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Toxicity Effects

CAS Registry Number: 131860-33-8

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

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    Human Toxicity Excerpts

    • GENOTOXICITY: In vitro chromosome aberrations in human lymphocytes assay: The test was positive for the induction of chromosomal aberrations in both the presence and absence of S9 activation at doses (5-50 ug/mL +S9) that were moderately to severely cytotoxic (ie, > or = 16-70% reductions in mitotic cells, respectively).[USEPA; Azoxystrobin: Human Health Risk Assessment. (Attachment 2) (September 22, 2000). Available from, as of December 29, 2011: http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-128810_22-Sep-00_092.pdf] **PEER REVIEWED**

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    Non-Human Toxicity Excerpts

    • GENOTOXICITY: In vivo bone marrow micronucleus assay: The test in negative in C57BL/6JfBL10/Alpk mice up to 5000 mg/kg, the highest dose tested, when administered once by oral gavage. Overt toxicity and depression of erythropoiesis seen in the high-dose group; cytotoxic effects on the target cell were significant in the males.[USEPA; Azoxystrobin: Human Health Risk Assessment. (Attachment 2) (September 22, 2000). Available from, as of December 29, 2011: http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-128810_22-Sep-00_092.pdf] **PEER REVIEWED**
    • GENOTOXICITY: In vivo/in vitro unscheduled DNA synthesis in rate hepatocytes: The test is negative in Alderley Park rats. no toxicity to the treated animals or cytotoxic effects on recovered hepatocytes up to the proposed new limit dose for acute testing (2000 mg/kg) when administered by oral gavage.[USEPA; Azoxystrobin: Human Health Risk Assessment. (Attachment 2) (September 22, 2000). Available from, as of December 29, 2011: http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-128810_22-Sep-00_092.pdf] **PEER REVIEWED**
    • GENOTOXICITY: Mouse lymphoma L5178Y TK+/- forward gene mutation assay: Nonlinear, slight but significant increases in the mutation frequency were seen at 15-60 mg/mL +/- S9. Despite the absence of a dose response, increased mutation frequencies were reproducible; therefore, azoxystrobin is considered positive in this test system. colony sizing was not performed.[USEPA; Azoxystrobin: Human Health Risk Assessment. (Attachment 2) (September 22, 2000). Available from, as of December 29, 2011: http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-128810_22-Sep-00_092.pdf] **PEER REVIEWED**
    • GENOTOXICITY: Salmonella typhimurium/Escherichia coli reverse gene mutation assay: The test is negative up to 5000 ug/plate +/- S9, the highest dose tested using both plate incorporation and preincubation protocols. Cytotoxicity and compound precipitation were seen at the high dose.[USEPA; Azoxystrobin: Human Health Risk Assessment. (Attachment 2) (September 22, 2000). Available from, as of December 29, 2011: http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-128810_22-Sep-00_092.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: Five male and five female young adult Wistar (Crl:(WI)BR) rats were exposed dermally to azoxystrobin (purity, 95.2%) at 2000 mg/kg bw as a paste in corn oil applied to approximately 10% of the (shaved) body surface area. The test substance was maintained in contact with the skin for 24 hr using an occlusive dressing. The rats were observed for 14 days. Body weights were recorded at intervals throughout the study. All rats were subjected to a post-mortem examination at termination. Slight skin irritation (slight erythema) was observed during the study, but there were no significant signs of systemic toxicity and none of the rats died. All rats lost weight initially, but all had exceeded their initial weights by day 6. Post-mortem examination did not reveal any treatment-related pathological effects.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.11 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: Groups of five male and five female young adult CD-1 mice were given azoxystrobin (purity, 95.2%) as a single dose at 0, or 5000 mg/kg bw by gavage in corn oil. Treated mice were subjected to gross necropsy after 14 days. Two male mice died owing to dosing accidents and were replaced. There were no treatment-related mortalities. Clinical observations were confined to slight piloerection and slight urinary incontinence in some mice. All clinical signs had regressed by day 6. There were no significant treatment-related clinical signs, necropsy findings or changes in body weight.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.11 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: Groups of five male and five female young adult Wistar rats (Crl:(WI)BR) rats were given azoxystrobin (purity, 95.2%) as a single dose at 0 and 5000 mg/kg bw by gavage in corn oil. Treated rats were subjected to gross necropsy after 14 days. One female rat died on day 2 from a dosing accident and was replaced. ... All rats lost weight initially, due to pre-dose fasting, but most had exceeded their initial weight by day 8, and continued to gain weight until the end of the study. There were no significant treatment-related clinical signs, necropsy findings or changes in body weight. There were no treatment-related deaths.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.11 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: In a study of acute toxicity after inhalation, groups of five male and five female young adult Wistar rats (Alpk:APfSD) were exposed nose-only to azoxystrobin (purity, 96.2%) for 4 hr at a concentration of 0.2, 0.5, or 0.8 mg/L. One additional group of five male rats was exposed to azoxystrobin at 1.0 mg/L. the rats were then observed for 14 days. The mean measured particulate concentrations were 0, 0.257, 0.511, 0.767 or 1.010 mg/L, which were chemically analysed as 0, 0.242, 0.481, 0.717 or 0.968 mg/L. Atmospheres generated had mean aerodynamic particle sizes of 1.13, 1.17, 1.35 and 1.17 um. No mortality was observed at 0.2 mg/L. Mortality occurred at 0.5 mg/L (one male and one female), 0.8 mg/L (one male and three females) and 1.0 mg/L (three males). Most rats exposed to azoxystrobin at 0.5, 0.8, or 1.0 mg/L developed slow deep breathing, auditory hypoesthesia, and breathing irregularities during and up to 4 days after exposure. In addition, many rats had a splayed gait and reduced splay reflex immediately after exposure. Surviving rats showed rapid recovery, and all treatment-related clinical signs had disappeared by day 7. Body weight was reduced in surviving rats in all groups after exposure, but by day 8 most rats were gaining weight and had exceeded their initial weights. All rats that died during exposure had dark red or mottled lungs. No other treatment related effects were observed.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.11 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: In a study of dermal sensitization with azoxystrobin (purity, 95.2%) mixed with corn oil, young male and female Dunkin-Hartley guinea pigs were tested using the maximization method of Magnusson & Kligman. For the main study, 10 female guinea-pigs were assigned to a control group, and 10 female guinea-pigs to the treatment group. In this study, the test concentrations chosen were 10% for intradermal induction, 64% for topical induction, and 37% or 67% for the challenge. Skin reactions at the challenge sites were observed at 24 hr and 48 hr after removal of the patch. No mortalities or clinical signs of toxicity were observed in the study. Challenge of previously induced guinea-pigs with a 67% or a 30% w/v preparation of azoxystrobin in corn oil caused light brown staining at some challenge sites, but this did not obscure the assessment of any erythematous response that may have been present. There were no signs of dermal reactions in any guinea-pigs in the induction or challenge phase. In a study designed to provide a positive control, challenge of previously induced guinea pigs with a 10% w/v dilution of a 40% w/v aqueous formaldehyde solution elicited an extreme skin sensitization response.