Pesticide residues in food â 2007: Toxicological ... - ipcs inchem

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117 Developmental target/critical effect Lowest relevant developmental NOAEL Neurotoxicity Other toxicological studies Studies on metabolites Mode of neuroendocrine action Mode of carcinogenic action Direct estrogenic activity Aromatase expression Effects on sexual development Effects on neuronal development Immunotoxicity Medical data Summary Atrazine Increased resorptions and incomplete ossification at maternally toxic doses; delayed sexual development 6.25 mg/kg bw per day (rat; male pubertal development) 5 mg/kg bw per day (rabbit) No evidence of neurotoxicity in standard tests for toxicity; however, neuroendocrine mode of action has been established for atrazine and its chloro-s-triazine metabolites DEA, DIA, DACT have the same neuroendocrine mode of action and similar potency to atrazine Hydoxyatrazine has a different mode of action and toxicity profile to atrazine Atrazine and its chlorometabolites modify hypothalamic catecholamine function and regulation, leading to alterations in pituitary LH and prolactin secretion The postulated mode of carcinogenic action in female Sprague-Dawley rats involves acceleration of the reproductive ageing process (suppression of LH surge, subsequent estrous cycle disruption), which is not relevant to humans Atrazine has no intrinsic estrogenic activity No effect on aromatase expression in rats Evidence of delayed sexual development in male and/or female rats by atrazine, DEA, DIA and DACT Evidence of impaired postnatal CNS development (and subsequent alterations in prolactin regulation) Evidence for immune system modulation at doses greater than LOAELs for neuroendocrine disruption or reproductive and developmental effects No evidence of atrazine causing effects in manufacturing plant personnel. Epidemiology studies do not support a causal association between exposure to atrazine and cancer in humans. Value Study Safety factor Group ADI a 0–0.02 mg/kg bw Sprague-Dawley rats; 6-month study of LH surge/estrous cycle disruption Group ARfD a 0.1 mg/kg bw Rat; special 4-day study of prolactin release, supported by studies of developmental toxicity in rats and rabbits Hydroxyatrazine ADI 0–0.04 mg/kg bw Sprague-Dawley rats; 2-year study 25 ARfD Unnecessary — — a Group ADI or ARfD for atrazine, deethyl-atrazine (DEA), deisopropyl-atrazine (DIA) and diaminochlorotriazine (DACT). CNS, central nervous sytem; GnRH, gonadotrophin-releasing hormone; LH, luteinizing hormone. 100 100 ATRAZINE 37–138 JMPR 2007
118 Appendix 1 Application of the IPCS Conceptual Framework for Cancer Risk Assessment (IPCS Framework for Analysing the Relevance of a Cancer Mode of Action for Humans): consideration of mammary gland tumours in female Sprague-Dawley rats exposed to atrazine This framework, developed by an International Programme on Chemical safety (IPCS) working group, provides a generic approach to the principles commonly used in evaluating a postulated mode of action (MOA) for tumour induction by a chemical (Boobis et al., 2006). The framework was used by the 2007 JMPR to provide a structured approach to the assessment of the overall weightof-evidence for the postulated MOA for the increased incidence of mammary tumours (adenomas, carcinomas, fibroadenomas) in rats that was observed after long-term administration of atrazine. The first stage of the framework is to determine whether it is possible to establish an MOA. This process comprises a series of key events along the causal pathway to cancer, identified using a weight-of-evidence approach on the basis of the Bradford-Hill criteria. The key events are then compared first qualitatively and then quantitatively between the experimental animals and humans. Finally, a statement of confidence, analysis, and implications is provided. Mammary gland tumours associated with atrazine exposure in female Sprague-Dawley rats I. Is the weight of evidence sufficient to establish an MOA in animals? 1. Introduction In seven studies of carcinogenicity in Sprague-Dawley rats fed diets containing atrazine at concentrations of up to 1000 ppm (equal to about 42 and 65 mg/kg bw per day in males and females, respectively), an increased incidence and/or an earlier appearance of spontaneously occurring mammary tumours (adenomas, carcinomas, fibroadenomas) was observed in four studies, while in two studies, there was an earlier appearance of mammary tumours, without any increase in their overall lifetime incidence (see monograph section 2.3). 2. Postulated MOA (theory of the case) The postulated MOA for mammary tumours induced by atrazine in female Sprague-Dawley rats involves disruption of the hypothalamic–pituitary–ovary axis. Atrazine modifies catecholamine function and the regulation of gonadotropin-releasing hormone (GnRH) pulsatility in the rat hypothalamus, with the consequence that the pulse of luteinizing hormone (LH) released from the pituitary gland is of insufficient amplitude or duration to trigger the ovulation. The failure to ovulate results in persistent secretion of estrogen, which provides a feedback to the pituitary leading to increased secretion of prolactin. The persistent stimulation of the mammary gland by estrogen and prolactin translates into a proliferative response characterized by an earlier appearance and/or a higher incidence of adenocarcinomas (high estrogen, moderate prolactin levels) or fibroadenomas (high prolactin with a background of estrogen) (McConnell, 1989; O’Connor et al., 2000; Simpkins, 2000; Simpkins et al., 2000; Cooper et al., 2007). 3. Key events The sequence of key events in the mode of carcinogenic action of atrazine in the mammary gland of female Sprague-Dawley rats includes: • Effect on the hypothalamus, leading to a modification of catecholamine function and the regulation of GnRH pulsatility; • In consequence, the pulse of LH released from the pituitary gland is of insufficient amplitude or duration to trigger the ovulation; ATRAZINE 37–138 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
