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

More documents

Recommendations

Info

407 1.3 Effects on enzymes and other biochemical parameters Profenofos is stereospecifically converted to a more potent inhibitor of acetylcholinesterase by oxidation of the sulfur on the phosphorus by a liver microsomal mixed-function oxidase system in the mouse. The net effect of this was that the chiral S (−) isomer was a 34 times more potent inhibitor of acetylcholinesterase in vitro, while the less toxic R (+) isomer was metabolically deactivated by a factor of 2, via esteratic cleavage. Prior treatment with inhibitors of mixed function oxidase markedly decreased the activation and also protected against inhibition of brain acetylcholinesterase activity and cholinergic symptoms resulting from administration of S-profenofos in chicks (Wing et al., 1983). Acetylcholinesterase activity inhibited by the S-isomer did not reactivate, probably as a result of rapid ageing (Glickman et al., 1984). Table 1. Results of studies of acute toxicity with profenofos Species Strain Sex Route LD 50 (mg/kg bw) LC 50 (mg/l air) Reference Rat Tif: RAI (SPF) Males and females Rat Tif: RAIf (SPF) Males and females Rat HSD:(SD) Males and females Oral 358 (range, 318–403) — Bathe (1974a) Oral 502 (range, 391–727) — Kobel (1983) Oral Males: 492 (range, 363–666) Females: 809 (range, 600–1090) Males and females: 630 — Kuhn (1990a) Rat Sprague-Dawley Females Oral 1178 (range, 630–2000 — Merkel (2004a) Rat Sprague-Dawley Females Oral 621 (range, 350–1100) — Durando (2005a) Mouse Tif: MAG (SPF) Males and females Rabbit Russian Males and females Rat Tif: RAI (SPF) Males and females Rat Sprague-Dawley Males and females Rat Sprague-Dawley Males and females Rabbit Mixed breed Males and females Rabbit Rabbit Rat Rat New Zealand White New Zealand White Sprague-Dawley Crl:CD (SD) BR Wistar-derived Alpk:APfSD Males and females Males and females Males and females Males and females Rat Sprague-Dawley Males and females Oral 298 (range, 268–332) — Bathe (1974b) Oral 700 — Sachsse (1974a) Dermal 3300 — Bathe (1974c) Dermal > 2000 — Merkel (2004b) Dermal > 2000 — Durando (2005b) Dermal 472 (range, 304–733) — Sachsse (1974b) Dermal Males: 111 (range, 84.5–145) Females: 155 (range, 124–193) Males and f emales: 131 (range, 110–156) — Cannelongo (1982a) Dermal 2560 (range, 2190–2990) — Kuhn (1989) Inhalation (4-h, whole-body) Inhalation (4-h, nose-only) Inhalation (4-h, nose-only) — 3.36 Horath (1982) — > 2.2 Rattray (2004) — > 2.03 Durando (2005c) PROFENOFOS 403–443 JMPR 2007
408 2. Toxicological studies 2.1 Acute toxicity Profenofos has a moderate toxic potential in laboratory animals via the oral route of exposure with median lethal dose (LD 50 ) values ranging from 298 to 1178 mg/kg bw. It is practically non-toxic when applied to the abraded or intact skin in rats and rabbits (LD 50 , > 2000 mg/kg bw and 3000 mg/ kg bw, respectively). However if the compound is massaged into the shaved skin and kept under occlusive dressing it can be moderately toxic to rabbits (LD 50 , ≥ 131 mg/kg bw). Whole body or noseonly inhalation exposure for 4 h is not lethal to rats (LC 50 , > 2.0 mg/l). In laboratory animals, single oral or dermal exposure and exposure by inhalation for 4 h causes clinical signs of toxicity that are characteristic of organophosphorus compounds. These include piloerection, salivation, lacrimation, hunched posture, sedation, prostration, tremors and ataxia. The results of studies of acute oral toxicity suggested that the clinical signs characteristic of exposure to organophosphorus compounds were observed at doses greater than 100 mg/kg bw. (a) Oral administration Rats Five studies were available for review. In the first study, groups of five male and five female fasted adult Tif:RAI rats were given profenofos (purity unknown) as a single dose at 215, 278, 359 or 600 mg/kg bw by gavage in 2% aqueous carboxymethylcellulose. Treated rats were examined by gross necropsy at the end of a 14-day observation period. The study was not conducted in accordance with GLP regulations. Within 48 h, 100% mortality was