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.12 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: In a study of primary dermal irritation, six young adult female New Zealand White rabbits were dermally exposed to 0.5 g of azoxystrobin (purity, 95.2%), moistened with distilled water, for 4 hr. The treated area was covered by an occlusive dressing. The application site was washed after removal of the dressing and dermal irritation was assessed after 30-60 min and then daily for up to seven days. Very slight erythema and edema were present for three days after dosing in one rabbit, and for 1 hr in another. No other signs of irritation were observed. ... /It was/ concluded that azoxystrobin was a slight dermal irritant in rabbits given a single application for 4 hr. The mean erythema and mean edema scores over the first 3 days were calculated to be 0.2 and 0.2, respectively.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.12 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: In a study of primary eye irritation, 0.1 mL of azoxystrobin (purity, 95.2%), was instilled into the conjunctival sac of one eye of each of six young adult female New Zealand White rabbits. The initial pain reaction was assessed immediately after treatment. Irritation was scored by the method of Draize at 1-2 hr, and 1, 2, and 3 days after exposure. The test material induced slight to moderate erythema and slight chemosis in all rabbits within 1 hr, but the effects resolved within 48 hr after treatment. Additional signs of irritation included slight mucoid and Harderian discharge and partial hemorrhaging of the nictitating membrane. These effects had completely regressed 2 days after dosing. ... /It was/ considered that azoxystrobin was slightly irritating (class 3 on a 1-8 scale) to the eyes of rabbits.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.12 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Acute Exposure: Slight eye & skin irritation (rabbits).[Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994., p. 579] **PEER REVIEWED**
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In a 1-year study of oral toxicity, groups of four male and four female beagle dogs were given capsules containing azoxystrobin (purity, 96.2%) at a dose of 0, 3, 25, or 200 mg/kg bw per day for 52 weeks. The dogs were inspected twice per day for morbidity or mortality, with clinical signs being checked daily. Thorough examinations were given weekly. Body weights were recorded weekly and food consumption was measured daily. Eyes were examined by indirect ophthalmoscopy at weeks 13, 26, 39 and before termination. Clinical examinations, including cardiac and pulmonary auscultation, were conducted at weeks 13, 26, 39, and before termination. Blood was collected from all dogs before the test, and during weeks 4, 13, 26 and 52 for measurement of hematological and clinical parameters. Urine analysis was performed on all dogs before the test, at week 26 and at termination. At the end of the study, a complete gross post mortem was done. The adrenals, brain, epididymides, kidneys, liver, thyroid and parathyroid, and testes/ovaries were weighed. The organs specified were examined microscopically. No dogs died before the scheduled termination date. There were no effects on body weight or food consumption related to the administration of azoxystrobin. There were no treatment-related findings noted at the veterinary or ophthalmic examinations. The most notable treatment-related clinical observation was an increase in the incidence of fluid feces in males and females at 200 mg/ kg bw per day: there were 414 occurrences in 4 out of 4 males and 115 occurrences in 4 out of 4 females compared with 3 occurrences in 2 out of 4 males and 6 occurrences in 2 out of 4 females in the control group (statistical analysis was not performed). Females at the highest dose had minor increases in salivation (21 occurrences in 3 out of 4 females at the highest dose compared with 0 out of 4 in the control group) and salivation at dosing (80 occurrences in 3 out of 4 females at the highest dose, compared with 0 out of 4in the control group), although the combined frequency was similar to that of males in the concurrent control group. The Meeting considered that these clinical signs were treatment-related, but not relevant for the identification of a NOAEL, being judged to be secondary effects attributable to local gastrointestinal irritation/disturbances and bolus dosing (capsule). Minor changes in MCV, MCH, prothrombin time, leukocyte count, neutrophils, kaolin-cephalin time, platelets, lymphocytes, and monocytes were observed; however, these changes in hematological parameters were not considered to be toxicologically significant, being small in magnitude, without a dose-response relationship and transient in nature. Treatment-related clinical chemistry changes at 200 mg/kg bw per day (p < or = 0.05 or 0.01) for one or more weeks included increased concentrations of plasma cholesterol (males and females, 14-48%), triglycerides (males and females, 65-124%,), alkaline phosphatase activity (males and females, 17-156%), gamma-glutamyl transferase activity (females, 74-112%) and lowered plasma albumin (males, 9.4-13%). Males at the intermediate dose had increased concentrations of cholesterol (23-27%) and triglycerides (65%). These results suggest that azoxystrobin has an effect on liver and possibly biliary function. Minor and/or transient alterations (p < or = 0.05 or 0.01) in total plasma protein, bilirubin, calcium, phosphorus, urea, potassium, and sodium concentrations were observed in one or both sexes. Clinical chemistry changes observed in males and females lacked histopathological correlates. There was a small decrease in absolute brain weight in males at the highest dose (6.5%, p < or = 0.05) that is of uncertain biological significance. This small decrease in absolute brain weight was of unknown etiology and uncertain biological significance: it was not correlated with any histopathological findi
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In a combined long-term study of toxicity and carcinogenicity, groups of 52 male and 52 female Alpk:APfSD rats were given diets containing azoxystrobin, (purity, 96.2%) at a concentration of 0, 60, 300 or 750 ppm/1500 ppm (males/females), equal to 0, 3.6, 18.2, and 34.0 mg/kg bw per day for males and 0, 4.5, 22.3, and 117.1 mg/kg bw per day for females, for 104 weeks. An additional 12 males and 12 females per group were designated for interim sacrifice at week 52. Owing to excessive mortality, the highest dose was reduced to 750 ppm, equal to 34 mg/kg bw per day, in males from week 52 and the rats in this group designated for interim sacrifice were retained with the main study. Additional groups of seven males and seven females were used as microbiological sentinels and fed either control diet or diet containing azoxystrobin at 1500/750 ppm. Diets were prepared in batches of 30 or 60 kg throughout the study. Stability, homogeneity and dietary concentrations were confirmed analytically. The rats were inspected twice per day for mortality and morbidity. Changes in clinical condition and behavior were recorded daily. Detailed clinical observations were recorded weekly. Body weights were measured weekly for the first 14 weeks, then every 2 weeks for the rest of the study. Food consumption was measured for the first 14 weeks, at week 16, and every fourth week thereafter. Water consumption was not measured. An ophthalmoscopic examination was performed before treatment and at week 54. The eyes of rats in the control group and the group at the highest dose were examined before termination. Blood was collected at weeks 14, 27, 53, 78 and week 105 of treatment. Urine was collected at weeks 13, 26, 52, 78 and 104. Hematological parameters examined were erythrocyte count, leukocyte count, hematocrit (erythrocyte volume fraction), hemoglobin concentration, platelet count, differential leukocyte count and cell morphology. Standard clinical chemistry and urine analysis parameters were examined. At weeks 53 or 105, the designated rats were necropsied and examined histopathologically. Liver, kidney, brain, testes, ovaries, and adrenals were removed