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PYRIMETHANIL First draft prepared by P.V. Shah and Vicki Dellarco United States Environmental Protection Agency, Office of Pesticide Programs, Washington, DC, USA Explanation ...................................................................................................... 445 Evaluation for acceptable daily intake ............................................................. 446 1. Biochemical aspects: absorption, distribution, and excretion ........... 446 2. Toxicological studies ......................................................................... 455 2.1 Acute toxicity ............................................................................. 455 (a) Oral administration ............................................................. 455 (b) Dermal irritation ................................................................. 456 (c) Ocular irritation .................................................................. 456 (d) Dermal sensitization ........................................................... 456 2.2 Short-term studies of toxicity ..................................................... 457 2.3 Long-term studies of toxicity and carcinogenicity ..................... 465 2.4 Genotoxicity ............................................................................... 469 2.5 Reproductive toxicity ................................................................. 470 (a) Multigeneration studies ...................................................... 470 (b) Developmental toxicity ....................................................... 471 2.6 Special studies ............................................................................ 473 (a) Acute neurotoxicity ............................................................. 473 (b) Short-term studies of neurotoxicity .................................... 474 3. Studies with metabolites .................................................................... 476 Comments ........................................................................................................ 477 Toxicological evaluation .................................................................................. 479 References ....................................................................................................... 481 Explanation Pyrimethanil is the approved International Organization for Standards (ISO) name for N- (4,6-dimethylpyrimidin-2-yl)aniline (International Union of Pure and Applied Chemistry, IUPAC), also known as 4,6-dimethyl-N-phenyl-2-pyrimidinamine (Chemical Abstracts Service, CAS No. 53112-28-0). Pyrimethanil is an anilinopyrimidine fungicide that inhibits the secretion of fungal enzymes. It is a fungicide that is intended for the control of Botrytis cinerea on grapes and s trawberries. Pyrimethanil has not been evaluated previously by JMPR and was evaluated by the present Meeting at the request of the Thirty-ninth Session of the Codex Committee on Pesticide Residues (CCPR). All pivotal studies with pyrimethanil were certified as complying with good laboratory practice (GLP). PYRIMETHANIL 445–486 JMPR 2007
446 Evaluation for acceptable daily intake Unless otherwise stated, studies evaluated in this monograph were performed by GLP-certified laboratories and complied with the relevant Organisation for Economic Co-operation and D evelopment (OECD) and/or United States Environment Protection Agency (EPA) test guideline(s). 1. Biochemical aspects: absorption, distribution, and excretion Rats The absorption, distribution, and elimination of pyrimethanil was studied after oral dosing with pyrimethanil radiolabelled with 14 C as shown in Figure 1. In a toxicokinetic study, groups of five male and five female Crl:CD(SD)BR rats were given [U-phenyl ring 14 C]pyrimethanil (purity, 98.1–98.4%) as a single oral dose at 11.8 or 800 mg/kg bw by gavage in an aqueous solution of 1% (w/v) gum tragacanth. Treated rats were housed in Radley all-glass metabolism cages for 96 h. Urine and faeces were collected at 24, 48, 72 and 96 h after dosing. Cages were washed at 24 h and 96 h after dosing. At 96 h, various organs and tissues were removed and blood was sampled and all were analysed for radioactivity. Tissues were either combusted or solubilized. All samples were analysed for radioactivity by liquid scintillation counting (LSC). Pyrimethanil was rapidly excreted in both groups, with more than 95% of the lower dose and 63–67% of the higher dose being excreted in the first 24 h (Table 1). The major route of excretion was in the urine that, together with the cage wash, accounted for about 80% of the administered dose in both groups, indicating at least 80% of the orally administered dose was absorbed in 96 h. There were no sex-related differences in the route or rate of elimination in the two dosed groups. At the lower dose, most of the tissues examined had radioactive residues that were below the limit of detection at 96 h, except the carcass and the liver (0.082–0.223 mg pyrimethanil equivalent/ kg). At the higher dose, the highest residues were found in the liver (10.33–11.27 mg pyrimethanil equivalent/kg) and kidneys (8.845–8.566 mg pyrimethanil equivalent/kg). The concentrations of residue in the bone, brain, eyes, muscle, pituitary, plasma, renal fat and gonads were less than 1 mg pyrimethanil equivalent/kg. There were no significant differences between the residue concentrations seen in the tissues of male and female rats. There were no significant sex-related differences in the rate, route or tissue distribution were observed in male and female rats (Needham & Hemmings, 1991). In a kinetic study in plasma, two groups of 24 male Crl:CD(SD)BR rats were dosed orally with an aqueous suspension of [U-phenyl ring 14 C]pyrimethanil (purity, 100%)at a nominal dose of 10 or 1000 mg/kg bw by gavage. The actual achieved doses were 9.99 and 748 mg/kg bw for the lower and higher dose, respectively. Groups of three rats were killed at 20 min, 1 h, 1.5 h, 3 h, 5 h, 7 h, 12 h and Figure 1. Position of the pyrimethanil radiolabel used in pharmacokinetic studies in rats * Position of radiolabel. PYRIMETHANIL 445–486 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
Page 408 and 409: 393 The Meeting concluded that the
Page 410 and 411: 395 Toxicologically significant com
Page 412 and 413: 397 Harada, T. (1983) A review on m
Page 414 and 415: 399 Murakami, M., Yoshitake, A. & H
Page 416: 401 Tarui, H. (2005b) In vitro meta
Page 419 and 420: 404 Explanation Profenofos is the I
Page 421 and 422: 406 The metabolism of ring-labelled
Page 423 and 424: 408 2. Toxicological studies 2.1 Ac
Page 425 and 426: 410 Rabbits Groups of two male and
Page 427 and 428: 412 Groups of five male and five fe
Page 429 and 430: 414 control group and in the test g
Page 431 and 432: 416 of the rabbits at the highest d
Page 433 and 434: 418 The NOAEL for brain acetylcholi
Page 435 and 436: 420 Table 2. Histopathological find
Page 437 and 438: 422 1 out of 70; lowest dose, 3 out
Page 439 and 440: 424 body‐weight gains (3-10% decr
Page 441 and 442: 426 treated groups for body-weight
Page 443 and 444: 428 (b) Short-term studies of neuro
Page 445 and 446: 430 represented as equally as possi
Page 447 and 448: 432 pound and the equitoxic mixture
Page 449 and 450: 434 Inhibition of brain acetylcholi
Page 451 and 452: 436 Toxicological evaluation Erythr
Page 453 and 454: 438 Neurotoxicity/delayed neurotoxi
Page 455 and 456: 440 Harris, S.B. (1982) A teratolog
Page 457 and 458: 442 Puri, E. (1982a) Autoradiograph
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
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495 were also found in the urine, a
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497 owing to the absence of a dose-
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499 The NOAEL was 30 000 ppm, equiv
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501 Table 9. Haematological finding
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503 Table 11. Body weight, food con
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505 daily for signs of moribundity,
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507 Table 14 Results of studies of
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509 phase. The study was certified
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511 Table 16. Spleen weights and hi
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513 FOB/motor activity assessment,
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515 Excretion was primarily in the
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517 days 14 to 21. Increased relati
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519 Lowest relevant inhalation NOAE
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521 Morrison, R.D. & Gillette, D.M.
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ANNEX 1 Reports and other documents
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525 31. Pesticide residues in food:
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527 67. Pesticide residues in food
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529 101. Pesticide residues in food
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