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167 Critical end-points for setting guidance values of exposure for azinphos-methyl Absorption, distribution, excretion and metabolism in mammals Rate and extent of oral absorption Almost complete absorption. Maximum plasma concentration 2–3 h after dosing. Dermal absorption See previous azinphos-methyl monographs Distribution Extensive Potential for accumulation Low, no evidence of accumulation Rate and extent of excretion Largely complete within 48 h; approximately 95% excreted in urine and bile. Metabolism in animals Extensive; two major urinary metabolites and six other products. Five faecal metabolites (10–12% of the administered dose). Toxicologically significant compounds in animals, Azinphos methyl,azinphos-methyl oxon plants and the environment Acute toxicity Rat, LD 50 , oral Rat, LD 50 , dermal Rat, LC 50 , inhalation Skin sensitization (test method used) Short-term studies of toxicity Target/critical effect Lowest relevant oral NOAEL Lowest relevant dermal NOAEL Lowest relevant inhalation NOAEC Genotoxicity Long-term studies of toxicity and carcinogenicity Target/critical effect Lowest relevant NOAEL Carcinogenicity Reproductive toxicity Reproduction target/critical effect Lowest relevant reproductive NOAEL Developmental target/critical effect Lowest relevant developmental NOAEL Neurotoxicity/delayed neurotoxicity NOAEL: 1 mg/kg bw in a repeat-dose study of neurotoxicity in rats Medical data 4.4–26 mg/kg bw See previous azinphos-methyl monographs See previous azinphos-methyl monographs See previous azinphos-methyl monographs Inhibition of brain cholinesterase activity 0.7 mg/kg bw per day (dog) See previous azinphos-methyl monographs See previous azinphos-methyl monographs Unlikely to pose a genotoxic risk in vivo Inhibition of brain cholinesterase activity 0.9 mg/kg bw per day (rat) Not carcinogenic in rats and mice Inhibition of brain cholinesterase activity in dams 0.5 mg/kg bw per day (rats) Delayed ossification at maternally toxic doses (rats, rabbits) 1.0 mg/kg bw per day (rats); 2.5 mg/kg bw per day (rabbits) No evidence of delayed neuropathy observed in hens Medical examinations of workers involved in formulating azinphos-methyl products revealed no effects, except for one case of possible dermatosis resulting in sensitive dry skin. AZINPHOS-METHYL 139–172 JMPR 2007
168 Summary Value Study Safety factor ADI 0–0.03 mg/kg bw per day Humans, 30-day oral-dosing study 10 ARfD 0.1 mg/kg bw Humans, study of acute toxicity 10 References Alam, M.T., Corbeil, M., Chagnon, A., & Kasatiya, S.S. (1974). Chromosomal anomalies induced by the o rganic phosphate pesticide guthion in Chinese hamster cells. Chromosoma (Berl.), 49, 77–86. Allen, T.R., Frei, T., Janiak, T., Luetkemeier, H., Vogel, O., Biedermann, K., & Wilson, J. (1990) 52-week oral toxicity (feeding) study with azinphos-methyl in the dog. Unpublished report from Research and C onsulting Company AG. Submitted to WHO by Bayer AG, Leverkusen, Germany. Arnold, D. (1971) Mutagenic study with Guthion in albino mice. Unpublished report No. E8921 from Industrial Bio-Test Laboratories Inc., Northbrook, IL, USA. Submitted to WHO by Chemagro Corp., Kansas City, MO, USA. Astroff, A.B. &Young, A.D. (1998) The relationship between maternal and fetal effects following maternal organophosphate exposure during gestation in the rat. Toxicol. Ind. Health, 14, 869–889. Broadmeadow, A. (1987) Cotnion technical: Toxicity study by oral (gavage) administration to CD rats for 13 weeks. Unpublished Report no. 86/MAK057/342 from Life Sciences Research Ltd., Eye, Suffolk, E ngland. Submitted to WHO by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel. Chen, H.H., Sirianni, S.R., & Huang, C.C. (1982a) Sister chromatid exchanges and cell cycle delay in Chinese hamster V79 cells treated with 9 organophosphorus compounds (8 pesticides and 1 defoliant). Mutat. Res., 103, 307–313. Chen, H.H., Sirianni, S.R., & Huang, C.C. (1982b) Sister chromatid exchanges in Chinese hamster cells treated with seventeen organophosphorus compounds in the presence of a metabolic activation system. Environ. Mutagen., 4, 621–624. Clemens, G.R., Bare, J.J., & Hartnagel, R.E. (1988) A teratology study in the rabbit with azinphos-methyl. Unpublished report from Miles Inc., Toxicology Department, Elkhart, IN, USA. Submitted to WHO by Bayer AG, Leverkusen, Germany. Crawford, C.R. & Anderson, R.H. (1974) The acute oral toxicity