and weighed. All tissues were examined histologically, except oral and nasal cavities, which were stored. The common bile duct and intraduodenal bile duct were taken from all rats with bile duct distension from approximately week 39 and from all rats killed or found dead from week 53. Azoxystrobin was uniformly distributed in the diet and was stable at room temperature for 66 days. The measured test concentrations ranged from 91.2% to 110.7% of the nominal values. Overall mean achieved dietary concentrations were within +/- 2.0% of the nominal concentrations. Distended abdomens were observed in males starting from week 17, with 5, 0, 5, and 15 rats affected in the control group, and at 60, 300, and 1500/750 ppm, respectively. Hunched posture was observed in males in a dose-related manner, with 3, 11, 12, and 17 rats affected, respectively. There was an apparent increased incidence of opaque eyes in males (0, 4, 2, and 5 rats in the control group, and at 60, 300 and 1500/750 ppm, respectively). No treatment-related clinical signs were observed in females at any dose. By week 52, survival rates of the males receiving the diets containing azoxystrobin at 0, 60, 300, or 1500 ppm were 97%, 100%, 98%, and 86%, respectively, prompting the dose reduction for the group receiving the highest dietary concentration. Survival rates at week 104 for the control group, and at the lowest, intermediate and highest dose were 37%, 38%, 29%, and 30%, respectively, for males and 45%, 62%, 62%, and 68%, respectively, for females. The lower survival rate for females in the control group did not develop until after week 100. Males at the highest dose had statistically significantly lower body weights (92-95%) compared with those of males in the control group beginnin
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In a study of carcinogenicity, groups of 55 male and 55 female C57BL/10JfAP/Alpk mice were given diets containing azoxystrobin (purity, 96.2%) at a concentration of 0, 50, 300, or 2000 ppm (equal to 0, 6.2, 37.5, or 272.4 and 0, 8.5, 51.3, or 363.3 mg/kg bw per day for males and females, respectively) for 104 weeks. Additional groups of five males and five females were used as microbiological sentinels and fed either control diet or diet containing azoxystrobin at 2000 ppm. Prepared diets were stored at room temperature. Stability, homogeneity and dietary concentrations were confirmed analytically. The mice were inspected daily for mortality and morbidity. Changes in clinical condition or behavior were recorded daily. Body weights were measured weekly for the first 12 weeks, then every 2 weeks thereafter and at termination. Food consumption was measured weekly for the first 12 weeks, then every 4 weeks thereafter until termination. Water consumption was not measured. An ophthalmoscopic examination was not done. Blood was collected from 11 males and 11 females per group at weeks 53, 79 and at termination. Differential leukocte counts and erythrocyte morphology were performed on mice in the control group and mice at 2000 ppm. Clinical chemistry and urine analysis were not performed. All mice that died and those that were sacrificed on schedule were subjected to gross pathological examination and selected organs were weighed (adrenals, brain, kidneys, liver and testes/ovaries). Tissues were collected for histological examination. Azoxystrobin was homogenously distributed in the diet and was stable in the diet for 56 days storage at room temperature. The measured test concentrations were within the range of 10% of the target concentrations except for one diet containing azoxystrobin at 2000 ppm that was 117% of the target concentration. At the end of the study, the survival of males was 58%, 61%, 60% and 63% (control, lowest, intermediate and highest dose, respectively). The survival of /females/ was similar at 47%, 38%, 45% and 56% (control, lowest, intermediate and highest dose, respectively). No effects were observed on mortality, clinical signs, hematology, or gross or microscopic pathology. Mean body weights of males at 2000 ppm were significantly (p < or = 0.01) lower (5.12%) than those of mice in the control group from week 2 and continuing until the end of the study. Final body weights of males at the highest dose were 94% those of the controls. Body weights of males at 300 ppm were also statistically significantly lower compared with those of the controls at weeks 2, 3, 35, and 61.83; however, final body weights gave evidence for recovery (101% of mice in the control group). No differences in body weights were observed for males at 50 ppm when compared with mice in the control group. Females at 2000 ppm had significantly (p < or = 0.01 at week 8 only, p < or = 0.05) lower mean body weights (2.7%) compared with those of the controls from study week 3 and continuing until the end of the study. Final body weights of females at the highest dose were 93% those of females in the control group. Although food consumption was similar in treated and control groups, overall food utilization was significantly (p < or = 0.01) lower in males and females at the highest dose during weeks 1-12 (the only interval for which food utilization values were calculated). Absolute kidney weights of males at 2000 ppm were significantly (p < or = 0.05) less than those of the controls. Absolute kidney weights of females at 2000 ppm were slightly lower than those of the controls (not significant). No significant differences in adjusted kidney weights (organ weight adjusted for body weight) were observed in males and females at 2000 ppm. Absolute liver weights were not affected at any dose tested. However, adjusted liver weights were increased compared with those of mice in the control group for
    • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 21 female New Zealand White rabbits were given azoxystrobin (purity, 96.2%) at a dose of 0, 50, 150 or 500 mg/kg bw per day by gavage in corn oil (dosing volume, 1 ml/kg bw) from days 8 to 20 of gestation, inclusive. Rabbits in the control group received the appropriate volume of corn oil only. ... None of the intercurrent deaths in the study was considered to be associated with the administration of azoxystrobin. The occurrence of intercurrent deaths was one, two, one, and two in the control group and at 50, 150 and 500 mg/kg bw per day, respectively. One rabbit at 500 mg/kg bw per day was killed on day 11 and was found to have an intussusception of the colon and severe body-weight loss. This death was not considered to be treatment-related. Two rabbits in the group at 150 mg/kg bw per day were killed; one was killed on day 21 of gestation after abortion and other rabbit on day 17 of gestation because of excessive body-weight loss starting from day 8 of gestation. Clinical signs included diarrhea and/or staining in the genital area in 1, 7, 15, and 18 rabbits in the control group and at 50, 150 and 500 mg/kg bw per day, respectively, beginning generally around days 9 and 10 of gestation. No other treatment-related signs were observed. ... /It was/ considered that these clinical signs were treatment-related but not relevant for the identification of a NOAEL, being considered to be secondary effects caused by local gastrointestinal irritation/disturbances and a bolus dosing by gavage in corn oil. At 150 mg/kg bw per day and 500 mg/kg bw per day, significant (p < 0.01) but transient reductions (-33%, -51%, respectively) in food consumption were observed during the first 3 days of dosing. At 500 mg/kg bw per day, decreased body-weight gain (-45%) was observed during the dosing period. Slight reductions in body weights were observed on days 9-12 at 50 and 150 mg/kg bw per day; however, the decrease in body weights did not occur in a dose-related manner. No treatment related increases in gross lesions were observed. No dose-related or statistically significant increases in external or visceral anomalies were observed. Although skeletal anomalies, mainly variations, were common in all groups (including concurrent controls), there were no statistically significant increases, nor were there any trends in dose-response observed. The LOAEL for developmental toxicity was > 500 mg/kg bw per day. The NOAEL for developmental toxicity was 500 mg/kg bw per day. The NOAEL for maternal toxicity was 150 mg/kg bw per day on the basis of decreased body-weight gain seen at the LOAEL of 500 mg/kg bw per day. The NOAEL for developmental toxicity was 500 mg/kg bw per day, the highest dose tested. The study author identified the NOAEL for maternal toxicity as 50 mg/kg bw per day owing to marginal decreases in body weight, diarrhea and food consumption at 150 mg/kg bw per day.