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145 Estimate of acute reference dose 0.04 mg/kg bw Information that would be useful for the continued evaluation of the compound Results from epidemiological, occupational health and other such observational studies of human exposures Critical end-points for setting guidance values for exposure to cyfluthrin or beta-cyfluthrin Absorption, distribution, excretion and metabolism in animals Rate and extent of absorption Rapid and extensive (rats) Distribution Highest concentrations in liver, kidney, adrenals, spleen (rats) Potential for accumulation Low Rate and extent of excretion Rapid (75–91% in urine within 24 h in rats) Metabolism in animals Major metabolites: 3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropane carboxylic acid (DCVA), 3-phenoxy-4- fluorobenzoic acid, 4´-hydroxy-3-phenoxy-4-fluorobenzoic acid (rats) Toxicologically significant compounds (plants, Cyfluthrin, beta-cyfluthrin animals and the environment) Acute toxicity Rat, LD 50 , oral Rat, LD 50 , dermal Rat, LC 50 , inhalation Rabbit, skin irritation Rabbit, eye irritation Guinea-pig, skin sensitization Short-term studies of toxicity Target/critical effect Lowest relevant oral NOAEL Lowest relevant dermal NOAEL Lowest relevant inhalatory NOAEC Long-term studies of toxicity and carcinogenicity Target/critical effect Lowest relevant NOAEL Carcinogenicity Genotoxicity Reproductive toxicity Reproduction target/critical effect Lowest relevant reproductive NOAEL 11 to > 1000 mg/kg bw > 5000 mg/kg bw 0.081 to > 1.0 mg/l of air Not an irritant Slightly irritating Not sensitizing (maximization test) Reduced body weight, clinical signs (rats, dogs) 1 mg/kg bw per day (beta-cyfluthrin, rats) 60 ppm, equal to 1.3 mg/kg bw per day (beta-cyfluthrin, dogs) 340 mg/kg bw per day (cyfluthrin, rats) 0.09 μg/l (cyfluthrin, rats) Reduced body weight (rats) 150 ppm, equal to 6.2 mg/kg bw per day (cyfluthrin, rats) Not carcinogenic (mice, rats) Not genotoxic in vitro or in vivo No reproductive effects (rats) 450 ppm, equal to 34.7 mg/kg bw per day, i.e. highest dose tested (cyfluthrin, rats) CYFLUTHRIN AND BETA-CYFLUTHRIN X-X JMPR 2006
146 Developmental target Lowest relevant developmental NOAEL Neurotoxicity/delayed neurotoxicity Neurotoxicity Lowest relevant oral NOAEL Other toxicological studies Medical data delayed ossification (rats); increased post-implantation loss (rabbits) 9.4 mg/kg bw per day (beta-cyfluthrin, rats) Behavioural effects (increased motility, grooming and digging movements) 1 mg/kg bw (single and repeated dose by gavage, beta-cyfluthrin and cyfluthrin, rats) No data Topical skin effect, characterized by a stinging sensation in the affected areas in laboratory workers. Areas most commonly affected were the face, and mucosal tissues. Summary for cyfluthrin and beta-cyfluthrin Value Study Safety factor Group ADI Group ARfD 0–0.04 mg/kg bw 0.04 mg/kg bw Based on the ARfD Rat, acute neurotoxicity, beta-cyfluthrin 25 25 References Andrews, P. (1999) Cyfluthrin (c.n.: cyfluthrin) – special study for acute oral toxicity in rats (slip angle test). Unpublished report No. 29371 from Bayer AG, Wuppertal, Germany. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Astroff, A.B. (1996) A developmental toxicity study with FCR 4545 technical in the Wistar rat. Unpublished report No. BC7989 from Bayer Corporation, Stilwell, KS, USA. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Becker, H. (1983). Embryotoxicity (including teratogenicity) study with FCR 1272 in the rat. Unpublished report No. R2773 from Research and Consulting Company, AG, Itingen, Switzerland. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Becker, H. & Biedermann, K. (1992) Embryotocity study (including teratogenicity) with FCR 1272 in the rabbit. Unpublished report No. 5770 from the Bayer Institute of Toxicology. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Bomann, W. (1991) FCR 1272 – study for acute oral toxicity in rats. Unpublished report No. 19852 from Bayer AG, Wuppertal, Germany. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Brusick, D.J. (1982a) Mutagenicity evaluation of FCR 1272 in the reverse mutation induction assay with Saccharomyces cerevisiae strains S138 and S211, final report. Unpublished report No. 2200 from Bayer Institute of Toxicology. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Brusick, D.J. (1982b) Evaluation of FCR 1272 in the reverse mutation induction assay with Saccharomyces cerevisiae strains S138 and S211, addendum to the final report. Unpublished report No. 2248 from Bayer Institute of Toxicology. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. Brusick, D.J. (1982c) Evaluation of FCR 1272 in the induced mitotic crossing over, reverse mutation and gene conversion assay in Saccharomyces cerevisiae strain D7. Addendum to final report. Unpublished report No. 2249 from Bayer Institute of Toxicology. Submitted to WHO by Bayer CropScience AG, Monheim, Germany. CYFLUTHRIN AND BETA-CYFLUTHRIN X-X JMPR 2006
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Pesticide residues in food — 2006
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TABLE OF CONTENTS Page List of part
