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211 Table 3. Results of studies of acute toxicity with difenoconazole Species Strain Sex Route LD 50 (mg/ kg bw) LC 50 (mg/l air) Other results, clinical signs Reference Rat Mouse Sprague- Dawley Tif: MAG f (SPF) Males and females Males and females Rabbit NZW Males and females Rat Tif: RAI f (SPF) Males and females Rabbit NZW Males and females Rabbit NZW Males and females Oral 1453 — Hypoactivity, stains around the mouth, perineal staining, ataxia, lacrimation, soft faeces, hypothermia, prostration, chromodacryorrhoea, chromorhinorrhoea, spasms, salivation, unkempt appearance, rhinorrhoea, hypopnoea, or ptosis. Oral > 2000 — Piloerection, abnormal body positions, and dyspnoea, reduced locomotor activity and ataxia, tonic spasms Dermal > 2010 — Clinical observations were unremarkable for all rabbits Inhalation — 3.3 Piloerection, hunched posture, dyspnoea, and reduced locomotion. Dermal i rritation Ocular i rritation Guinea- pig Hartley Female Dermal sensitization ( modified Buehler) NZW, New Zealand White. — — Very slightly and transiently irritating — — Moderately and transiently irritating Argus et al. (1987) Hartmann (1990) Mastrocco et al. (1987a) Hartmann (1991) Glaza (1991a) Glaza (1991b) — — Non-sensitizing Mastrocco et al. (1987b) and 48 h after challenge a pplications dermal reactions were assessed and graded. Body weights were recorded at weekly intervals. Epidermal induction caused no skin reactions in any of the guinea-pigs given undiluted difenoconazole. No positive reactions were observed at the application site in any of these animals 24 and 48 h after challenge application and there were no signs of toxicity. The positive control, DNCB, produced significant skin reactions in six out of nine guinea-pigs after 24 h and in four out of nine guinea-pigs after 48 h. One guinea-pig in the positive-control group died during the induction phase (Mastrocco et al., 1987b). The Meeting concluded that difenoconazole was not sensitizing in this modified Buehler test. The results of these studies of acute toxicity are summarized in Table 3. 2.2 Short-term studies of toxicity Mice Groups of 15 male and 15 female CD-1®(ICR) mice were given diets containing difenoconazole technical (purity, 94.5%) at a concentration of 0, 20, 200, 2500, 7500 or 15 000 ppm, which, in the groups receiving the four lower dose was equal to 0, 3.3, 34.2 and 440 mg/kg bw per day in males DIFENOCONAZOLE 201–272 JMPR 2007
212 and 0, 4.6, 45.2 and 639 mg/kg bw per day in females, for 13 weeks. Because of mortalities occurring at a very early stage in this study, the intake of difenoconazole was not calculated for the two groups at the highest dose. An additional five males and five females were included in the control group. Mortality was checked twice per day, clinical signs were recorded once per day and detailed physical examinations were performed each week. Food consumption and body weight were determined once per week. Eye examinations were conducted on all mice before treatment and at the end of treatment in week 13. Haematology investigations were conducted on 10 males and 10 females per group at the end of the treatment period. Ten males and ten females per group were killed in week 13. All these mice were subjected to complete gross examinations, and weights of selected organs were determined. Autopsies were also carried out on mice that were found dead or killed in extremis. Microscopic examinations were conducted on all organs from mice in the control group and the group at the highest dose and on lung, liver, kidneys and all gross lesions from mice from all dose groups. Specified organs of mice scheduled to be killed were weighed and all specified tissues were collected, fixed and examined microscopically. The stability of difenoconazole in the diet was verified and the homogeneity of the dietary mixtures was verified before the start of the study. Dietary administration of difenoconazole at doses of 7500 and 15 000 ppm for up to 3 months resulted in very high mortality by week 3. All female mice receiving difenoconazole at 7500 or 15 000 ppm died or were found in a moribund condition and were killed on study days 3–7. Males survived a few days longer, but all males at 15 000 ppm were dead by day 11 and 13 out of 15 males at 7500 ppm were dead by day 18. The remaining two males at 7500 ppm were removed from the study by day 21. One female at 2500 ppm was also found dead during week 3. In addition, one male in the control group, one male at 20 ppm and one female at 200 ppm died on day 16. A female at 200 ppm was considered to have died accidentally after blood collection during week 13. Clinical signs in the groups at 2500 ppm or less were noted at low frequencies and there was no dose–response pattern, although polypnoea was seen in most females at 2500 ppm during the first study week. Ophthalmoscopy revealed no treatment-related findings. Unilateral diffuse retinochoroidal degeneration was seen in one male at 2500 ppm and in one female at 2500 ppm, but owing to the low incidence these findings were considered to be incidental to treatment. Body weights of the group of mice at 2500 ppm were somewhat lower than those of the mice in the control group throughout the study, but food consumption was not affected by treatment. Dark areas in the stomach were noted at necrospy in 5 out of 13 males at 7500 ppm, 14 out of 15 males at 15 000 ppm, 15 out of 15 females at 7500 ppm and 14 out of 15 females at 15 000 ppm. These findings corresponded to microscopic findings of erosion/ulceration of the glandular stomach and/or hyperkeratosis in the non-glandular stomach in most of these mice. Haematology parameters were not different among the groups. There was a statistically significant positive trend in platelet counts in males, but there was no trend in the females and no other findings that would indicate this was a meaningful effect. None of the other parameters measured were remarkable. Absolute and relative liver weights were increased in mice at 2500 ppm and relative liver weights were increased in males at 200 ppm. The only other statistically significant organ-weight changes were a 25% reduction in absolute ovary weight and a 7.7% reduction in absolute heart weight in females in the group at 2500 ppm. Liver enlargement and prominent reticular patterns were seen at an increased frequency in the group of mice at 2500 ppm. There was an increased incidence of diffuse hepatocellular enlargement in all male and female mice of this same group and some minimal centrilobular hepatocellular enlargement in males at 200 ppm. Hepatic vacuolization also occurred with greater frequency and severity in the group of mice at 2500 ppm. Since minimal centrilobular hepatocellular enlargement only occurred in males of the group at 200 ppm it probably represented a less severe manifestation of the diffuse response to difenoconazole at higher doses seen in this organ. This can be considered to be an adaptive change at this dose (Cox, 1987a). 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
