound Results from epidemiological, occupational health and other such observational studies of human exposures Critical end-points for setting guidance values for exposure to atrazine Absorption, distribution, excretion and metabolism in animals Rate and extent of oral absorption Rapid, > 80% in rats Distribution Widely distributed Rate and extent of excretion > 50% in 24 h and > 93% within 7 days; approximately 73% via urine, approximately 20% via faeces (approximately 7% via bile) Potential for accumulation Low; binding to rat haemoglobin, not relevant to humans Metabolism in mammals Extensive (> 95%) to at least 25 metabolites; major pathway is N- dealkylation Toxicologically significant compounds in animals, 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 Short-term studies of toxicity Target/critical effect Lowest relevant oral NOAEL Lowest relevant dermal NOAEL Lowest relevant inhalation NOAEC Genotoxicity Long-term studies of toxicity and carcinogenicity Target/critical effect Lowest relevant NOAEL Carcinogenicity Reproductive toxicity Reproductive target/critical effect Lowest relevant reproductive NOAEL Parent compound, chloro-s-triazine metabolites DEA, DIA, DACT (animals, environment), hydroxyatrazine (plants, environment) 1870–3090 mg/kg bw > 2000 mg/kg bw > 5.8 mg/l Not an irritant Not an irritant Sensitizer (Magnusson & Kligman; Maurer optimization test) Reduced body-weight gain, ovaries (inhibition of ovulation), cardiotoxicity (in dogs only) 3.3 mg/kg bw per day (90-day study in rats) 100 mg/kg bw per day (25-day study in rabbits) No data Unlikely to be genotoxic in vivo Ovaries (inhibition of ovulation) and related endocrine changes 1.8 mg/kg bw per day (6-month –study of LH-surge in Sprague- Dawley rats) No relevant carcinogenicity Reduced body-weight gain in pups at parentally toxic doses 3.6 mg/kg bw per day ATRAZINE 37–138 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
Page 80 and 81: 65 Table 10. Selected studies of ge
Page 82 and 83: 67 End-point Test object Concentrat
Page 84 and 85: 69 Table 12. Relevant findings in a
Page 88 and 89: 73 respectively) and in males at th
Page 92 and 93: 77 All dams survived until the end
Page 94 and 95: 79 250 and 500 ppm. Body-weight gai
Page 96 and 97: 81 In an assay for reverse mutation
Page 98 and 99: 83 on pubertal development in femal
Page 100 and 101: 85 parameters (decreased pH, specif
Page 104 and 105: 89 0, 75, 150 or 300 mg/kg bw per d
Page 106 and 107: 91 The NOAEL was 25 ppm, equal to 1
Page 108 and 109: 93 In a study on the effect of atra
Page 110 and 111: 95 Delayed parturition was seen at
Page 112 and 113: 97 observed in the pair-fed group.
Page 114 and 115: 99 examined, offspring in the atraz
Page 116 and 117: 101 antagonize E2-induced luciferas
Page 118 and 119: 103 increase in steroidogenesis is
Page 120 and 121: 105 The immune system of adult mice
Page 122 and 123: 107 In a later review of cancer epi
Page 124 and 125: 109 In a 25-day study in rabbits tr
Page 126 and 127: 111 developmental toxicity were 10
Page 128 and 129: 113 regulation in male offspring in
Page 132 and 133: 117 Developmental target/critical e
Page 134 and 135: 119 • The failure to ovulate resu
Page 136 and 137: 121 The relationship between increa
Page 138 and 139: 123 Table A2. Comparison of paramet
Page 140 and 141: 125 Ballantine, L., Murphy, T. G. &
Page 142 and 143: 127 Dunkelberg, H., Fuchs, J., Heng
Page 144 and 145: 129 Heneweer, M., van den Berg, M.
Page 146 and 147: 131 Lindsay, L.A., Wimbert, K.V., G
Page 148 and 149: 133 Morseth, S.L. (1996d) Chronic (
Page 150 and 151: 135 Rudzki, M.W., Batastina, G., &
Page 152 and 153: 137 Tennant, A.H., Peng, B. & Klige
Page 154 and 155: AZINPHOS-METHYL First draft prepare
Page 156 and 157: 141 methylation and oxidation of me
Page 158 and 159: 143 Table 1. Acute oral toxicity of
Page 160 and 161: 145 Table 2. Cholinesterase activit
Page 162 and 163: 147 at the highest dose. In both sp
Page 164 and 165: 149 Table 6. Cholinesterase activit
Page 166 and 167: 151 Table 8. Fertility of F 0 and F
Page 168 and 169: 153 Table 10. Fertility parameters
Page 170 and 171: 155 Groups of 22 mated Sprague-Dawl
Page 172 and 173: 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
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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
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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
Page 508 and 509:
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
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
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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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