Pesticide residues in food â 2007: Toxicological ... - ipcs inchem

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DIMETHOMORPH First draft prepared by Jürg Zarn 1 and Maria Tasheva 2 1 Food Toxicology Section, Swiss Federal Office of Public Health, Zurich, Switzerland; and 2 National Center of Public Health Protection, Sofia, Bulgaria Explanation ...................................................................................................... 274 Evaluation for acceptable daily intake ............................................................. 274 1. Biochemical aspects ........................................................................... 274 1.1 Absorption, distribution, metabolism and excretion .................. 274 1.2 Effects on enzymes and other biochemical parameters ............. 279 2. Toxicological studies ......................................................................... 280 2.1 Acute toxicity.............................................................................. 280 (a) Oral administration............................................................. 280 (b) Dermal application ............................................................ 282 (c) Exposure by inhalation ...................................................... 282 (d) Dermal and ocular irritation .............................................. 282 (e) Dermal sensitization .......................................................... 283 2.2 Short-term studies of toxicity ..................................................... 284 2.3 Long-term studies of toxicity and carcinogenicity ..................... 291 2.4 Genotoxicity................................................................................ 297 2.5 Reproductive toxicity ................................................................. 299 (a) Multigeneration studies ..................................................... 299 (b) Developmental toxicity....................................................... 300 2.6 Special studies: pharmacology.................................................... 304 (a) Anticonvulsive activity in mice........................................... 304 (b) Potentiation of hexobarbiton sleeping time in mice .......... 305 (c) Alteration of body temperature in mice.............................. 305 (d) Spontaneus motor activity in mice .................................... 305 (e) Tail flick test for analgesia ................................................. 305 (f) Effect on the Irwin test in mice........................................... 305 (g) Charcoal meal transit times in the rat small intestines ...... 305 (h) Effect on motility of uterine smooth muscle in rats .......... 305 (i) Assessment of potential anti-inflammatory activity in rats.................................................................................. 305 (j) Cardiovascular, respiratory and nictitating membrane alterations in cat ................................................................ 306 (k) Effect on the spontaneous motility of isolated rabbit ileum .................................................................................. 306 (l) Effect on the isolated guinea-pig ileum and action on four agonists .............................................................................. 306 (m) Surface anaesthetic activity in the guinea- pig.................. 306 3. Observations in humans ..................................................................... 306 Comments......................................................................................................... 306 References ....................................................................................................... 311 DIMETHOMORPH 273–315 JMPR 2007
274 Explanation Dimethomorph is a cinnamic acid derivative for which the chemical name is (E,Z)-4-[3-(4- chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine or (EZ)-4-[3-(4-chlorophenyl)-3-(3,4- dimethoxyphenyl)-1-oxo-2-propenyl]morpholine, according to International Union of Pure and Applied Chemistry (IUPAC) and Chemical Abstract Service (CAS) nomenclatures respectively (CAS No. 110488-70-5). Dimethomorph is a mixture of E and Z isomers in the ratio of approximately 1 : 1. Dimethomorph is a fungicide that disrupts fungal cell-wall formation. Fungicidal activity is primarily associated with the Z isomer. Dimethomorph has not been evaluated previously by the JMPR and was reviewed at the present Meeting at the request of the Codex Committee on Pesticide Residues (CCPR). All pivotal studies with dimethomorph were certified as complying with good laboratory practice (GLP). Evaluation for acceptable daily intake 1. Biochemical aspects 1.1 Absorption, distribution, metabolism and excretion Absorption, distribution, metabolism and excretion of [ 14 C]dimethomorph was studied in male and female Sprague-Dawley CD rats. [ 14 C]Dimethomorph labelled uniformly on the chlorophenyl ring (radiochemical purity, 98.5%) had a specific activity of 0.647 GBq/mmol and the E : Z isomer ratio was 44–47 : 56–53. Non-labelled dimethomorph had a purity of 99.2% and the isomer ratio was virtually 50 : 50. Figure 1. E- and Z-isomers of dimethomorph O O O O O N O O N O Cl Cl (Z)- (E)- Table 1. Dosing regimen for a study in rats treated with [ 14 C]dimethomorph Group No. of rats of each sex Dose (mg/kg bw) Remark A 1 500 Single dose, expired air B 5 10 Single dose C 5 10 Repeated doses of non-labelled dimethomorph for 14 days, followed by a single radiolabelled dose D 5 500 Single dose E 5 10 Repeated doses of radiolabelled dimethomorph for 7 consecutive days From Schluter (1990) DIMETHOMORPH 273–315 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
Page 238 and 239: 223 There was very high mortality a
Page 240 and 241: 225 Table 6. Treatment-related hist
Page 242 and 243: 227 Rats Groups of 80 CRL:CD(SD)®
Page 244 and 245: 229 Table 7. Histopathology finding
Page 246 and 247: 231 D. Temporal association. The fe
Page 248 and 249: 233 2.5 Reproductive toxicity (a) M
Page 250 and 251: 235 t estes weights in the males at
Page 252 and 253: 237 continued to be lower than thos
Page 254 and 255: 239 Corpora lutea in each ovary wer
Page 256 and 257: 241 S1 + S2, not ossified — —
Page 258 and 259: 243 in the control group and in the
Page 260 and 261: 245 physically examined for changes
Page 262 and 263: 247 Table 16. Results of studies of
Page 264 and 265: 249 can occur in untreated mice, in
Page 266 and 267: 251 Study of reproductive toxicity
Page 272 and 273: 257 of the test article on microsom
Page 274 and 275: 259 Ophthalmoscopic examinations pe
Page 276 and 277: 261 the radioactivity was re-elimin
Page 278 and 279: 263 In a single-dose study of neuro
Page 280 and 281: 265 Estimate of acceptable daily in
Page 282 and 283: 267 Clapp, M.J.L., Killick, M.E., H
Page 284 and 285: 269 Herbold, B. (1983c) THS 2212 tr
Page 286 and 287: 271 Pinto, P. (2006b) Difenoconazol
Page 290 and 291: 275 Five different treatment groups
Page 292 and 293: 277 To investigate the significance
Page 294 and 295: 279 and the E : Z isomer ratio was
Page 296 and 297: 281 Table 10. Tissue distribution o
Page 298 and 299: 283 (e) Dermal sensitization The de
Page 300 and 301: 285 females at the highest dose, to
Page 302 and 303: 287 The NOAEL was 10 mg/kg bw per d
Page 304 and 305: 289 concentrations in females were
Page 306 and 307: 291 health, moribundity and mortali
Page 308 and 309: 293 0-9%, mean, 3.5%; only one out
Page 310 and 311: Table 26. Organ weights adjusted to
Page 312 and 313: 297 cell hyperplasia. The testes tu
Page 314 and 315: 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
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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
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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
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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
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517 days 14 to 21. Increased relati
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519 Lowest relevant inhalation NOAE
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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:
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527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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