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Dr Helen Hakansson, Institute of En
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Abbreviations used ADI ALT APDM ARf
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Introduction The toxicological mono
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BIFENAZATE First draft prepared by
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5 In a series of experiments, group
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7 In a study of the time-course of
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9 the administered dose in males an
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11 limited absorption of parent com
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13 NAME/No. STRUCTURE D1989 OCH 3 D
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15 2.1 Acute toxicity Results of st
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17 (f) Sensitization In a study of
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19 Table 9. Clinical chemistry effe
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21 The degree of this finding was m
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23 On histopathological examination
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25 (equal to 0, 0.9, 10.4 or 25 mg/
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27 Haemoglobin (g/dl): Before treat
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29 weekly. Blood and urine samples
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31 (females) (equal to 0, 1.0, 3.9,
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33 Cytogenetic test Chinese hamster
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35 groups of 30 males and 30 female
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37 and placed in 10% ammonium sulfi
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39 was > 5000 mg/kg bw. The LC 50 i
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41 Multigeneration study of reprodu
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43 Medical data No significant adve
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45 Trutter, J.A. (1997a) 28-Day die
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48 Evaluation for acceptable daily
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50 Table 2. Radioactivity in blood
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52 10 10 0.42 0.0462 0.63 0.0080 8.
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54 Figure 2. Transfer of radioactiv
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56 Skin 33.07 61.59 0.5 17.94 17.29
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58 Table 10. Summary of metabolites
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60 Table 14. Summary of identified
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62 Table 18. Summary of metabolites
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64 Table 19. Structures of identifi
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66 Metabolite Structure O M510F14 N
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68 Metabolite Structure M510F39 N O
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70 2. Toxicological studies 2.1 Acu
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72 1% Tylose CB 30.000. The injecti
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74 the end of dosing. Blood samples
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76 examinations were carried out 8
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78 concentrations were increased at
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80 times were slightly, but signifi
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82 in males and females rats at 250
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84 End-point Test object Dose a (LE
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86 parental rats was not markedly a
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88 groups in conception frequencies
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90 0.7 ± 3.5%, 1.8 ± 4.2%, 2.9 ±
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92 In this study of developmental n
Page 107 and 108: 94 3. Observations in humans In the
Page 109 and 110: 96 was 100 ppm, equal to 10 mg/kg b
Page 111 and 112: 98 Acute toxicity Rat, LD 50 , oral
Page 113 and 114: 100 Mellert, W., Kaufmann, W. & Hil
Page 116 and 117: CYFLUTHRIN AND BETA-CYFLUTHRIN Firs
Page 118 and 119: 105 Table 1. Diastereoisomer pairs
Page 120 and 121: 107 (i) In vivo Rats Four groups of
Page 122 and 123: 109 2. Toxicological studies 2.1 Ac
Page 124 and 125: 111 Species Strain Sex Route Formul
Page 126 and 127: 113 Rat Groups of 20 male and 20 fe
Page 128 and 129: 115 group and in the groups at the
Page 130 and 131: 117 cyfluthrin (purity, 95.5-95.9%)
Page 132 and 133: 119 In a short-term study of exposu
Page 134 and 135: 121 and dissection. At termination,
Page 136 and 137: 123 2.5 Reproductive toxicity (a) M
Page 138 and 139: 125 gestation. The vehicle was 1% C
Page 140 and 141: 127 females was exposed during days
Page 142 and 143: 129 were not seen in rats in the co