Page 176 and 177: 161 sensitivity with that of labora
Page 178 and 179: 163 measures to prevent worker expo
Page 180 and 181: 165 when brain cholinesterase activ
Page 182 and 183: 167 Critical end-points for setting
Page 184 and 185: 169 Eiben, R., Schmidt, W., & Loese
Page 186 and 187: 171 Myhr, B.C. (1983) Evaluation of
Page 188 and 189: LAMBDA-CYHALOTHRIN First draft prep
Page 190 and 191: 175 Figure 1. Chemical structures o
Page 192 and 193: 177 In a comparative study, the abs
Page 194 and 195: 179 Figure 2. Main pathways of biot
Page 196 and 197: 181 (iv) Dermal sensitization In a
Page 198 and 199: 183 observed in rats at the highest
Page 200 and 201: 185 Mortality was not affected by t
Page 202 and 203: 187 the group at 100 ppm, reduction
Page 204 and 205: 189 and five females per group were
Page 206 and 207: 191 10-12%) than those of controls
Page 208 and 209: 193 Comments Biochemical aspects Or
Page 210 and 211: 195 Toxicological evaluation Althou
Page 212 and 213: 197 Metabolism in animals Toxicolog
Page 214 and 215: 199 Harrison, M.P. (1984a) Cyhaloth
Page 216 and 217: 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 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 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
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261 the radioactivity was re-elimin
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263 In a single-dose study of neuro
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265 Estimate of acceptable daily in
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267 Clapp, M.J.L., Killick, M.E., H
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269 Herbold, B. (1983c) THS 2212 tr
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271 Pinto, P. (2006b) Difenoconazol
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DIMETHOMORPH First draft prepared b
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275 Five different treatment groups
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277 To investigate the significance
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279 and the E : Z isomer ratio was
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281 Table 10. Tissue distribution o
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283 (e) Dermal sensitization The de
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285 females at the highest dose, to
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287 The NOAEL was 10 mg/kg bw per d
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289 concentrations in females were
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291 health, moribundity and mortali
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293 0-9%, mean, 3.5%; only one out
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Table 26. Organ weights adjusted to
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297 cell hyperplasia. The testes tu
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299 unscheduled DNA synthesis, the
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301 Figure 3. Cumulative percentage
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303 Rabbits In a dose-range finding
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305 (b) Potentiation of hexobarbito
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307 0.2% or less of the administere
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309 eye-opening, pinna unfolding or
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311 Lowest relevant inhalation NOAE
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313 Gardner, J.R. (1989) CME 151 te
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315 van de Waart, E.J. (1991b) Eval
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318 Committee on Pesticide residues
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320 (a) Ocular irritation Rabbits T
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322 weights were decreased in males
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324 toxicity was 5 mg/kg bw per day
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326 respectively; range for histori
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328 Table 4. Incidence of Leydig-ce
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330 and/or bilateral) was noted in
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332 No treatment-related signs of m
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334 Table 6. Incidence of selected
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336 or teratogenic potential at the
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338 and progesterone. The concentra
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340 the doses used in the 1-year st
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342 No neurotoxic effects were seen
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344 Lowest relevant reproductive NO
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346 Keller, D.A. (1992c) Oncogenici
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PROCYMIDONE First draft prepared by
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351 Rats Groups of five male and fe
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353 Table 1. Pharmacokinetic parame
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355 Seven doses C max (µg equivale
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357 Three groups of five male and f
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359 The excretion of radioactivity
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361 Figure 1. Proposed metabolic pa
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363 water consumption were determin
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365 finding. Histopathology reveale
