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325 Table 2. Incidence of liver tumours and associated histopathological lesions reported in combined studies in mice fed diets containing flusilazole Finding Study Dietary concentration (ppm) Range for historical Brock et al. 0 — 5 25 — 200 — — — controls (1985) (%) c Keller (1992b) — 0 — — 100 — 500 1000 2000 Males Dietary intake 0 0 0.66 3.4 14.3 27.0 73.1 144.0 — — (mg/kg bw per day) Hepatocellular 20 16 16 15 29 30 25 23 — 7.5–21.8 tumours (%) a Hepatocellular 10 10 10 10 18 14 19 15 — 5.0–21.8 adenomas (%) Hepatocellular 10 6 6 4 10 11 6 6 — 0–6.8 carcinomas Foci of cellular 4 4 5 3 5 4 12 29* — — alteration (%) Degeneration, 5 0 4 10 1.2 50* 11.2* 11.4* — — centrilobular (%) b Degeneration, 4 3.8 3 8 12.5 3 13.8 15.0* — — focal (%) Relative liver 4.9 5.4 4.8 4.7 6.4* 5.5* 7.6* 9.2* — — weight (% body weight) Females Dietary intake 0 0 0.92 4.6 19.4 36.0 — 200 384 — (mg/kg bw per day) Hepatocellular 1.3 1.3 2.5 0 3.8 1.2 — 13.8* 53.8* 0–2.6 tumours (%) a Hepatocellular 1.0 0 3.0 0 2.5 1.0 — 10.0* 14.0* 0–2.6 adenomas (%) Hepatocellular 0 1.3 0 0 1.2 0 — 1.3 26.0* 0–1.3 carcinomas Foci of cellular 0 2.5 0 0 1.2 1.0 — 9.0* 34.0* — alteration (%) Degeneration, 3.0 1.3 5.0 4.0 0 30.0* — 1.2 0 — centrilobular (%) b Degeneration, 10.0 12.7 9.0 5.0 7.5 5.0 — 10.0 12.5 — focal (%) Relative liver weight (% body weight) 5.4 5.2 5.0* 5.3 5.3 5.5 — 8.9* 12.7* — From Brock et al. (1985) and Keller (1992b) a Mice with at least one liver tumour. b Includes lesions described as fatty change. c Historical controls or controls from laboratory carrying out the study. * p < 0.05. FLUSILAZOLE 317–347 JMPR 2007
326 respectively; range for historical controls, 7.5–21.8%) and in females at the two higher doses (1 out of 79, 3 out of 80, 11 out of 77 and 43 out of 76 at 0, 100, 1000 and 2000 ppm, respectively; range for historical control, 0–2.6%). The increase in incidence of tumours was not dose-related nor statistically significant in males, but found to be dose-dependent and statistically significant in females. On the basis of these results, no NOAEL for systemic toxicity could be identified. The overall NOAEL for oncogenicity was 200 ppm (36 mg/kg bw per day) for females and 1000 ppm (144 mg/kg bw per day) for males (Keller, 1992b). Rats In a GLP-compliant study, groups of 70 male and 70 female rats of strain Crl:CD(SD)BR were given diets containing flusilazole technical (purity, 95.6%) at a concentration of 0, 10, 50 or 250 ppm (equal to 0, 0.4, 2.0, and 10 mg/kg bw per day in males and 0, 0.5, 2.6 and 13 mg/kg bw per day in females) for 2 years. Each group had two satellite groups of 10 males and 10 females for interim killing at 6 months and 1 year, respectively. At approximately 100 days after the start of treatment, 20 males and 20 females from each group were mated for the reproduction phase of the study. These rats were returned to the long-term study after weaning of the second litter. The rats killed at 6 months were examined for bladder lesions only. No treatment-related effect on mortality was observed; survival rate was > 50% in all groups until week 98. No signs of systemic toxicity were evident at the lowest dose of 10 ppm. At the next higher dose of 50 ppm, there was a dose-related increase in the incidence of pyelonephritis in females at 2 years (3 out of 66, 3 out of 62, 8 out of 67 and 10 out of 65 at 0, 10, 50, and 250 ppm, respectively). Increases in relative liver weight (females) and incidence of hydronephrosis (males) were also observed at interim kill at 1 year. These effects were not considered adverse. At the highest dose of 250 ppm, additional treatment-related changes included: increased incidence of hepatic lesions in females (centrilobular hepatocellular hypertrophy and polyploidy) and hydro-nephrosis in males at 1 year; and increased incidence of acidophilic foci of hepatocellular alteration (13 out of 65 compared with 3 out of 66 in controls) and hepatic diffuse fatty changes (23 out of 65 compared with 9 out of 66 in controls) in females at 2 years. No hepatic lesions were observed in males