observed at 600 mg/kg bw, while only one male and two females died at 359 mg/kg bw. Clinical signs, seen in all dosed groups within 2 h of treatment, but more accentuated with increased doses, were sedation, dyspnoea, exophthalmos, ruffled fur, trismus tonic-clonic muscle spasms and hunched body posture. No other details of clinical signs (incidence or duration of observation) were provided in the study report. Surviving rats recovered within 6–7 days. No effects on body weights were observed within 14 days. Necropsy of rats that were killed or that died during the study did not show any substance-related gross changes to organs. The calculated oral LD 50 (with 95% confidence interval) for males and females combined was 358 (95% CI, 318–403) mg/kg bw (Bathe, 1974a). In a second study, groups of five male and five female fasted Tif:RAIf rats were given profenofos (purity, 88.5%) as a single dose at 100, 200, 450 or 800 mg/kg bw by gavage in 0.5% aqueous carboxymethylcellulose. Rats were observed for a 14 days. This study was not conducted in a ccordance with GLP regulations. All rats of the group at 800 mg/kg bw and one male and one female from the group at 450 mg/kg bw died within 3 days, while surviving rats recovered from all clinical signs within 13 days. Clinical signs seen within 1 h of dosing in all groups were similar to those observed in the previous study. At 100 and 200 mg/kg bw, the clinical signs were non-specific. Clinical signs in rats in the control group were not reported. Rats in the groups at 450 and 800 mg/kg bw exhibited tremors, sedation and loss of postural tone. The surviving rats gained weight during the study period. The oral LD 50 in male and female rats was calculated to be 491 (95% CI, 325–1016) and for males and females combined it was 502 (95% CI, 391–727) mg/kg bw (Kobel, 1983). In the third study, groups of five male and five female fasted Harlan Sprague-Dawley rats were given undiluted profenofos technical (purity unknown) as a single dose at 200, 400 or 1000 mg/kg PROFENOFOS 403–443 JMPR 2007
Page 2 and 3:
Pesticide residues in food — 2007
Page 4:
TABLE OF CONTENTS Page List of part
Page 7 and 8:
Dr Vicki L. Dellarco, Office of Pes
Page 10 and 11:
Abbreviations used 3-MC ACTH ADI ai
Page 12 and 13:
MRL MS MS/MS MTD NMR NOAEC NOAEL NO
Page 14:
Introduction The toxicological mono
Page 18 and 19:
AMINOPYRALID First draft prepared b
Page 20 and 21:
5 higher renal excretion in the gro
Page 22 and 23:
7 Table 4. Recovery of radioactivit
Page 24 and 25:
9 Table 7. Pharmacokinetic paramete
Page 26 and 27:
11 (c) Exposure by inhalation Five
Page 28 and 29:
13 Table 9. Acute toxicity of amino
Page 30 and 31:
15 The data from urine analysis rev
Page 32 and 33:
17 18, monthly for palpable masses.
Page 34 and 35:
19 Table 12. Body weights of rats f
Page 36 and 37:
21 Table 15. Results of assays for
Page 38 and 39:
23 in both groups, feed consumption
Page 40 and 41:
25 neurotoxicity after 12 months. B
Page 42 and 43:
27 The same five time-mated NZW rab
Page 44 and 45:
29 Mortality was increased in all g
Page 46 and 47:
31 Levels relevant to risk assessme
Page 48 and 49:
33 References Brooks, K.J. (2001a)
Page 50 and 51:
35 Consulting, The Dow Chemical Com
Page 52 and 53:
ATRAZINE First draft prepared by Ru
Page 54 and 55:
39 in the early 1990s; this reflect
Page 56 and 57:
41 Maximum concentrations in the bl
Page 58 and 59:
43 In a study on comparative metabo
Page 60 and 61:
45 Table 1. Metabolism of atrazine
Page 62 and 63:
47 Figure 2. Proposed metabolic pat
Page 64 and 65:
49 to intact skin; and that no read
Page 66 and 67:
51 the highest dose, and food consu
Page 68 and 69:
53 mice (evaluated as roughly equiv
Page 70 and 71:
55 Table 5. Incidence of mammary tu
Page 72 and 73:
57 Table 6. Selected findings from
Page 74 and 75:
59 was decreased when compared with
Page 76 and 77:
61 Table 9. Selected findings of a
Page 78 and 79:
63 proestrus at the expense of days
Page 80 and 81:
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 86 and 87:
Page 88 and 89:
73 respectively) and in males at th
Page 90 and 91:
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 102 and 103:
