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495 were also found in the urine, accounting for approximately 3% of the administered dose. An additional 1.6% of the administered radioactivity was excreted in the faeces as the parent chemical (Wu & Gu, 1998a). Metabolite RH141,455 (3,5-dichloro-terphthalic acid) The absorption, distribution, metabolism and elimination of [ 14 C]RH-141,455 (lot No. 958.0005; specific activity, 74.46 mCi/g) in male rats were studied. Four male rats were given a single oral dose of [ 14 C]RH-141,455 in pH-adjusted water at a nominal dose of 1000 mg/kg bw. The rats were sacrificed 168 h after dosing and the total recovery of radiolabelled residues was determined. More than 96% of radioactivity excreted from faeces (72%) and urine plus cage wash (20%) was identified as unchanged RH-141,455. Some minor metabolites were also observed in urine samples, but were not identified owing to their low concentrations (Wu & Gu, 1998b). 2. Toxicological studies 2.1 Acute toxicity (a) Lethal doses The results of studies of acute toxicity with zoxamide administered by the oral, dermal and inhalation routes, and two of its metabolites, are presented in Table 5. Zoxamide was of low acute toxicity by all routes. The metabolites RH 141-452 & 141,455 were of low acute oral toxicity. (b) Dermal and ocular irritation and dermal sensitization Zoxamide was not irritating to the skin of rabbits (Gingrich & Parno, 1996c) but exhibited slight, transient irritation to the rabbit eye (Gingrich & Parno, 1996d). Zoxamide produced delayed contact hypersensitivity in the guinea-pig in the Magnusson & Kligman maximization study (Glaza, 1997) and in Buehler skin sensitization tests (Robison et al., 1998a). Low concentrations (< 0.25% w/w) were shown to be not sensitizing to the skin of guinea-pigs (Robison et al., 1998b). Table 5. Acute toxicity with zoxamide and its metabolites Test substance Species Strain Sex Route LD 50 (mg/kg bw) LC 50 (mg/l air) Purity (%) Vehicle Reference Zoxamide Rat Crl:CDBR Males & females Zoxamide Mouse Crl:CD-1- (ICR)BR Males & females Zoxamide Rat Crl:CDBR Males & females Zoxamide Rat Crl:CDBR Males & females RH-141,452 Mouse Crl:CD-1- (ICR)BR RH-141,452 Mouse Crl:CD-1- (ICR)BR Males & females Males & females Oral > 5000 — 92.3 Corn oil Gingrich & Parno (1996a) Oral > 5000 — 94.4 Corn oil Ferguson & Lutz (1998) Dermal > 2000 — 92.3 Corn oil Gingrich & Parno (1996b) Inhalation (4-h, nose-only) — > 5.3 (MMAD 4.3 μm) 92.3 None (dust aerosol) Bernacki,& Ferguson (1996) Oral > 5000 — 97.7 Corn oil Ferguson et al. (1998c) Oral > 5000 — 98.7 Corn oil Ferguson et al. (1998a) MMAD, mass median aerodynamic diameter. ZOXAMIDE 487–522 JMPR 2007
496 2.2 Short-term studies of toxicity Mice Groups of 10 male and 10 female Crl:CD-1(ICR)BR mice were given diets containing zoxamide (purity, 94.2%) at a concentration of 0, 70, 700, 2500 or 7000 ppm (equal to 0, 12, 123, 436 and 1212 mg/kg bw per day respectively in males, and 0, 17, 174, 574, 1666 mg/kg bw per day in females) for 90 days. All mice were observed daily for signs of ill health or reaction to treatment. Physical examinations were performed each week. Body weight and feed consumption were determined each week. At the end of the study period, all surviving mice were bled for haematology and clinical chemistry investigations, killed and necropsied. Selected organ weights were recorded and tissues were collected for histopathological evaluation. The study was certified to be compliant with GLP and satisfied the essential criteria of OECD guideline 408. No treatment-related deaths or clinical signs of toxicity were observed. There were no treatment-related effects on body weight or body-weight change in males at any dose. After 4 weeks of treatment, there was a persistent and apparently treatment-related but statistically non-significant decrease in body weight and cumulative body-weight gain in females at 7000 ppm compared with concurrent controls (Table 6). In males, a number of statistically significant decreases in mean body weight and cumulative body-weight gain were observed in the groups at 700 ppm and 2500 ppm throughout the treatment period, but these decreases were not considered to be treatment-related Table 6. Body weights, body-weight gain and liver weight in mice fed diets containing zoxamide for 90 days Parameter Dietary concentration (ppm) 0 70 700 2500 7000 Males Body weight (g): Week 0 30.8 30.4 30.2 29.2 29.8 Week 4 34.6 33.7 33.2* 32.0 32.8 Week 8 37.9 36.3 35.8* 34.3* 35.4 Week 13 (mean ± SD) 41.1 ± 4.9 38.5 ± 2.2 38.0 ± 1.9* 36.7 ± 3.5 38.3 ± 3.9 Cumulative body-weight gain, week 13 (g, mean ± SD) 12.3 ± 4.2 9.5 ± 1.9 9.1 ± 1.1* 8.9 ± 2.7 10.0 ± 2.7 Absolute liver weight (g, mean ± SD) 2.1 ± 0.24 2.0 ± 0.20 1.9 ± 0.13 2.1 ± 0.25 2.2 ± 0.21 Relative liver weight (%, mean ± SD) 5.2 ± 0.41 5.2 ± 0.39 5.2 ± 0.25 5.8 ± 0.49* 5.8 ± 0.55* Females Body weight (g): Week 0 23.3 23.3 22.2 22.8 20.9 Week 4 26.8 26.8 25.6 25.1 23.6 Week 8 28.1 28.9 27.3 26.8 25.0 Week 13 (mean ± SD) 30.6 ± 4.8 31.1 ± 3.2 29.3 ± 3.8 28.7 ± 3.3 25.8 ± 2.1 Cumulative body-weight gain, week 13 (g, mean ± SD) 7.4 ± 3.1 7.7 ± 2.4 7.0 ± 2.6 5.9 ± 2.0 4.9 ± 1.7* Absolute liver weight (g, mean ± SD) 1.5 ± 0.16 1.6 ± 0.16 1.7 ± 0.21 1.6 ± 0.24 1.5 ± 0.17 Relative liver weight (%, mean ± SD) 5.2 ± 0.51 5.3 ± 0.26 5.7 ± 0.52 5.7 ± 0.57 6.0 ± 0.51* From Shuey et al. (1996) SD, standard deviation. * Significant difference from controls (p < 0.05). ZOXAMIDE 487–522 JMPR 2007
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Pesticide residues in food — 2007
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TABLE OF CONTENTS Page List of part