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.23 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a study of developmental toxicity, groups of 20 pregnant New Zealand white rabbits were given azoxystrobin (purity, 96.2%) at a dose of 0, 7.5, 20, or 50 mg/kg bw per day by gavage in corn oil (dosing volume, 2 ml/kg bw) on days 8-20 of gestation, inclusive. Test substance formulations were prepared daily. Stability, homogeneity and dose concentrations were confirmed analytically. All rabbits were observed twice per day for mortality or clinical signs of toxicity. Maternal body weights were recorded on days 0 and 4 of gestation and daily on days 8-20, and on days 23, 26 and 30 of gestation. Food consumption was measured on days 8, 11, 14, 17, 20, 23 and 26 of gestation. On day 30 of gestation, all surviving does were killed and subjected to gross necropsy. The uterus and ovaries were excised and the number of corpora lutea on each ovary was recorded. Gravid uteri were weighed, opened, and the location and number of viable and nonviable fetuses, early and late resorptions, and the total number of implantations were recorded. All fetuses were weighed and examined for external malformations/variations. Each fetus was examined viscerally by fresh dissection and the sex determined. The brain from each fetus was examined by mid-coronal slice. All carcasses were eviscerated and processed for skeletal examination. The analytical data indicated that the mixing procedure for the dosing solution was adequate and that the variation between nominal and actual doses received by the rabbits was acceptable (within 3% of nominal values). There were two, four, three and seven deaths in the control group and at 7.5, 20 and 50 mg/kg bw per day, respectively. One rabbit at 50 mg/kg bw per day was found dead; the other deaths resulted from premature termination after abortion or deterioration in clinical condition, usually between days 12 and 20 of gestation. The following clinical observations were reported: blood on tray, sporadic in two, one, two, six rabbits in the control group and at 7.5, 20 and 50 mg/kg bw per day, respectively; general coat staining, two, two, three, five rabbits in the control group and at 7.5, 20 and 50 mg/kg bw per day, respectively; diarrhea, two, four, seven, seven rabbits in the control group and at 7.5, 20 and 50 mg/kg bw per day, respectively. While these occurrences were observed in a dose-related manner, their toxicological significance is uncertain. At the start of dosing, slight loss of body weight for all groups including the controls was observed. The loss in body weight was more severe at 20 and 50 mg/kg bw per day than in the control group. Five rabbits at 50 mg/kg bw per day showed progressive body-weight loss from which they did not recover and were therefore killed. However, two, three and two rabbits were killed for similar reasons in the control group and at 7.5 and 20 mg/kg bw per day, respectively. Food consumption data were inconclusive owing to food wastage and other factors. Some rabbits showed very little food consumption. The number of rabbits showing negligible food consumption during the dosing period was five, six, eight and nine in the control group and at the lowest, intermediate and highest dose, respectively. No dose-related adverse effects were noted during necropsy, either in rabbits that died during the study, or in rabbits sacrificed at the end of the study. The incidence of fetuses with major defects was 8, 0, 2 and 13 in the control group and at 7.5, 20 and 50 mg/kg bw per day, respectively. At the highest dose, nine fetuses (8.6%) from two litters (16.7%) had open eye, the majority being bilateral. One fetus at the highest dose had cleft palate. Other effects were of low occurrence, were not dose-related, and were not associated with treatment. These effects included internal hydrocephaly, encephalocoele, fenestration in parietal, reduced pulmonary artery, enlarged aorta. Many of these effects occurred in the control gr
    • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a study of developmental toxicity, groups of 24 female Alpk:APfSD rats were given azoxystrobin (purity, 95.2%) at a dose of 0, 25, 100 or 300 mg/kg bw per day by gavage in corn oil (dosing volume, 1 mL/100 g bw) from day 7 to 16 of gestation, inclusive. Stability, homogeneity and dose concentrations were confirmed analytically. All rats were observed daily for clinical signs of toxicity, mortality and moribundity. Maternal body weights were recorded on days 1, 4, 7-16, 19 and 22 of gestation. Food consumption was determined at 3-day intervals until day 22 of gestation. On day 22 of gestation, all surviving dams were sacrificed and subjected to gross necropsy. Examinations at sacrifice comprised uterine weight, number and positions of implantations; corpora lutea in each ovary, individual fetal weights, percentage preimplantation loss, percentage postimplantation loss, early and late intrauterine deaths. All fetuses were weighed, sexed, and examined for external malformations/ variations. Each fetus was examined viscerally by fresh dissection and the sex was verified. The fetuses were then eviscerated and fixed in 70% industrial methylated spirits. After approximately 24 h, the brain was examined for macroscopic abnormalities and the carcasses were stained with Alizarin Red S for evaluation of the skeleton. Analysis of the dosing solution indicated that the test material was homogenously distributed and was stable for 25 days. The achieved concentrations were within 4% of the nominal values. Three rats at 300 mg/kg bw per day were found dead after receiving two daily doses and one rat was killed in extremis. Severe signs of toxicity were observed in another 12 rats. Dosing of the remaining rats in this group was suspended. These rats were able to recover and continue to scheduled termination. The remaining 12 rats at the highest dose did not start treatment and no assessment of developmental toxicity was made at this dose. Gross necropsy of rats at the highest dose that were found dead revealed red areas and thin walls in the stomach or jejunum. In the groups at the intermediate dose, two animals showed hemorrhagic areas in the stomach at terminal necropsy; these findings were considered to be likely to be related to local irritation caused by the administration of azoxystrobin by gavage. At 100 mg/kg bw per day, minimally reduced body weights (< 2%) were observed (p < 0.05), although body-weight gain and food consumption were not affected. Clinical signs during dosing included diarrhea (42%), urinary incontinence (17%) and salivation between days 9 and 16 (71%). At 25 mg/kg/bw per day, salivation was observed in 29% of rats between days 11 and 16. The Meeting considered that these clinical signs were treatment-related but not relevant for the identification of a NOAEL, being considered to be secondary effects caused by local gastrointestinal irritation/ disturbances and bolus dosing by gavage in corn oil. In the conceptus, no significant adverse developmental effects were observed. General reduced ossification was seen at all doses, the incidence of which was not statistically different between the controls group and groups receiving azoxystrobin. There was, however, a statistical increase (6.9% vs 2.6%, p < 0.05) in the rats with a PES score of 6 at 100 mg/kg bw per day vs controls. Since this possible minimal increase in reduced ossification was not supported by increases in other related end-points, and was not statistically different from controls, the Meeting considered that it was not of toxicological significance. The NOAEL for maternal and developmental toxicity was 100 mg/kg bw per day, the highest dose tested. The study author concluded that the NOAEL for maternal and developmental toxicity was 25 mg/kg bw per day, considering that minimal reduction in ossification was a treatment-related effect.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation fo
    • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a two-generation study of reproductive toxicity, groups of 26 male and 26 female Alpk:APfSD (Wistar-derived) rats were given diets containing azoxystrobin (purity, 96.2%) at a concentration of 0, 60, 300, or 1500 ppm. The average achieved intake of azoxystrobin during the premating interval for the F0 and F1 generations was as follows: 0, 6.4, 32.3, or 165.4 mg/kg bw for males and 0, 6.8, 33.8, or 175.0 mg/kg bw per day for females. All rats were mated on a 1:1 ratio. All rats were exposed continuously to diets containing the test material throughout the study. Diets were prepared in batches of 60 kg and stored at room temperature. Stability, homogeneity and dietary concentrations were confirmed analytically. The rats were inspected daily for clinical observations, mortality, and morbidity. Physical examinations were performed weekly. Body weights were recorded weekly during the mating period. Females were weighed on days 1, 8, 15, and 22 of gestation, and days 1, 5, 11, 16, 22 and 29 of lactation. Food consumption was measured weekly throughout the mating period and for females during gestation and lactation. Estrous cycles were monitored with vaginal smears taken during the mating period and until mating was confirmed. The duration of gestation was calculated. Females were allowed to deliver normally and rear young to weaning on day 29. Litters were examined after delivery and pups were sexed, examined for gross abnormalities and the number of stillborn and live pups recorded. Litters were then examined daily for survival. The number, sex and weight of pups were recorded on postnatal days 1, 5, 11, 16, 22, and 29. All parental (F0) and F1 rats and those found dead and killed in extremis were necropsied and examined macroscopically. All pups that were not selected for the next generation were killed on postnatal day 29. Selected male and female pups received a full examination post mortem. Selected tissues (liver, uterus, cervix, vagina, ovaries, mammary glands, testes, epididymides, prostate, seminal vesicle and pituitary gland) were examined histopathologically. Liver, epididymides, and testes/ovaries were weighed. The analytical data indicated that the mixing procedure for the diets was adequate and that the variation between nominal and actual dietary concentrations received was within 10% of the nominal values. There were no treatment-related clinical signs of toxicity or increases in mortality noted at any dose. However, one F0 male and one F1 male from the groups at 1500 ppm were sacrificed in a moribund condition and exhibited treatment-related distention of the common bile duct. At 1500 ppm, systemic toxicity in the F0 and F1 adults (males and females) was apparent as reduced adjusted body weights (3.12%, p < or = 0.01 or 0.05) and food consumption (5.14%, p < or = 0.05 or 0.01) during the pre-mating intervals. At 1500 ppm, gestational body weights were reduced (within 5% of values for controls) for F0 and F1 females. In addition, treatment-related increases in liver weights adjusted for final body weights were noted in the F0 and F1 males and females (15.38%, p < or = 0.01 or 0.05) at 1500 ppm. Treatment-related distention of the common bile duct was also noted in 3 and 11 of the F0 and F1 males at 1500 ppm, respectively, on examining grossly. Treatment-related histopathological lesions of the common bile duct in the adult males at the highest dose were characterized as epithelial hyperplasia of the intraduodenal portion, cholangitis, ulceration of the dilated region, and small basophilic deposits in the lumen. Treatment-related increases in severity of proliferative cholangitis were also observed in the livers of the F0 and F1 males at 1500 ppm. Males and female in the F1a and F2a at 1500 ppm had treatment-related increases in the adjusted (for final body weight) liver weights (10.13%, p < or = 0.01). No treatment-related clinical signs of toxicity wer
    • LABORATORY ANIMALS: Neurotoxicity: In a short-term study of neurotoxicity, groups of 12 male and 12 female Alpk:APfSD rats were given diets containing azoxystrobin (purity, 96.2%) at a concentration of 0, 100, 500 or 2000 ppm (equal to 0, 8.0, 38.5 or 161 mg/kg bw per day in males and 0, 9.1, 47.9 or 201.5 mg/kg bw per day in females) for 13 weeks. All rats were evaluated in functional observational battery (FOB) and motor activity tests in weeks -1, 5, 9 and 14. All rats were observed before the study start and daily throughout the study for any changes in clinical condition. Body weights and food consumption were measured weekly throughout the study. Six male and six female rats from the control group and at the highest dose were perfused in situ and evaluated for microscopic neuropathology. Analysis of the dietary preparations showed that diets were stable at room temperature for 56 days and the test article was homogeneously distributed in the diet. The overall mean dietary concentrations were within 8% of the nominal values. There were no deaths or treatment-related changes in clinical condition observed during the study. At 2000 ppm, mean body weights of males were statistically significantly decreased throughout the study (at week 13, 12.6% less than controls). Mean body weights of females were slightly decreased (at week 13, 5.1% less than controls; significant only at week 2). Cumulative body-weight gains were 18% lower (males) and 10% lower (females) than those of the controls. Food consumption was statistically significantly lower than those of the controls in males (5.4% to 15.4%) but not females. Food utilization in males at 2000 ppm was statistically significantly decreased during weeks 1.4 (9.7%) and 1.13 (11.7%) and was non-significantly less in females during the same periods (11.8% and 14.4%, respectively). There were no consistent indications of treatment-related neurotoxicity (clinical signs, qualitative or quantitative neurobehavioral effects, brain weight/ dimensions, or gross/microscopic pathology). Statistically significant decreases in landing foot splay in males (week 5: 19%, 16.4% and 24.1%, for the lowest to the highest dose, respectively; week 9, 18% at the highest dose), forelimb grip strength (males: week 5, 14.3%, 14.3% and 19%, for the lowest to the highest dose, respectively; and females, week 14, 12.9%, highest dose), hind-limb grip strength in males (week 5, 13.3%, 15.3% and 12.9%, for the lowest to the highest dose, respectively) and motor activity in females (21%, week 9) were noted but not considered to be treatment-related owing to lack of a dose-response relationship, inconsistency of observations at different time-points, variability of pre-treatment values and/or small magnitude of response. Brain weight and length were unaffected by treatment. There were no macroscopic or treatment-related microscopic findings at the end of the study. The LOAEL for systemic toxicity was 2000 ppm, equal to 161 mg/kg bw per day, on the basis of decreased body weight/body-weight gain and food utilization in males and females (marginal in females). The NOAEL was 500 ppm, equal to 38.5 mg/kg bw per day. The NOAEL for neurotoxicity was > or = 2000 ppm, equal to > or = 161 mg/kg bw per day[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.25 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Neurotoxicity: In an acute neurotoxicity study, ICIA5504 (azoxystrobin, 96.2% ai) was administered once in corn oil (10 mL/kg body weight) by gavage to 3 groups of 10 Alpk:ApfSD rats/sex/dose at doses of 0, 200, 600, or 2000 mg/kg. All animals were evaluated in functional observational battery (FOB) and motor activity testing on days -7 (7 days prior to dosing), 1 (2 hours post dosing), 8, and 15. Five control and high dose animals/sex perfused in situ were evaluated for microscopic neuropathology. At 200 mg/kg and higher, diarrhea/signs of diarrhea were observed at 2 hours post-dosing in both sexes (males, 1, 4, 5 and 10; females, 0, 9, 9 and 6). Tip-toe gait and upwardly curved spine at 2 hr were also observed in treated but not control animals (no dose-response observed). No treatment-related effects on survival, food consumption, motor activity, brain weight/dimensions, or gross microscopic pathology were observed. Body weights of males at 2000 mg/kg were slightly decreased (2.9% and 2.6% at day 8 and 15). Statistically significant increases in landing foot splay and on day 8 in females at 600 and 2000 mg/kg are noted (23.7% and 20.5% higher than controls, respectively; on day 1 females at 600 and 2000 mg/kg had nonstatistically significantly increased values of 11.8 and 12.5%, respectively). These were not considered indicative of neurotoxicity because of the lack of effect on day of dosing (only marginal non-significant increase seen) and to lack of a clear dose-response and indications of other effects. The systemic toxicity LOAEL is 200 mg/kg, based on occurrence of transient diarrhea in both sexes. The systemic toxicity NOAEL is less than 200 mg/kg. there was no indication of neurotoxicity at the doses tested.