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 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 182 and 183:
167 Critical end-points for setting
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
Page 232 and 233:
217 hepatocellular enlargement. In
Page 234 and 235:
219 i.e. males lost 15.4% and femal
Page 236 and 237:
221 and 357. This reduced food cons
Page 238 and 239:
223 There was very high mortality a
Page 240 and 241:
225 Table 6. Treatment-related hist
Page 242 and 243:
227 Rats Groups of 80 CRL:CD(SD)®
Page 244 and 245:
229 Table 7. Histopathology finding
Page 246 and 247:
231 D. Temporal association. The fe
Page 248 and 249:
233 2.5 Reproductive toxicity (a) M
Page 250 and 251:
235 t estes weights in the males at
Page 252 and 253:
237 continued to be lower than thos
Page 254 and 255:
239 Corpora lutea in each ovary wer
Page 256 and 257:
241 S1 + S2, not ossified — —
Page 258 and 259:
243 in the control group and in the
Page 260 and 261:
245 physically examined for changes
Page 262 and 263:
Page 264 and 265:
249 can occur in untreated mice, in
Page 266 and 267:
251 Study of reproductive toxicity
Page 268 and 269:
Page 270 and 271:
Page 272 and 273:
257 of the test article on microsom
Page 274 and 275:
259 Ophthalmoscopic examinations pe
Page 276 and 277:
261 the radioactivity was re-elimin
Page 278 and 279:
263 In a single-dose study of neuro
Page 280 and 281:
265 Estimate of acceptable daily in
Page 282 and 283:
267 Clapp, M.J.L., Killick, M.E., H
Page 284 and 285:
269 Herbold, B. (1983c) THS 2212 tr
Page 286 and 287:
271 Pinto, P. (2006b) Difenoconazol
Page 288 and 289:
DIMETHOMORPH First draft prepared b
Page 290 and 291:
275 Five different treatment groups
Page 292 and 293:
277 To investigate the significance
Page 294 and 295:
279 and the E : Z isomer ratio was
Page 296 and 297:
281 Table 10. Tissue distribution o
Page 298 and 299:
283 (e) Dermal sensitization The de
Page 300 and 301:
285 females at the highest dose, to
Page 302 and 303:
287 The NOAEL was 10 mg/kg bw per d
Page 304 and 305:
289 concentrations in females were
Page 306 and 307:
291 health, moribundity and mortali
Page 308 and 309:
293 0-9%, mean, 3.5%; only one out
Page 310 and 311:
Table 26. Organ weights adjusted to
Page 312 and 313:
297 cell hyperplasia. The testes tu
Page 314 and 315:
299 unscheduled DNA synthesis, the
Page 316 and 317:
301 Figure 3. Cumulative percentage
Page 318 and 319:
303 Rabbits In a dose-range finding
Page 320 and 321:
305 (b) Potentiation of hexobarbito
Page 322 and 323:
307 0.2% or less of the administere
Page 324 and 325:
309 eye-opening, pinna unfolding or
Page 326 and 327:
311 Lowest relevant inhalation NOAE
Page 328 and 329:
313 Gardner, J.R. (1989) CME 151 te
Page 330:
315 van de Waart, E.J. (1991b) Eval
Page 333 and 334:
318 Committee on Pesticide residues
Page 335 and 336:
320 (a) Ocular irritation Rabbits T
Page 337 and 338:
322 weights were decreased in males
Page 339 and 340:
324 toxicity was 5 mg/kg bw per day
Page 341 and 342:
326 respectively; range for histori
Page 343 and 344:
328 Table 4. Incidence of Leydig-ce
Page 345 and 346:
330 and/or bilateral) was noted in
Page 347 and 348:
332 No treatment-related signs of m
Page 349 and 350:
334 Table 6. Incidence of selected
Page 351 and 352:
336 or teratogenic potential at the
Page 353 and 354:
338 and progesterone. The concentra
Page 355 and 356:
340 the doses used in the 1-year st
Page 357 and 358:
342 No neurotoxic effects were seen
Page 359 and 360:
344 Lowest relevant reproductive NO
Page 361 and 362:
346 Keller, D.A. (1992c) Oncogenici
Page 364 and 365:
PROCYMIDONE First draft prepared by
Page 366 and 367:
351 Rats Groups of five male and fe
Page 368 and 369:
353 Table 1. Pharmacokinetic parame
Page 370 and 371:
355 Seven doses C max (µg equivale
Page 372 and 373: 357 Three groups of five male and f
Page 374 and 375: 359 The excretion of radioactivity
Page 376 and 377: 361 Figure 1. Proposed metabolic pa
Page 378 and 379: 363 water consumption were determin
Page 380 and 381: 365 finding. Histopathology reveale
Page 382 and 383: 367 The NOAEL was 500 ppm, equivale