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Dr Vicki L. Dellarco, Office of Pes
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Abbreviations used 3-MC ACTH ADI ai
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MRL MS MS/MS MTD NMR NOAEC NOAEL NO
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Introduction The toxicological mono
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AMINOPYRALID First draft prepared b
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5 higher renal excretion in the gro
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7 Table 4. Recovery of radioactivit
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9 Table 7. Pharmacokinetic paramete
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11 (c) Exposure by inhalation Five
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13 Table 9. Acute toxicity of amino
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15 The data from urine analysis rev
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17 18, monthly for palpable masses.
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19 Table 12. Body weights of rats f
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21 Table 15. Results of assays for
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23 in both groups, feed consumption
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25 neurotoxicity after 12 months. B
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27 The same five time-mated NZW rab
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29 Mortality was increased in all g
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31 Levels relevant to risk assessme
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33 References Brooks, K.J. (2001a)
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35 Consulting, The Dow Chemical Com
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ATRAZINE First draft prepared by Ru
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39 in the early 1990s; this reflect
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41 Maximum concentrations in the bl
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43 In a study on comparative metabo
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45 Table 1. Metabolism of atrazine
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47 Figure 2. Proposed metabolic pat
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49 to intact skin; and that no read
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51 the highest dose, and food consu
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53 mice (evaluated as roughly equiv
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55 Table 5. Incidence of mammary tu
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57 Table 6. Selected findings from
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59 was decreased when compared with
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61 Table 9. Selected findings of a
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63 proestrus at the expense of days
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65 Table 10. Selected studies of ge
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67 End-point Test object Concentrat
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69 Table 12. Relevant findings in a
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73 respectively) and in males at th
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77 All dams survived until the end
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79 250 and 500 ppm. Body-weight gai
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81 In an assay for reverse mutation
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83 on pubertal development in femal
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85 parameters (decreased pH, specif
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89 0, 75, 150 or 300 mg/kg bw per d
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91 The NOAEL was 25 ppm, equal to 1
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93 In a study on the effect of atra
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95 Delayed parturition was seen at
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97 observed in the pair-fed group.
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99 examined, offspring in the atraz
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101 antagonize E2-induced luciferas
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103 increase in steroidogenesis is
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105 The immune system of adult mice
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107 In a later review of cancer epi
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109 In a 25-day study in rabbits tr
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111 developmental toxicity were 10
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113 regulation in male offspring in
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115 (d) Diaminochlorotriazine (DACT
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117 Developmental target/critical e
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119 • The failure to ovulate resu
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121 The relationship between increa
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123 Table A2. Comparison of paramet
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125 Ballantine, L., Murphy, T. G. &
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127 Dunkelberg, H., Fuchs, J., Heng
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129 Heneweer, M., van den Berg, M.