[USEPA; Azoxystrobin: Human Health Risk Assessment. (Attachment 2) (September 22, 2000). Available from, as of December 29, 2011: http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-128810_22-Sep-00_092.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In a 21-day study of dermal toxicity after repeated doses, groups of five male and five female Wistar (Alpk:APfSD) rats received dermal applications of azoxystrobin (purity, 96.2%) at a dose of 0, 200, 500 or 1000 mg/kg bw per day formulated in deionized water, for 6 hr/day, for a total of 21 days over a 30-day period. The hair was clipped from the back of each rat before the first application, then periodically as required. The application site was then wrapped in occlusive gauze bandage covered by a patch of plastic film and secured with polyvinyl chloride (PVC) tape for 6 hr. After the exposure, the gauze and tape were removed and the application site was cleansed free of any residual test material, using a clean swab of cotton wool soaked in warm water, and dried. The control group received distilled water applied with the same method. The rats were observed twice per day for signs of mortality, morbidity, toxicity, and the presence of dermal irritation. Dermal reactions at the application site were scored daily (before dosing) using the Draize score. Body weight was measured before dosing then daily thereafter. Food consumption was calculated on a daily basis. Blood was taken at the end of the study, and the standard test parameters were examined. At the end of the study, all rats were examined grossly post mortem. Testes, kidneys and liver were weighed. The adrenals, brain, kidneys, liver, testes, epididymides, treated skin, and untreated skin were removed and examined microscopically. This study was conducted in accordance with GLP regulations. No mortality was observed and there were no significant treatment-related clinical abnormalities. There were no treatment-related effects on body weight, food consumption, organ weights, clinical biochemistry, or hematology. There were no treatment-related pathological abnormalities. Abdominal scabs and scabs at the edge of the application area were observed in all groups of females and were attributed to the bandaging method and were not of toxicological significance. The no-observed-adverse-effect level (NOAEL) for systemic toxicity and dermal irritation with azoxystrobin was 1000 mg/kg bw per day (the highest dose tested). A lowest-observed-adverse effect level (LOAEL) was not identified.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.13 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In a 90-day study of toxicity, groups of 12 male and 12 female Wistar-derived (Alpk:APfSD) rats were given diets containing azoxystrobin (purity, 95.2%) diet at a concentration of 0, 200, 2000 or 4000 ppm (equal to 0, 20.4, 211.0 or 443.8 mg/kg bw per day for males and 0, 22.4, 223.0 or 448.6 mg/kg bw per day for females) for 13 weeks. The groups given diets at 4000 ppm were initially given diets at 6000 ppm, but this concentration was reduced after 15 days owing to reduced food consumption and a marked reduction in growth. After 5 days on control diet, this group was subsequently fed diets containing azoxystrobin at 4000 ppm for the rest of the study. Diets were prepared at the initiation of the study and stored frozen. Stability, homogeneity and dietary concentrations were confirmed analytically. Rats were inspected daily for signs of toxicity and mortality, with detailed cage-side observations done weekly. Body weight and food consumption were measured weekly. At termination, blood was taken for hematological and clinical chemistry analysis. Urine analysis and ophthalmoscopic examinations were performed during the week of termination. All rats that died and those that were sacrificed on schedule were given gross pathological examinations and selected organs were weighed. Selected tissues were collected for histological examination. Diets were stable for 64 days at room temperature. The test article homogeneity results were within the acceptable range (-0.8 to +1.4% deviation from the mean). The analysis of test substance concentration indicated that the measured concentrations of azoxystrobin ranged from 92% to 111% of the target concentrations. No mortality occurred during the study. Distended abdomen was seen in males and females at 2000 and 4000 ppm, consistent with local gastrointestinal disturbances and reduced nutritional status. At termination, males (11 out of 12) and females (10 out of 12) in the group at 4000 ppm appeared to be of small size compared with rats in the control group or at 200 ppm. No other treatment-related clinical signs of toxicity were observed. Final body weights of males and females at 4000 ppm were reduced by 32% and 18%, respectively, and final body weights of males and females at 2000 ppm were reduced by 18% and 11%, respectively. Food consumption and food efficiency were reduced in males and females at 4000 ppm, particularly during weeks 1-2 or weeks 1-4. However, by the end of the study, food efficiency of females at 4000 ppm was not significantly reduced compared with that of controls. The results of ophthalmological examination of rats at 4000 ppm were comparable to those for rats in the control group. Minimal reductions in hemoglobin, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed only in females at 4000 ppm. Minor but statistically significant reductions in MCV at 200 and 2000 ppm and MCH at 2000 ppm were observed in females. Leukocyte count was statistically significantly increased in females at 4000 ppm. Platelet counts were slightly decreased in males and females at 4000 ppm. Clotting parameters were not affected. The changes in hematological parameters were small; these changes were therefore not considered to be toxicologically significant. Changes in clinical chemistry parameters such as reduced cholesterol (males), glucose (females), decreased triglycerides (males and females), and decreases in some plasma enzyme activities (males and females) were observed at 4000 ppm. All these findings were less marked in the groups at 2000 ppm and were absent in the groups at 200 ppm. The total urinary protein of males at 4000 ppm was reduced. Blood was present in the urine of males in the control group and in a number of male and female rats at 2000 and 4000 ppm. Increases in liver and kidney weights adjusted for body weight in rats at 2000 and 4000 ppm were attributable to treatment with azoxystrobi
    • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In a 90-day study of toxicity, groups of four male and four female beagle dogs were given capsules containing azoxystrobin (purity, 96.2%) at a dose of 0, 10, 50, or 250 mg/kg bw per day for 92 or 93 days. Equal numbers of dogs in each group were treated for each number of days. The dogs were inspected twice per day for clinical or behavioral abnormalities. A detailed physical examination was performed before the start of treatment and at termination. Eyes were examined by indirect ophthalmoscopy at week 1 and before termination. Body weight and food consumption were measured weekly. Blood for measurement of hematological and clinical chemistry parameters was collected from all dogs before the test, and after 4, 8 and 13 weeks of treatment. Urine analysis was performed on all dogs at termination. At the end of the study, a complete gross post mortem was done. The adrenals, brain, kidneys, liver, epididymides, testes and thyroid glands were weighed. The organs specified were examined microscopically. No dogs died during the study. Treatment-related clinical observations in males and females included increases in salivation at dosing and increased incidence of salivation, fluid feces, vomiting, and regurgitation primarily in dogs at 250 mg/kg bw per day (statistical analysis was not performed). All males and three of the females at 250 mg/kg bw per day exhibited salivation and/or salivation at dosing. Isolated occurrences of salivation/salivation at dosing were seen in one female at 50 mg/kg bw per day and one male in each group at 50 and 10 mg/kg bw per day. The incidence of salivation and gastrointestinal findings at 10 mg/kg bw per day was minimal. There was a dose-related increase in the incidence of fluid feces, which was prominent in dogs at 250 mg/kg bw per day. Minor increases were seen in the incidence of regurgitation and vomiting in males and females at 250 mg/kg bw per day. The Meeting considered that these clinical signs were treatment-related but not relevant for the identification of a NOAEL, being judged to be secondary to local gastrointestinal irritation/ disturbances and bolus dosing (capsule). The weekly body weights of males and females differed statistically significantly from those of dogs in the control group for most weeks at 250 mg/kg bw per day and in females at 50 mg/ kg bw per day, although values were within 9% of controls (p < or = 0.05 or 0.01). Total body-weight gains were 34% and 38% lower than those of dogs in the control groups for males and females, respectively, at the highest dose. Hematological alterations in one or both sexes at 250 mg/kg bw per day were small, sporadic compared with values for concurrent controls and/or pre-treatment values and not toxicologically relevant. Clinical chemistry parameters that were altered statistically significantly for one or more weeks in males and females at the highest dose compared with those in dogs in the control group included plasma cholesterol (13-26% increase), triglycerides (42-89% increase), alkaline phosphatase activity (24-87% increase), and plasma albumin (7.9-11.6% decrease). Cholesterol was increased in males at the intermediate and lowest dose (17-25%). These results were accompanied by increased absolute liver weight in females at the intermediate and lowest dose (6.3% and 9.3%, respectively), and are consistent with an adverse effect on liver and possibly biliary function. The lack of histopathological correlates and of a clear dose- and time-related response in some cases indicated that the clinical and liver-weight changes were an adaptive response in the liver of dogs at the lowest and intermediate doses. Other clinical chemistry changes did not appear to be treatment-related (plasma sodium, creatinine, and total protein). There were no treatment-related effects on gross or microscopic pathology, food consumption, ophthalmology, or urine analysis. In the absence of histologica

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    Human Toxicity Values

    • None found

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    Non-Human Toxicity Values

    • LD50 Rat oral >5000 mg/kg[Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994., p. 579] **PEER REVIEWED**
    • LD50 Rat percutaneous >2000 mg/kg[Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994., p. 579] **PEER REVIEWED**

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    Absorption, Distribution And Excretion

    • Eight male and female rats were given 14 consecutive daily oral doses of unlabelled azoxystrobin at 1 mg/kg bw followed by a single oral dose of (14)C-pyrimidinyl-labelled azoxystrobin at 1 mg/kg bw. For the repeated doses, about 89.1% and 86.5% of the administered dose was excreted in the feces of the males and females rats within 7 days, respectively, and about 12.5% and 17.0% of the administered dose was excreted in the urine of the males and females rats within 7 days, respectively. In males and females, excretion of radioactivity was rapid, with > 96% being excreted during the first 48 hr. Approximately 0.62% and 0.39% of the administered dose was found in the carcass and tissues within 7 days after dosing in male and female rats, respectively. For the repeated dose, the highest concentrations of azoxystrobin-derived radioactivity were found in the kidneys (males and females, < 0.04 ug equivalents/g). The concentrations found in the liver were 0.02 and 0.01 ug equivalents/g for males and females, respectively. At termination, the total concentration of radioactivity in blood was 0.01 ug equivalents/g for males and females.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.6 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • In toxicokinetic studies, groups of male and female Alpk:APfSD rats (five to eight per group, depending on experiment) were given azoxystrobin (purity, 99%) with or without pyrimidinyl label as a single dose at 1 or 100 mg/kg bw by gavage or as 14 repeated doses of 1 mg/kg bw per day. Biliary metabolites were assessed using rats with cannulated bile ducts given a single dose at 100 mg/kg bw by gavage. The vehicle was polyethylene glycol (PEG 600) at 4 mL/kg bw. Treated rats were housed in stainless steel metabolism cages for 7 days. Urine was collected at 6 hr, and urine and feces were collected separately at 12, 24, 36, 48 h and at 24 hr intervals until 7 days after dosing. At each collection, cages were rinsed with water and cage-washing collected together with the urine. At the end of the study, cages were thoroughly rinsed with ethanol/water (1:1 v/v) and retained for radiochemical analysis. Carbon dioxide and volatiles were trapped. After 7 days, various organs and tissues were removed and analyzed for radioactivity. ... For rats receiving a single lower dose (1 mg/kg bw), total excretion of radioactivity (urine, feces, and cage wash) was 93.75% and 91.44% for males and females, respectively over the 7 days. Most (> 85%) of the urinary and fecal excretion took place during the first 36 hr after dosing. In these rats, about 83.2% and 72.6% of the administered dose was excreted in the feces of males and females within 7 days, respectively, and about 10.2% and 17.9% of the administered dose was excreted in the urine of the males and females within 7 days, respectively. Approximately 0.34% and 0.31% of the administered dose was found in the carcass and tissues within 7 days after dosing in males and females, respectively. For rats at this dose (1 mg/kg bw), the highest concentrations of radiolabel were found in the liver (mean for males and females, 0.009 ug equivalents/g) and in the kidneys (males, 0.027 ug equivalents/g; and females, 0.023 ug equivalents/g). At termination, the total concentration of radioactivity in blood was 0.004 ug equivalents/g for males and females. Less than 0.6% of the administered dose was recovered in the expired. For rats receiving the single higher dose (100 mg/kg bw), total excretion of radioactivity (urine, feces, and cage wash) was 98.29% and 97.22% for males and females, respectively, over the 7 days. Most (> 82%) of the urinary and fecal excretion took place during the first 48 hr after dosing. At this dose, about 89.37% and 84.53% of the administered dose was excreted in the feces of the males and females within 7 days, respectively, and about 8.54% and 11.54% of the administered dose was excreted in the urine of the males and females within 7 days, respectively. Approximately 0.33% and 0.33% of the administered dose was found in the carcass and tissues within 7 days after dosing in males and females rats, respectively. At this higher dose, the highest concentrations of radiolabel were found in the kidneys (males, 1.373 ug equivalents/g; and females, 1.118 ug equivalents/g) and in the