at any time during the study and no lesions of the urinary bladder were evident in either sex at either interim (6 or 12 months) or terminal kill. There was no treatment-related increase in incidence of any tumour type at any dose tested in the study. At 250 ppm, males showed a slightly higher incidence of squamous cell carcinomas of the oral and nasal cavities (0 out of 66, 1 out of 63, 0 out of 67 and 3 out of 64, at 0, 10, 50, and 250 ppm, respectively). On the basis of data on historical controls from six 2-year feeding studies in rats (five studies with no tumours of this type and one study with an incidence of 2 out of 60), the incidence of nasal tumours in this study was judged to be incidental. Flusilazole technical was, therefore, not oncogenic in the rat under the conditions of this study. The NOAEL for systemic toxicity was 50 ppm, equal to 2.0 mg/kg bw per day. The Meeting noted, however, that the systemic effects reported in this study were relatively mild and higher doses might have been tolerated (Pastoor et al., 1986). In a more recent study, groups of 65 male and 65 female Crl:CD(SD)BR rats were fed diets containing flusilazole technical (purity, 95%) at a concentration of 0, 125, 375, or 750 ppm (equal to 0, 5.03, 14.8, and 30.8 mg/kg bw per day in males and 0, 6.83, 20.5 and 45.6 mg/kg bw per day in females) for 2 years. Each group included a satellite group of 10 males and 10 females destined for interim kill at 1 year. The study complied with GLP and test guideline OECD 451. At the lowest dose of 125 ppm (equal to 5.03 mg/kg bw per day), dose-related increases in incidence of hepatocellular hypertrophy were observed in both sexes at either interim (males, 0 out of 10, 4 out of 10, 8 out of 10 and 8 out of 10; females, 0 out of 10, 7 out of 10, 10 out of 10 and 10 out of 10; at 0, 125, 375 and 750 ppm, respectively) or terminal kill (males, 2 out of 53, 2 out of 51, 10 out of 53 and 19 out of 53; females, 2 out of 56, 4 out of 55, 12 out of 53 and 25 out of 54; values exclude FLUSILAZOLE 317–347 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
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
Page 324 and 325: 309 eye-opening, pinna unfolding or
Page 326 and 327: 311 Lowest relevant inhalation NOAE
Page 328 and 329: 313 Gardner, J.R. (1989) CME 151 te
Page 330: 315 van de Waart, E.J. (1991b) Eval
Page 333 and 334: 318 Committee on Pesticide residues
Page 335 and 336: 320 (a) Ocular irritation Rabbits T
Page 337 and 338: 322 weights were decreased in males
Page 339: 324 toxicity was 5 mg/kg bw per day
Page 343 and 344: 328 Table 4. Incidence of Leydig-ce
Page 345 and 346: 330 and/or bilateral) was noted in
Page 347 and 348: 332 No treatment-related signs of m
Page 349 and 350: 334 Table 6. Incidence of selected
Page 351 and 352: 336 or teratogenic potential at the
Page 353 and 354: 338 and progesterone. The concentra
Page 355 and 356: 340 the doses used in the 1-year st
Page 357 and 358: 342 No neurotoxic effects were seen
Page 359 and 360: 344 Lowest relevant reproductive NO
Page 361 and 362: 346 Keller, D.A. (1992c) Oncogenici
Page 364 and 365: PROCYMIDONE First draft prepared by
Page 366 and 367: 351 Rats Groups of five male and fe
Page 368 and 369: 353 Table 1. Pharmacokinetic parame
Page 370 and 371: 355 Seven doses C max (µg equivale
Page 372 and 373: 357 Three groups of five male and f
Page 374 and 375: 359 The excretion of radioactivity
Page 376 and 377: 361 Figure 1. Proposed metabolic pa
Page 378 and 379: 363 water consumption were determin
Page 380 and 381: 365 finding. Histopathology reveale
Page 382 and 383: 367 The NOAEL was 500 ppm, equivale
Page 384 and 385: 369 The NOAEL was 100 mg/kg bw per
Page 386 and 387: 371 at 2000 ppm. Histopathology rev
Page 388 and 389: 373 b Each test was conducted in tr
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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,
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:
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527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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