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367 The NOAEL was 500 ppm, equivale
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369 The NOAEL was 100 mg/kg bw per
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371 at 2000 ppm. Histopathology rev
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373 b Each test was conducted in tr
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375 experimental period. Rats were
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377 hypospadias, testicular atrophy
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379 a single dose, which produced o
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381 The anti-androgenic activities
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383 but only at 6000 ppm after 13 w
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385 The results are summarized in T
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387 males (all litters) in the grou
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389 procymidone (18-27% of the admi
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391 Procymidone induced liver tumou
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393 The Meeting concluded that the
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395 Toxicologically significant com
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397 Harada, T. (1983) A review on m
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399 Murakami, M., Yoshitake, A. & H
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401 Tarui, H. (2005b) In vitro meta
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404 Explanation Profenofos is the I
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406 The metabolism of ring-labelled
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408 2. Toxicological studies 2.1 Ac
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410 Rabbits Groups of two male and
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412 Groups of five male and five fe
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414 control group and in the test g
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416 of the rabbits at the highest d
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418 The NOAEL for brain acetylcholi
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420 Table 2. Histopathological find
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422 1 out of 70; lowest dose, 3 out
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424 body‐weight gains (3-10% decr
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426 treated groups for body-weight
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428 (b) Short-term studies of neuro
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430 represented as equally as possi
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432 pound and the equitoxic mixture
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434 Inhibition of brain acetylcholi
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436 Toxicological evaluation Erythr
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438 Neurotoxicity/delayed neurotoxi
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440 Harris, S.B. (1982) A teratolog
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442 Puri, E. (1982a) Autoradiograph
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PYRIMETHANIL First draft prepared b
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447 Table 1. Excretion profile in r
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449 Table 3. Half-life of pyrimetha
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451 Table 4. Identification of meta
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453 SN 614 277. The presence of the
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455 2. Toxicological studies 2.1 Ac
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457 treated rabbits showed slight e
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459 still evident in the liver; how
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461 In a 90-day feeding study, grou
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463 per day or 800 mg/kg bw per day
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465 The dosing solutions were prepa
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467 mortality and morbidity. Change
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469 2.4 Genotoxicity Pyrimethanil w
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471 mean body‐weight gains. After
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473 Analysis of dosing solutions in
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475 In a 7-day feeding study, group
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477 at 200 mg/kg bw. These clinical
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479 s ystemic toxicity was 400 ppm
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481 Acute toxicity Rat, LD 50 , ora
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483 Grosshans, F. (2003) Pyrimethan
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485 Markham, L.P. (1989d) Technical
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ZOXAMIDE First draft prepared by I.
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489 The excretion of radioactivity
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491 Table 3. Mean concentration of
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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,
Page 522 and 523:
507 Table 14 Results of studies of
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509 phase. The study was certified
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511 Table 16. Spleen weights and hi
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513 FOB/motor activity assessment,
Page 530 and 531:
515 Excretion was primarily in the
Page 532 and 533:
517 days 14 to 21. Increased relati
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519 Lowest relevant inhalation NOAE
Page 536 and 537:
521 Morrison, R.D. & Gillette, D.M.
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ANNEX 1 Reports and other documents
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525 31. Pesticide residues in food:
Page 542 and 543:
527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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