Page 384 and 385: 369 The NOAEL was 100 mg/kg bw per
Page 386 and 387: 371 at 2000 ppm. Histopathology rev
Page 388 and 389: 373 b Each test was conducted in tr
Page 390 and 391: 375 experimental period. Rats were
Page 392 and 393: 377 hypospadias, testicular atrophy
Page 394 and 395: 379 a single dose, which produced o
Page 396 and 397: 381 The anti-androgenic activities
Page 398 and 399: 383 but only at 6000 ppm after 13 w
Page 400 and 401: 385 The results are summarized in T
Page 402 and 403: 387 males (all litters) in the grou
Page 404 and 405: 389 procymidone (18-27% of the admi
Page 406 and 407: 391 Procymidone induced liver tumou
Page 408 and 409: 393 The Meeting concluded that the
Page 410 and 411: 395 Toxicologically significant com
Page 412 and 413: 397 Harada, T. (1983) A review on m
Page 414 and 415: 399 Murakami, M., Yoshitake, A. & H
Page 416: 401 Tarui, H. (2005b) In vitro meta
Page 419 and 420: 404 Explanation Profenofos is the I
Page 421: 406 The metabolism of ring-labelled
Page 425 and 426: 410 Rabbits Groups of two male and
Page 427 and 428: 412 Groups of five male and five fe
Page 429 and 430: 414 control group and in the test g
Page 431 and 432: 416 of the rabbits at the highest d
Page 433 and 434: 418 The NOAEL for brain acetylcholi
Page 435 and 436: 420 Table 2. Histopathological find
Page 437 and 438: 422 1 out of 70; lowest dose, 3 out
Page 439 and 440: 424 body‐weight gains (3-10% decr
Page 441 and 442: 426 treated groups for body-weight
Page 443 and 444: 428 (b) Short-term studies of neuro
Page 445 and 446: 430 represented as equally as possi
Page 447 and 448: 432 pound and the equitoxic mixture
Page 449 and 450: 434 Inhibition of brain acetylcholi
Page 451 and 452: 436 Toxicological evaluation Erythr
Page 453 and 454: 438 Neurotoxicity/delayed neurotoxi
Page 455 and 456: 440 Harris, S.B. (1982) A teratolog
Page 457 and 458: 442 Puri, E. (1982a) Autoradiograph
Page 460 and 461: PYRIMETHANIL First draft prepared b
Page 462 and 463: 447 Table 1. Excretion profile in r
Page 464 and 465: 449 Table 3. Half-life of pyrimetha
Page 466 and 467: 451 Table 4. Identification of meta
Page 468 and 469: 453 SN 614 277. The presence of the
Page 470 and 471: 455 2. Toxicological studies 2.1 Ac
Page 472 and 473:
457 treated rabbits showed slight e
Page 474 and 475:
459 still evident in the liver; how
Page 476 and 477:
461 In a 90-day feeding study, grou
Page 478 and 479:
463 per day or 800 mg/kg bw per day
Page 480 and 481:
465 The dosing solutions were prepa
Page 482 and 483:
467 mortality and morbidity. Change
Page 484 and 485:
469 2.4 Genotoxicity Pyrimethanil w
Page 486 and 487:
471 mean body‐weight gains. After
Page 488 and 489:
473 Analysis of dosing solutions in
Page 490 and 491:
475 In a 7-day feeding study, group
Page 492 and 493:
477 at 200 mg/kg bw. These clinical
Page 494 and 495:
479 s ystemic toxicity was 400 ppm
Page 496 and 497:
481 Acute toxicity Rat, LD 50 , ora
Page 498 and 499:
483 Grosshans, F. (2003) Pyrimethan
Page 500 and 501:
485 Markham, L.P. (1989d) Technical
Page 502 and 503:
ZOXAMIDE First draft prepared by I.
Page 504 and 505:
489 The excretion of radioactivity
Page 506 and 507:
491 Table 3. Mean concentration of
Page 508 and 509:
493 Table 4. Distribution of metabo
Page 510 and 511:
495 were also found in the urine, a
Page 512 and 513:
497 owing to the absence of a dose-
Page 514 and 515:
499 The NOAEL was 30 000 ppm, equiv
Page 516 and 517:
501 Table 9. Haematological finding
Page 518 and 519:
503 Table 11. Body weight, food con
Page 520 and 521:
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
Page 526 and 527:
511 Table 16. Spleen weights and hi
Page 528 and 529:
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.
Page 538 and 539:
ANNEX 1 Reports and other documents
Page 540 and 541:
525 31. Pesticide residues in food:
Page 542 and 543:
527 67. Pesticide residues in food
Page 544:
529 101. Pesticide residues in food
show all

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

Create successful ePaper yourself

Delete template?

Save as template?

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