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559 Table 2. Selected findings in dogs given capsules containing thiophanate-methyl for 1 year Parameter Dose (mg/kg bw per day) Males Females 0 8 40 200 0 8 40 200 Body weight (kg), month 12 13.0 13.7 12.1 10.4 10.7 12.4 9.9 8.5 Body-weight gain (kg), 5.3 5.6 4.3 2.9 3.6 5.1 2.9 1.3* months 0–12 Erythrocyte count (T/l), 7.62 7.76 7.29 6.63** 7.61 7.23 7.35 7.25 month 12 Haemoglobin (g/dl), month 12 17.4 17.5 16.0 14.9** 16.9 16.1 16.8 16.6 Erythrocyte volume fraction, 0.523 0.531 0.485 0.451** 0.518 0.489 0.518 0.514 month 12 Alkaline phosphatase (IU/l), 50 35 76 150** 71 55 55 129 month 12 Cholesterol (mg/dl), month 12 166 170 216 236 169 232 210 298* Albumin/globulin ratio, 1.3 1.2 1.0* 0.9* 1.4 1.6 1.4 1.3 month 12 T3 (ng/ ml) 1.09 1.19 1.19 1.06 1.14 1.37 1.40 1.70 T4 (μg/ dl) 1.95 2.07 1.66 0.84* 1.96 2.23 2.42 2.07 TSH (ng/ ml) 3.39 4.48 4.91 10.13 1.65 3.54 3.90 7.11 Liver weight (g) 307.7 317.4 344.2 364.2 272.5 317.0 290.6 288.8 Liver weight, relative (× 100) 2.42 2.31 2.88 3.52** 2.58 2.57 2.94 3.47* Thyroid weight (g) 0.93 1.03 1.24 1.31 0.72 0.92 1.04* 1.00 Thyroid weight, relative 7.36 7.63 10.43 12.67 6.79 7.49 10.46** 11.91** (× 100 000) Thyroid; follicular epithelial 0 0 0 4 0 0 2 3 hypertrophy Thyroid; follicular epithelial 0 0 0 1 0 0 0 1 hyperplasia From Auletta (1992) * p < 0.05; ** p < 0.01 T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone. The animals at the highest dose also had decreased serum alanine aminotransferase activity, increased alkaline phosphatase activity, increased cholesterol levels (also at the intermediate dose), and decreased albumin : globulin ratios (also at the intermediate dose), calcium (also at the intermediate dose), potassium and phosphorus concentrations. In females at 200 mg/kg bw per day, serum alanine aminotransferase activity was decreased, and alkaline phosphatase activity and cholesterol levels were increased. Thyroid function tests revealed decreased thyroxine concentrations in males at the intermediate and highest doses but no clear effects on triiodothyronine or thyroid-stimulating hormone. Abnormalities seen post mortem included increased liver weights in dogs at the highest dose and THIOPHANATE-METHYL X-X JMPR 2006
560 increased thyroid weights in those at the intermediate and highest doses. Microscopic alterations attributed to treatment were limited to minimal to moderate hypertrophy and slight hyperplasia of the follicular epithelium of the thyroid in the dogs at the intermediate dose (hypertrophy in two females) and the highest dose (hypertrophy in four males and three females, and hyperplasia in one male and one female). The NOAEL was 8 mg/kg bw per day, on the basis of increased thyroid weights and hypertrophy of the thyroid follicular epithelium at 40 mg/kg bw per day (Auletta, 1992). In a short-term study of toxicity conducted in compliance with the test guidelines of the United States EPA, groups of four male and four female beagle dogs (aged approximately 7 months at the start of the study) were given gelatin capsules containing thiophanate-methyl (purity, 96.55%) at a dose of 0, 50, 200 or 800 mg/kg bw per day for 3 months, the last dose being lowered to 400 mg/kg bw per day on test day 50 because of severe toxicity. One male at the highest dose was sacrificed on day 41 because of severe toxicity; one male at 50 mg/kg bw per day died on day 36, but this death did not appear to be related to treatment. Dose-related clinical signs seen in animals at the highest dose and to a lesser extent at the intermediate dose included dehydration, thinness, and lethargy. Dose-related decreases in body weights and marked decreases in food consumption were seen at the intermediate and highest doses. There were no treatmentrelated ophthalmological findings. Slight anaemia, increased platelet counts and cholesterol levels, and decreases in serum alanine aminotransferase activity and albumin levels were seen at the intermediate and highest doses and increased activated partial thromboplastin time at the highest dose. Thyroid function tests revealed slightly decreased triiodothyronine levels in males at the highest dose and decreased triiodothyronine and thyroxine levels in females at the intermediate and highest doses; no clear effects on thyroid-stimulating hormone values were apparent. Urine analysis showed no treatment-related findings. At the intermediate and highest doses, the weights of the liver (in animals of each sex) and thyroid (males only) were increased. Gross examination post mortem revealed emaciation in one male at the intermediate dose and three at the highest dose. Dose-related histological alterations were seen in a number of organs. In thyroids, hypertrophy of the follicular epithelium was found in one, three and four males and one, two and four females at the lowest, intermediate and highest doses, respectively, with none in controls. The severity of the hypertrophy increased from minimal to marked with dose. Hyperplasia of the follicular epithelium was found in one male at the intermediate dose and in most animals at the highest dose. In two males at the highest dose in which both hypertrophy and hyperplasia were marked, a large decrease in the quantity of intrafollicular colloid was seen. In animals at the intermediate and highest doses, dose-related changes were found in the liver (reduction in vesiculation of the hepatocellular cytoplasm), gall-bladder (intracytoplasmic vacuoles), pancreas (atrophy of acinar cells owing to a decreased quantity of zymogen granules), spleen (lymphoid cell depletion), thymus (involution), prostate (atrophy), uterus (anestrus) and ovaries (inactive). No NOAEL was identified because of the presence of follicular cell hypertrophy in the thyroid of two dogs at the lowest dose (Auletta, 1991). 1.2 Genotoxicity In a test for micronucleus formation performed in compliance with the test guidelines of the Organisation for Economic Co-operation and Development (OECD) and the United States EPA, groups of five male and five female B6D2F 1 mice were given thiophanate-methyl (purity, 97.28%) in 1% aqueus methylcellulose by oral gavage as single doses at 0, 500, 1000 or 2000 mg/kg bw, while a positive-control group was given carbendazim (purity, 98%) at a dose of 1000 mg/kg bw. Bone-marrow THIOPHANATE-METHYL 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
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94 3. Observations in humans In the
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96 was 100 ppm, equal to 10 mg/kg b
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98 Acute toxicity Rat, LD 50 , oral
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100 Mellert, W., Kaufmann, W. & Hil