Page 144 and 145: 131 men was exposed for 1 h to actu
Page 146 and 147: 133 40 g/l, in a flowable concentra
Page 148 and 149: 135 were removed from five males an
Page 150 and 151: 137 weights and food consumption we
Page 152 and 153: 139 In females at the highest dose,
Page 154 and 155: 141 The dermal toxicity of cyfluthr
Page 156 and 157: 143 The Meeting concluded that the
Page 160 and 161: 147 Cage, S. (2004) [ 14 C]-beta-cy
Page 162 and 163: 149 Heimann, K.G. (1984c) FCR 4545
Page 164 and 165: 151 Jones, R.D. & Hastings, T.F. (1
Page 166 and 167: 153 Pauluhn, J. & Mohr, U. (1984).
Page 168: 155 Von Keutz, E. (1987) FCR 4545 -
Page 171 and 172: 158 Zeta-cypermethrin .............
Page 173 and 174: 160 Evaluation for acceptable daily
Page 175 and 176: 162 polar metabolites, which are fu
Page 177 and 178: 164 for up to 70 days. Signs typica
Page 179 and 180: 166 rapidly metabolized by cleavage
Page 183 and 184: 170 Table 2. Effect of cis : trans
Page 185 and 186: 172 Table 3. Significant haematolog
Page 187 and 188: 174 Rabbits Occluded dermal applica
Page 189 and 190: 176 1100 ppm in weeks 1-6, with inc
Page 191 and 192: 178 Wistar-derived (Alderley Park)
Page 193 and 194: 180 At 1500 ppm, liver APDM activit
Page 195 and 196: 182 for premature deaths, 10 male a
Page 197 and 198: 184 by gavage for days 7 to 19 of g
Page 199 and 200: 186 observed at the intermediate an
Page 201 and 202: 188 The females recovered from this
Page 203 and 204: 190 tibial nerve (SPTN), trigeminal
Page 207 and 208: 194 for 5 weeks. Observations inclu
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196 caused obvious irritation and r
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198 days 6-15 of gestation. After m
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200 was observed in two males at 72
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202 control and other treated group
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204 Table 14. Results of studies of
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206 (b) Developmental toxicity Rats
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208 mild and temporary paraesthesia
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210 range appeared to exist for the
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212 for which the LD 50 was > 2000
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214 substances. Since conventional
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216 Critical end-points relevant fo
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218 Butterworth, S.T.G. & Clark, D.
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220 East Millstone, New Jersey, USA
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222 Jersey, USA. Submitted to WHO b
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224 Toxicology Laboratory (Tunstall
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226 Ullrich, B. (2003) Report on a
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228 Cyromazine was first evaluated
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230 were taken for the measurement
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232 highest dose, rather than indic
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234 Tissue residues: Tissues a < 0.
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236 Because of the low total recove
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238 Name Description Compound found
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240 After each dose of [U- 14 C tri
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242 In male and female monkeys give
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244 stress and discomfort during th
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246 Table 18. Dermal absorption of
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248 rate under steady-state conditi
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250 2. Toxicological studies 2.1 Ac
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252 the test substance. The method
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254 taken for haematological and bi
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256 not differ appreciably from pre
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258 Analysis of the diets showed th
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260 considered to be biologically s
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262 observed incidence probably rel
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264 c Cyromazine was assayed twice
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266 2.5 Reproductive toxicity (a) M
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268 either sporadic or as a consequ
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270 fetuses were removed, weighed a
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272 The NOAEL for maternal toxicity
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274 In New Zealand White rabbits, c
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276 and litters with malformations.