Page 82 and 83: 67 End-point Test object Concentrat
Page 84 and 85: 69 Table 12. Relevant findings in a
Page 88 and 89: 73 respectively) and in males at th
Page 92 and 93: 77 All dams survived until the end
Page 94 and 95: 79 250 and 500 ppm. Body-weight gai
Page 96 and 97: 81 In an assay for reverse mutation
Page 98 and 99: 83 on pubertal development in femal
Page 100 and 101: 85 parameters (decreased pH, specif
Page 104 and 105: 89 0, 75, 150 or 300 mg/kg bw per d
Page 106 and 107: 91 The NOAEL was 25 ppm, equal to 1
Page 108 and 109: 93 In a study on the effect of atra
Page 110 and 111: 95 Delayed parturition was seen at
Page 112 and 113: 97 observed in the pair-fed group.
Page 114 and 115: 99 examined, offspring in the atraz
Page 116 and 117: 101 antagonize E2-induced luciferas
Page 118 and 119: 103 increase in steroidogenesis is
Page 120 and 121: 105 The immune system of adult mice
Page 122 and 123: 107 In a later review of cancer epi
Page 124 and 125: 109 In a 25-day study in rabbits tr
Page 126 and 127: 111 developmental toxicity were 10
Page 128 and 129: 113 regulation in male offspring in
Page 130 and 131: 115 (d) Diaminochlorotriazine (DACT
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
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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
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PYRIMETHANIL First draft prepared b
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447 Table 1. Excretion profile in r
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449 Table 3. Half-life of pyrimetha
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451 Table 4. Identification of meta
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453 SN 614 277. The presence of the
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455 2. Toxicological studies 2.1 Ac
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457 treated rabbits showed slight e
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459 still evident in the liver; how
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461 In a 90-day feeding study, grou
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463 per day or 800 mg/kg bw per day
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465 The dosing solutions were prepa
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467 mortality and morbidity. Change
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469 2.4 Genotoxicity Pyrimethanil w
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471 mean body‐weight gains. After
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473 Analysis of dosing solutions in
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475 In a 7-day feeding study, group
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477 at 200 mg/kg bw. These clinical
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479 s ystemic toxicity was 400 ppm
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481 Acute toxicity Rat, LD 50 , ora
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483 Grosshans, F. (2003) Pyrimethan
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485 Markham, L.P. (1989d) Technical
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ZOXAMIDE First draft prepared by I.
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489 The excretion of radioactivity
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491 Table 3. Mean concentration of
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493 Table 4. Distribution of metabo
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495 were also found in the urine, a
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497 owing to the absence of a dose-
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499 The NOAEL was 30 000 ppm, equiv
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501 Table 9. Haematological finding
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503 Table 11. Body weight, food con
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505 daily for signs of moribundity,
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507 Table 14 Results of studies of
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509 phase. The study was certified
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511 Table 16. Spleen weights and hi
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513 FOB/motor activity assessment,
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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
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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