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131 Lindsay, L.A., Wimbert, K.V., G
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133 Morseth, S.L. (1996d) Chronic (
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135 Rudzki, M.W., Batastina, G., &
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137 Tennant, A.H., Peng, B. & Klige
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AZINPHOS-METHYL First draft prepare
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141 methylation and oxidation of me
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143 Table 1. Acute oral toxicity of
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145 Table 2. Cholinesterase activit
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147 at the highest dose. In both sp
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149 Table 6. Cholinesterase activit
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151 Table 8. Fertility of F 0 and F
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153 Table 10. Fertility parameters
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155 Groups of 22 mated Sprague-Dawl
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157 after completion of the feeding
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159 reduced motor activity in males
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161 sensitivity with that of labora
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163 measures to prevent worker expo
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165 when brain cholinesterase activ
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167 Critical end-points for setting
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169 Eiben, R., Schmidt, W., & Loese
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171 Myhr, B.C. (1983) Evaluation of
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LAMBDA-CYHALOTHRIN First draft prep
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175 Figure 1. Chemical structures o
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177 In a comparative study, the abs
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179 Figure 2. Main pathways of biot
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181 (iv) Dermal sensitization In a
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183 observed in rats at the highest
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185 Mortality was not affected by t
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187 the group at 100 ppm, reduction
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189 and five females per group were
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191 10-12%) than those of controls
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193 Comments Biochemical aspects Or
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195 Toxicological evaluation Althou
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197 Metabolism in animals Toxicolog
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199 Harrison, M.P. (1984a) Cyhaloth
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DIFENOCONAZOLE First draft prepared
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203 a sex difference nor any marked
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205 demonstrated that the highest t
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207 Figure 3. Proposed metabolic pa
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209 of the study were unremarkable.
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211 Table 3. Results of studies of
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213 The no-observed-adverse-effect
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215 lower than those of rats in the
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217 hepatocellular enlargement. In
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219 i.e. males lost 15.4% and femal
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221 and 357. This reduced food cons
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223 There was very high mortality a
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225 Table 6. Treatment-related hist
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227 Rats Groups of 80 CRL:CD(SD)®
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229 Table 7. Histopathology finding
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231 D. Temporal association. The fe
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233 2.5 Reproductive toxicity (a) M
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235 t estes weights in the males at
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237 continued to be lower than thos
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239 Corpora lutea in each ovary wer
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241 S1 + S2, not ossified — —
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243 in the control group and in the
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245 physically examined for changes
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249 can occur in untreated mice, in
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251 Study of reproductive toxicity
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257 of the test article on microsom
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259 Ophthalmoscopic examinations pe
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261 the radioactivity was re-elimin
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263 In a single-dose study of neuro
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265 Estimate of acceptable daily in
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267 Clapp, M.J.L., Killick, M.E., H
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269 Herbold, B. (1983c) THS 2212 tr
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271 Pinto, P. (2006b) Difenoconazol
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DIMETHOMORPH First draft prepared b
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275 Five different treatment groups
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277 To investigate the significance
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279 and the E : Z isomer ratio was
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281 Table 10. Tissue distribution o
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283 (e) Dermal sensitization The de
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285 females at the highest dose, to
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287 The NOAEL was 10 mg/kg bw per d
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289 concentrations in females were
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291 health, moribundity and mortali
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293 0-9%, mean, 3.5%; only one out
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Table 26. Organ weights adjusted to
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297 cell hyperplasia. The testes tu
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299 unscheduled DNA synthesis, the
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301 Figure 3. Cumulative percentage
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303 Rabbits In a dose-range finding
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305 (b) Potentiation of hexobarbito
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307 0.2% or less of the administere
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309 eye-opening, pinna unfolding or
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311 Lowest relevant inhalation NOAE