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278 of melamine powder into the rab
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280 reduction in the survival of ma
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282 There is significantly less ris
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284 Toxicological data Cyromazine h
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286 Toxicological evaluation The Me
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288 Other toxicological studies Tox
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290 IARC (1999a) Some chemicals tha
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292 Simoneaux, B. & Marco, G. (1984
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294 Declaration of Helsinki (Cristi
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296 lowered arousal level at doses
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298 Cerebellum 3 1 51** 76** 80** 7
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300 Table 4. Maximum inhibition of
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302 auditory/physical examination w
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304 • • • • • Home-cage o
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306 Dogs Groups of four male and fo
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308 capsules. Some volunteers recei
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310 Blood was taken for measurement
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312 Human a Dietary administration
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314 Piccirillo, V.J. (1978) Acute o
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316 Haloxyfop (racemic), its sodium
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318 Recovery of radioactivity in ur
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320 skin of nine male and nine fema
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322 1.2 Biotransformation Mice In a
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324 2. Toxicological studies 2.1 Ac
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326 96%) at a concentration designe
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328 was centrilobular hepatocellula
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330 The treatment had no effect on
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332 All dogs were killed for autops
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334 with that of controls (but no s
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336 Table 4. Results of studies of
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338 doses of up to 1.0 mg/kg bw per
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340 delayed ossification in the hyo
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342 Mice In a GLP-compliant study,
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344 and in females at the highest d
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346 Between January 1999 and Januar
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348 The Meeting concluded that halo
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350 Critical end-points for setting
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352 Elcombe, B.M. (2002a) Effects o
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354 Scortichini, B.H., Bohl, R.W. &
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356 Economic Co-operation and Devel
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358 There were no treatment-related
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360 comparable to control levels. A
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362 Groups of 17 male and 17 female
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364 No compound-related effects wer
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366 Berry, D. & Gore, C.W. (1975) P
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368 Quinoxyfen has not been evaluat
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370 In the main study, which compli
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372 Concentrations of total radioac
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374 several hydroxy-quinoxyfen meta
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376 There were no mortalities or ad
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378 at doses of ≥ 100 mg/kg bw pe
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380 In a GLP-compliant study to det
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382 control group. This was observe
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384 The homogeneity and stability o
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386 Testes weight (g) at 24 months
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388 slight (3 out of 30) hepatocell
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390 marked inanition, decreased fae
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392 Females Relative liver weightt
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394 were patch-tested specifically
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396 In studies of developmental tox
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398 Rat, LC 50 , inhalation Rabbit,
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400 Gollapudi, B.B. & Lick, S.J. (1
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TEMEPHOS First draft prepared by De
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405 by thin-layer chromatography (T
Page 420 and 421:
407 In a special study to investiga