of ®GUTHION technical, benzazimide and methyl benzazimide to rats. Unpublished report from Chemagro. Submitted to WHO by Bayer AG, L everkusen, Germany. Crown, S. & Nyska, A. (1987) Cotnion-M. Acute oral toxicity study in the rat. Unpublished report No. MAK/116/ AZM from Life Science Research Israel Ltd, Ness Ziona, Israel. Submitted to WHO by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel. DuBois, K.P., Thursh, D.R. & Murphy, S.D. (1955) The acute mammalian toxicity and mechanism of action of Bayer 17147. Unpublished report from Department of Pharmacology, University of Chicago, Chicago, Illinois, USA. Submitted to WHO by Bayer AG, Leverkusen, Germany. DuBois, K.P., Thursh, D.R. & Murphy, S.D. (1957) Studies on the toxicity and pharmacologic actions of the dimethoxy ester of benzotriazine dithiophosphoric acid (DBD, Guthion). J. Pharmacol. Exp. Ther., 119, 208–218. Eiben, R. & Janda, B. (1987) R1582 (common name: azinphos-methyl, the active ingredient of Guthion): Twogeneration study on rats. Unpublished study No. T 6006415 from the Institute of Toxicology, Industrial Chemicals, Fachbereich Toxikologie, Bayer AG, Wuppertal, Germany. Submitted to WHO by Bayer AG, Leverkusen, Germany. AZINPHOS-METHYL 139–172 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
Page 132 and 133: 117 Developmental target/critical e
Page 134 and 135: 119 • The failure to ovulate resu
Page 136 and 137: 121 The relationship between increa
Page 138 and 139: 123 Table A2. Comparison of paramet
Page 140 and 141: 125 Ballantine, L., Murphy, T. G. &
Page 142 and 143: 127 Dunkelberg, H., Fuchs, J., Heng
Page 144 and 145: 129 Heneweer, M., van den Berg, M.
Page 146 and 147: 131 Lindsay, L.A., Wimbert, K.V., G
Page 148 and 149: 133 Morseth, S.L. (1996d) Chronic (
Page 150 and 151: 135 Rudzki, M.W., Batastina, G., &
Page 152 and 153: 137 Tennant, A.H., Peng, B. & Klige
Page 154 and 155: AZINPHOS-METHYL First draft prepare
Page 156 and 157: 141 methylation and oxidation of me
Page 158 and 159: 143 Table 1. Acute oral toxicity of
Page 160 and 161: 145 Table 2. Cholinesterase activit
Page 162 and 163: 147 at the highest dose. In both sp
Page 164 and 165: 149 Table 6. Cholinesterase activit
Page 166 and 167: 151 Table 8. Fertility of F 0 and F
Page 168 and 169: 153 Table 10. Fertility parameters
Page 170 and 171: 155 Groups of 22 mated Sprague-Dawl
Page 172 and 173: 157 after completion of the feeding
Page 174 and 175: 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 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 226 and 227: 211 Table 3. Results of studies of
Page 228 and 229: 213 The no-observed-adverse-effect
Page 230 and 231: 215 lower than those of rats in the
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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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247 Table 16. Results of studies of
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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
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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
Page 498 and 499:
483 Grosshans, F. (2003) Pyrimethan
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485 Markham, L.P. (1989d) Technical
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ZOXAMIDE First draft prepared by I.
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489 The excretion of radioactivity
Page 506 and 507:
491 Table 3. Mean concentration of
Page 508 and 509:
493 Table 4. Distribution of metabo
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495 were also found in the urine, a
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497 owing to the absence of a dose-
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499 The NOAEL was 30 000 ppm, equiv
Page 516 and 517:
501 Table 9. Haematological finding
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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
Page 524 and 525:
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
Page 534 and 535:
519 Lowest relevant inhalation NOAE
Page 536 and 537:
521 Morrison, R.D. & Gillette, D.M.
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ANNEX 1 Reports and other documents
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525 31. Pesticide residues in food:
Page 542 and 543:
527 67. Pesticide residues in food
Page 544:
529 101. Pesticide residues in food
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