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313 Gardner, J.R. (1989) CME 151 te
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315 van de Waart, E.J. (1991b) Eval
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318 Committee on Pesticide residues
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320 (a) Ocular irritation Rabbits T
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322 weights were decreased in males
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324 toxicity was 5 mg/kg bw per day
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326 respectively; range for histori
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328 Table 4. Incidence of Leydig-ce
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330 and/or bilateral) was noted in
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332 No treatment-related signs of m
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334 Table 6. Incidence of selected
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336 or teratogenic potential at the
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338 and progesterone. The concentra
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340 the doses used in the 1-year st
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342 No neurotoxic effects were seen
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344 Lowest relevant reproductive NO
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346 Keller, D.A. (1992c) Oncogenici
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PROCYMIDONE First draft prepared by
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351 Rats Groups of five male and fe
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353 Table 1. Pharmacokinetic parame
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355 Seven doses C max (µg equivale
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357 Three groups of five male and f
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359 The excretion of radioactivity
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361 Figure 1. Proposed metabolic pa
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363 water consumption were determin
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365 finding. Histopathology reveale
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367 The NOAEL was 500 ppm, equivale
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369 The NOAEL was 100 mg/kg bw per
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371 at 2000 ppm. Histopathology rev
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373 b Each test was conducted in tr
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375 experimental period. Rats were
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377 hypospadias, testicular atrophy
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379 a single dose, which produced o
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381 The anti-androgenic activities
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383 but only at 6000 ppm after 13 w
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385 The results are summarized in T
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387 males (all litters) in the grou
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389 procymidone (18-27% of the admi
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391 Procymidone induced liver tumou
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393 The Meeting concluded that the
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395 Toxicologically significant com
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397 Harada, T. (1983) A review on m
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399 Murakami, M., Yoshitake, A. & H
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401 Tarui, H. (2005b) In vitro meta
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404 Explanation Profenofos is the I
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406 The metabolism of ring-labelled
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408 2. Toxicological studies 2.1 Ac
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410 Rabbits Groups of two male and
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412 Groups of five male and five fe
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414 control group and in the test g
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416 of the rabbits at the highest d
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418 The NOAEL for brain acetylcholi
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420 Table 2. Histopathological find
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422 1 out of 70; lowest dose, 3 out
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424 body‐weight gains (3-10% decr
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426 treated groups for body-weight
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428 (b) Short-term studies of neuro
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430 represented as equally as possi
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432 pound and the equitoxic mixture
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434 Inhibition of brain acetylcholi
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436 Toxicological evaluation Erythr
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438 Neurotoxicity/delayed neurotoxi
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440 Harris, S.B. (1982) A teratolog
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442 Puri, E. (1982a) Autoradiograph
Page 460 and 461: PYRIMETHANIL First draft prepared b
Page 462 and 463: 447 Table 1. Excretion profile in r
Page 464 and 465: 449 Table 3. Half-life of pyrimetha
Page 466 and 467: 451 Table 4. Identification of meta
Page 468 and 469: 453 SN 614 277. The presence of the
Page 470 and 471: 455 2. Toxicological studies 2.1 Ac
Page 472 and 473: 457 treated rabbits showed slight e
Page 474 and 475: 459 still evident in the liver; how
Page 476 and 477: 461 In a 90-day feeding study, grou
Page 478 and 479: 463 per day or 800 mg/kg bw per day
Page 480 and 481: 465 The dosing solutions were prepa
Page 482 and 483: 467 mortality and morbidity. Change
Page 484 and 485: 469 2.4 Genotoxicity Pyrimethanil w
Page 486 and 487: 471 mean body‐weight gains. After
Page 488 and 489: 473 Analysis of dosing solutions in
Page 490 and 491: 475 In a 7-day feeding study, group
Page 492 and 493: 477 at 200 mg/kg bw. These clinical
Page 494 and 495: 479 s ystemic toxicity was 400 ppm
Page 496 and 497: 481 Acute toxicity Rat, LD 50 , ora
Page 498 and 499: 483 Grosshans, F. (2003) Pyrimethan
Page 500 and 501: 485 Markham, L.P. (1989d) Technical
Page 502 and 503: ZOXAMIDE First draft prepared by I.
Page 504 and 505: 489 The excretion of radioactivity
Page 506 and 507: 491 Table 3. Mean concentration of
Page 508 and 509: 493 Table 4. Distribution of metabo
Page 512 and 513: 497 owing to the absence of a dose-
Page 514 and 515: 499 The NOAEL was 30 000 ppm, equiv
Page 516 and 517: 501 Table 9. Haematological finding
Page 518 and 519: 503 Table 11. Body weight, food con
Page 520 and 521: 505 daily for signs of moribundity,
Page 522 and 523: 507 Table 14 Results of studies of
Page 524 and 525: 509 phase. The study was certified
Page 526 and 527: 511 Table 16. Spleen weights and hi
Page 528 and 529: 513 FOB/motor activity assessment,
Page 530 and 531: 515 Excretion was primarily in the
Page 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.
Page 538 and 539: ANNEX 1 Reports and other documents
Page 540 and 541: 525 31. Pesticide residues in food:
Page 542 and 543: 527 67. Pesticide residues in food
Page 544: 529 101. Pesticide residues in food
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