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409 concluded that temephos was of
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411 Table 3. Effects on mean erythr
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413 Females 0 1.091 1.224 1.324 1.3
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415 of up to 18 ppm. In the group a
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417 Chromosomal aberration DNA repa
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419 of the birds treated with temep
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421 concentration of 1 ppm. Only on
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423 being appreciably less than thi
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425 Lowest relevant developmental N
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427 WHO (1991) Safe use of pesticid
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430 All new studies with thiabendaz
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432 use of this dose form was consi
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434 At 1000 mg/kg bw, qualitative e
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436 At 100 mg/kg bw, slightly decre
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438 There were no treatment-related
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440 Table 6. Incidence of malformat
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442 Dose (mg/kg bw) (grouped by exp
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444 1157 12/21 (57.1)*** 27.2 ± 33
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446 versus placebo): increased appe
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448 activity, tiptoe gait, landing
Page 463 and 464:
450 Noakes, J.P. (2005a) Thianendaz
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452 tests normally performed and th
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454 Radiolabel was excreted primari
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456 the excretory organs, was the r
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458 Table 6. Excretion of radioacti
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460 of unchanged parent compound we
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462 M10 (KNO 1891) + M11 (KNO 1893)
Page 477 and 478:
464 on body weights. Exposure at 15
Page 479 and 480:
466 The no-observed-adverse-effect
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468 Hepatocytes, hypertrophy 0 2 6
Page 483 and 484:
470 they may also be related to var
Page 485 and 486:
472 weights of males were approxima
Page 487 and 488:
474 Thyroid weight (mg): Week 12 6
Page 489 and 490:
476 Table 17. Relevant findings in
Page 491 and 492:
478 Dogs In a dose range-finding st
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480 Prostate / uterine weight (g) 2
Page 495 and 496:
482 the treatment groups receiving
Page 497 and 498:
484 No gross findings were observed
Page 499 and 500:
486 received a macroscopic examinat
Page 501 and 502:
488 Although decreased concentratio
Page 503 and 504:
490 Sciatic nerve; No. examined 50
Page 505 and 506:
492 are caused by the higher incide
Page 507 and 508:
494 2.5 Reproductive toxicity (a) M
Page 509 and 510:
496 In a two-generation study of re
Page 511 and 512:
498 In dams that died or were sacri
Page 513 and 514:
500 No clinical signs or increased
Page 515 and 516:
502 Table 33. Selected variations a
Page 517 and 518:
504 Days 16-21 73.3 78.7 62.5 44.3*
Page 519 and 520:
506 Thiacloprid was not teratogenic
Page 521 and 522:
508 Table 37. Motor and locomotor a
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510 Day 91 19.78 20.00 19.58 18.22*
Page 525 and 526:
512 Table 40. Selected findings in
Page 527 and 528:
514 plate incorporation procedure,
Page 529 and 530:
516 (iv) Comparative study on liver
Page 531 and 532:
518 and relative liver weight in an
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520 at 2500 ppm. The administration
Page 535 and 536:
522 No macroscopic changes were det
Page 537 and 538:
524 The following procedures were p
Page 539 and 540:
526 litter for the group at 1000 pp
Page 541 and 542:
528 Hepatic enzyme activities in th
Page 543 and 544:
530 subtypes 1A1, 2B1, 2D1 and othe
Page 545 and 546:
532 Long-term studies of toxicity a
Page 547 and 548:
534 The Meeting concluded that ther
Page 549 and 550:
536 Estimate of acceptable daily in
Page 551 and 552:
538 dated 27 July, from Bayer AG, W
Page 553 and 554:
540 Kroetlinger, F. (1995a) YRC 289
Page 555 and 556:
542 Wetzig, H. & Geiss, V. (1998b)
Page 557 and 558:
544 Table A1. NOAELs and LOAELs for
Page 559 and 560:
546 2.2 Postulated mode of action (
Page 561 and 562:
548 • • • Chromosomal aberrat
Page 563 and 564:
550 Table A3. NOAELs and LOAELs for
Page 565 and 566:
552 Appendix 2 Table B1. List of an
Page 567 and 568:
554 Metabolite Structure / trivial
Page 569 and 570:
556 Metabolite Structure / trivial
Page 571 and 572:
558 Evaluation for acute reference
Page 573 and 574:
560 increased thyroid weights in th
Page 575 and 576:
562 Table 4. Results of bone-marrow
Page 577 and 578:
564 malformations between the contr
Page 579 and 580:
566 In a study of prenatal developm
Page 581 and 582:
568 combination of heparin and an a
Page 583 and 584:
570 Table 10. Selected findings fro
Page 585 and 586:
572 In a short-term study of neurot
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ANNEX 1 Reports and other documents
Page 590 and 591:
577 31. Pesticide residues in food:
Page 592 and 593:
579 66. Pesticide residues in food
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581 100. Pesticide residues in food
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