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253 Table 19. Results of studies of acute toxicity and short-term studies of toxicity with 1,2,4-triazolyl alanine Study Species Dose LD 50 (mg/ kg bw) NOAEL (mg/ kg bw per day) Adverse effect Reference Acute toxicity Oral Rat, mouse — > 5000 — — Mihail (1982) Oral Rat — > 2000 — — Henderson & Parkinson (1980) Intraperitoneal Rat — > 5000 — — Mihail (1982) Short-term studies of toxicity Twenty-eightday, gavage Rat 0, 25, 100 or 400 mg/kg bw per day — 400 mg/kg bw per day None observed Mihail & Vogel (1983) Ninety-day, feeding Ninety-day, feeding Rat 0, 1250, 5 000 and 20 000 ppm Dog 0, 3 200, 8 000 and 20 000 ppm — 5000 ppm, equivalent to 500 mg/kg bw per day — 8000 ppm equivalent to 200 mg/kg bw per day Reduced bodyweight gains in males at 20 000 ppm Reduced food intake and body-weight gains in females at 20 000 ppm Maruhn & Bomhard (1984) von Keutz & Gröning (1984) 500 mg/kg bw per day, and the NOAEL for fetal toxicity of 2000 ppm, equivalent to 100 mg/kg bw per day, on the basis of reduced birth weights at 10 000 ppm, equivalent to 500 mg/kg bw per day (Table 21). (iii) Toxicology of 1,2,4-triazolyl acetic acid 1,2,4-Triazolyl acetic acid (Figure 6) is a significant residue in plants treated with d ifenoconazole. The metabolism and pharmacokinetics of 1,2,4-triazolyl acetic acid have been evaluated in rats (Lai & Simoneax; 1986b, 1986c). In a repeat-dose study, oral administration of radiolabelled 1,2,4-triazolyl acetic acid resulted in negligible tissue residue with no unusual accumulation in any tissue or organ. Recovery of the administered dose was high and elimination was rapid, with 66–75% of the administered dose being excreted via the urine and 11–32% via the faeces. In all cases, only unchanged 1,2,4-triazolyl acetic acid was excreted. A balance study to further refine the uptake and rates of excretion of 1,2,4-triazolyl acetic acid after oral administration again confirmed that the primary route of excretion was via the urine. No significant differences were observed in excretion patterns between males and females. Excretion of radioactivity during the first 48 h after administration accounted for > 90% of the total activity at all three doses used, indicating that clearance was not saturable at the doses tested. The toxicity of 1,2,4-triazolyl acetic acid has been studied much less extensively than that of 1,2,4-triazolyl alanine. At a dose of 5000 mg/kg bw, no mortality was observed in rats given 1,2,4- triazolyl acetic acid as a single oral dose and after a 14-day observation period. The LD50 was > 5000 mg/kg bw (Thevenaz, 1984). In a 14-day dietary study, male and female rats were given diets containing 1,2,4-triazolyl acetic acid at a concentration of 0, 100, 1000 or 8000 ppm, equal to 0, 11, 103 and 788 mg/kg bw per day in males and 0, 10, 97 and 704 mg/kg bw per day in females. No mortality occurred in the study, nor were there any clinical signs of systemic toxicity. Ophthalmic and auditory examinations revealed no treatment-related reactions. The mean body-weight values and mean food and water DIFENOCONAZOLE 201–272 JMPR 2007
254 Table 20. Results of studies of genotoxicity with 1,2,4-triazolyl alanine End-point Test system Concentration or dose tested Result Reference In vitro Gene mutation S. typhimurium TA98, TA100, TA102, TA1535 and TA1537 Gene mutation S. typhimurium TA98, TA100, TA1535 and TA1537; E. coli strain WP2 uvrA Gene mutation S. typhimurium TA98, TA100, TA1535, TA1537 and TA1538 20–5 000 µg/plate Not mutagenic ±S9 in all test systems 312.5–5 000 µg/ plate Not mutagenic ±S9 in all test systems 20–12 500 µg/plate Not mutagenic ±S9 in all test systems Deparade (1986) Hertner (1993) Herbold (1983a) Gene mutation Chinese hamster V79 cells 500–10 000 µg/ml Not mutagenic ±S9 Dollenmeier (1986b) DNA repair E. coli (K 12) p 3478 (pol A1-) and E. coli W3110 (pol A+). Bacillus subtilis (rec+ ) strain H17 and (rec- ) strain M45 62.5–1 000 µg/plate No induction of DNA damage ±S9 20–1 000 µg / plate No induction of DNA damage ±S9 Herbold (1983b) Watanabe (1993) DNA repair Rat hepatocytes 80–10 000 μg/ml No induction of DNA damage Puri (1986) Cell t ransformation Cell t ransformation In vivo Micronucleus formation Micronucleus formation Micronucleus formation Balb/3T3 mouse fibroblasts 62.5–10 000 μg/ml No induction of cell transformation ±S9 Baby hamster kidney (BHK 21 C13) cells 500–8 000 μg/ml –S9; 1 000–16 000 μg/ml +S9 Induction of cell transformation suggested. Method inadequate. Invalid result. Beilstein (1984) Richold et al. (1981) Mouse (NMRI) 8 000 mg/kg, oral Not clastogenic or aneugenic Herbold (1983c) Mouse (CBC F1) Chinese hamsters S9, 9000 × g supernatant from rat livers. 2 500 and 5 000 mg/ kg, intraperitoneal 5 000 mg/kg bw, oral Not clastogenic or aneugenic Not clastogenic or aneugenic Watkins (1982) Strasser (1986) Figure 6. 1,2,4-Triazolyl acetic acid N N N COOH consumption values of all treated rats were similar to those of the respective controls during the entire treatment period. No differences were observed in clinical chemistry evaluations and analysis of organ weights and organ weight ratios revealed no treatment-related effects. Autopsy revealed no evidence of a reaction to treatment and there were no microscopic lesions or changes that could be attributed to treatment. The NOAEL was 8000 ppm, equal to 788 mg/kg bw per day, the highest dose tested (Thevenaz, 1986). DIFENOCONAZOLE 201–272 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
Page 218 and 219: 203 a sex difference nor any marked
Page 220 and 221: 205 demonstrated that the highest t
Page 222 and 223: 207 Figure 3. Proposed metabolic pa
Page 224 and 225: 209 of the study were unremarkable.
Page 226 and 227: 211 Table 3. Results of studies of
Page 228 and 229: 213 The no-observed-adverse-effect
Page 230 and 231: 215 lower than those of rats in the
Page 232 and 233: 217 hepatocellular enlargement. In
Page 234 and 235: 219 i.e. males lost 15.4% and femal
Page 236 and 237: 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 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 288 and 289: DIMETHOMORPH First draft prepared b
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
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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
Page 366 and 367:
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
Page 457 and 458:
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
Page 488 and 489:
473 Analysis of dosing solutions in
Page 490 and 491:
475 In a 7-day feeding study, group
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477 at 200 mg/kg bw. These clinical
Page 494 and 495:
479 s ystemic toxicity was 400 ppm
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481 Acute toxicity Rat, LD 50 , ora
Page 498 and 499:
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
Page 508 and 509:
493 Table 4. Distribution of metabo
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495 were also found in the urine, a
Page 512 and 513:
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
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 532 and 533:
517 days 14 to 21. Increased relati
Page 534 and 535:
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
Page 544:
529 101. Pesticide residues in food
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