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CYFLUTHRIN AND BETA-CYFLUTHRIN Firs
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105 Table 1. Diastereoisomer pairs
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107 (i) In vivo Rats Four groups of
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109 2. Toxicological studies 2.1 Ac
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111 Species Strain Sex Route Formul
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113 Rat Groups of 20 male and 20 fe
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115 group and in the groups at the
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117 cyfluthrin (purity, 95.5-95.9%)
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119 In a short-term study of exposu
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121 and dissection. At termination,
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123 2.5 Reproductive toxicity (a) M
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125 gestation. The vehicle was 1% C
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127 females was exposed during days
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129 were not seen in rats in the co
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131 men was exposed for 1 h to actu
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133 40 g/l, in a flowable concentra
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135 were removed from five males an
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137 weights and food consumption we
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139 In females at the highest dose,
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141 The dermal toxicity of cyfluthr
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143 The Meeting concluded that the
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145 Estimate of acute reference dos
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147 Cage, S. (2004) [ 14 C]-beta-cy
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149 Heimann, K.G. (1984c) FCR 4545
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151 Jones, R.D. & Hastings, T.F. (1
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153 Pauluhn, J. & Mohr, U. (1984).
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155 Von Keutz, E. (1987) FCR 4545 -
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158 Zeta-cypermethrin .............
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160 Evaluation for acceptable daily
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162 polar metabolites, which are fu
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164 for up to 70 days. Signs typica
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166 rapidly metabolized by cleavage
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170 Table 2. Effect of cis : trans
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172 Table 3. Significant haematolog
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174 Rabbits Occluded dermal applica
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176 1100 ppm in weeks 1-6, with inc
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178 Wistar-derived (Alderley Park)
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180 At 1500 ppm, liver APDM activit
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182 for premature deaths, 10 male a
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184 by gavage for days 7 to 19 of g
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186 observed at the intermediate an
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188 The females recovered from this
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190 tibial nerve (SPTN), trigeminal
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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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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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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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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
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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
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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)
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464 on body weights. Exposure at 15
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466 The no-observed-adverse-effect
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468 Hepatocytes, hypertrophy 0 2 6
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470 they may also be related to var
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472 weights of males were approxima
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474 Thyroid weight (mg): Week 12 6
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476 Table 17. Relevant findings in
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478 Dogs In a dose range-finding st
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480 Prostate / uterine weight (g) 2
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482 the treatment groups receiving
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484 No gross findings were observed
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486 received a macroscopic examinat
Page 501 and 502:
488 Although decreased concentratio
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490 Sciatic nerve; No. examined 50
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492 are caused by the higher incide
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496 In a two-generation study of re
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498 In dams that died or were sacri
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500 No clinical signs or increased
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502 Table 33. Selected variations a
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504 Days 16-21 73.3 78.7 62.5 44.3*
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506 Thiacloprid was not teratogenic
Page 521 and 522: 508 Table 37. Motor and locomotor a
Page 523 and 524: 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
Page 533 and 534: 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: 558 Evaluation for acute reference
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
Page 588 and 589: 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
Page 594: 581 100. Pesticide residues in food
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