liver (males, 0.812 ug equivalents/g; and females, 0.714 ug equivalents/g). At termination, the total concentration of radioactivity in blood was 0.389 ug equivalents/g for males and 0.379 ug equivalents/g for females[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.5 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • The excretion and tissue distribution of radioactivity was investigated for 48 h in male and female rats given a single dose of azoxystrobin at 1 mg/kg bw by gavage. Treated rats were housed in metabolism cages to facilitate the collection of urine, feces, exhaled air and volatiles. One male and one female rat receiving azoxystrobin radiolabelled in each position were killed at 24 hr and 48 hr after dosing. Each carcass was frozen and sectioned in preparation for whole-body radiography. About 89% and 86% of the administered dose of (14)C-pyrimidinyl-labelled azoxystrobin was excreted within 48 hr in the urine and feces of male and female rats, respectively. Most of the radioactivity was excreted in the feces, with < 17% in the urine. The male and female rats treated with (14)C-phenylacrylate-labelled azoxystrobin excreted about 80% and 97% of the administered dose within 48 hr, respectively. Most of the radioactivity was excreted via the feces with < 21% in the urine. At 48 hr, males and females, excreted approximately 0.01% of the administered dose as carbon dioxide trap and approximately 0.01% as volatile metabolites. The male and female rats treated with (14)C-cyanophenyl- labelled azoxystrobin excreted about 95% and 98% of the administered dose within 48 hr, respectively. Most of the radioactivity was excreted via the feces, with < 16% in the urine. At 48 hr, males and females excreted small amounts of radioactivity as carbon dioxide (< 0.3%) and as volatile metabolites (0.01%). For all radiolabels, the distribution of radioactivity was similar in males and females, as shown by whole-body autoradiography. At 24 hr, most of the radiolabel was present in the alimentary canal, moderate amounts in the kidneys and small amounts in the liver. Forty-eight hours after dosing, the whole-body autoradiography results showed a marked reduction in radioactivity. The results of these studies indicated that there were no significant differences between the rates and routes of excretion or tissue distribution of azoxystrobin labelled in one of three positions. No sex-related difference in excretion profile was evident. Minor differences in excretion were primarily due to the small numbers of rats used in the study. No significant differences in the amount of radioactivity recovered in the exhaled air and as volatiles were observed between the three radiolabels or between sexes. On the basis of the results of this study, other studies of excretion and tissue retention were conducted using only pyrimidinyl-labelled azoxystrobin.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.4 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**

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    Metabolism/Metabolites

    • ... (14)C-Cyanophenyl-labelled azoxystrobin was given to bile duct cannulated and non-cannulated rats at a dose of 100 mg/kg bw. Samples of urine, feces and bile were collected for up to 72 hr. The purpose of this study was to reevaluate certain plant and goat metabolites that were previously not identified in rats and further elucidate the metabolic pathway of azoxystrobin in rats. Three further metabolites, previously detected in either plants or goats, were identified. Compound 13 (2-hydroxybenzonitrile), resulting from cleavage of the diphenyl ether link, was detected in the bile and urine as the glucoronide conjugate at a concentration of up to 1.8% of the administered dose. Compound 20 ((2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy) phenyl)acetic acid) was also detected in the bile and urine at a concentration of up to 1.3%. Compound 35 (2-(2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy) phenyl)glycolic acid) was detected in the urine, feces and bile at a concentration of up to 0.6%. Compounds 24 (Methyl 2-(2(6-(2-cyanophenoxy)pyrimidin-4-yloxy) phenyl)-glycolate) and 30 (2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy) benzoic acid) were not detected.[WHO/FAO; Joint Meeting on Pesticide Residues Evaluation for Azoxystrobin (131860-33-8) p.8 (2008). Available from, as of December 27, 2011: http://www.inchem.org/pages/jmpr.html] **PEER REVIEWED**
    • Bile-duct cannulated rats were given azoxystrobin radiolabelled in either the pyrimidinyl, cyanophenyl or phenylacrylate rings at 100 mg/kg bw by gavage. Comparison of the rates and routes of excretion and the profile of the metabolites showed (as previously) that there were no significant differences in the metabolism of the three differently labelled forms, thus indicating that there was minimal cleavage of the ether linkages between the aromatic rings. Experiments designed to identify metabolites were therefore conducted in bile-duct cannulated rats given (14)C-pyrimidinyl labelled azoxystrobin by gavage. In the bile-duct cannulated rats, excreta, bile, and cage wash were collected at 6, 12, 24, 36, and 48 hr and stored at -20 deg C. Samples of bile, feces and urine were collected between 0 hr and 48 hr and pooled. Samples for males and females were separated. Urine and feces were collected at up to 168 hr after dosing from rats given the single dose (higher or lower) and from rats receiving repeated doses for 14 days, and were used for quantification of metabolites. Some bile samples were enzymatically digested using cholylglycine hydrolase at 30 units/mL, pH 5.6 at 37 deg C overnight. Metabolites were identified using various analytical techniques, such as thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (NMR) and mass spectrophotometry (MS). On the basis of biliary excretion data for rats given a single dose of either (14)C-pyrimidinyl-, (14)C-phenylacrylate-, or (14)C-cyanophenyl-labelled azoxystrobin at 100 mg/kg bw, 74.4% (males) and 80.7% (females) of the pyrimidinyl-derived radioactivity was excreted in the bile after 48 hr. For the cyanophenyl-derived radioactivity, 56.6% and 62.5% was excreted in the bile of males and females, respectively. For the phenylacrylate-derived radioactivity, 64.4% (males) and 63.6% (females) was excreted in the bile. Quantitatively, there were no significant differences in biliary excretion between males and females. Azoxystrobin was found to undergo extensive metabolism in rats. A total of 15 metabolites were detected in the excreta and subsequently identified. Seven additional metabolites were detected but not identified. None of the unidentified metabolites represented more than 4.9% of the administered dose. The quantitative data for the various metabolites in the faeces, urine and bile of rats receiving a single dose of azoxystrobin at 100 mg/kg bw ... . The mass balance for the study of metabolite identification indicated that a substantial percentage of the administered radiolabel (45.6-73.6%) was unaccounted for, although the studies of excretion showed total recovery of 91.75-103.99%, with 72.6-89.3% being in the feces. The percentage of unaccounted-for radiolabel was especially notable in the groups receiving a single lower dose and a repeated lower dose. The study authors indicated that the variable efficiency in recovery could be explained by the fact that, for metabolite identification, feces were extracted with acetonitrile which allowed partitioning of the parent compound when it was present in the faeces (i.e. rats receiving the higher dose). For the groups receiving a single lower dose or repeated lower dose (where quantities of the parent compound were minimal), most of the faecal radiolabel was associated with polar metabolites that would not be present in the acetonitrile extract. The resulting concentration of radiolabel in the extract would, therefore, be very low. For the group receiving the higher dose, greater amounts of parent compound were left unabsorbed, thereby resulting in greater amounts of parent compound available for partitioning into the acetonitrile extract. The glucuronide conjugate (metabolite V) was the most prevalent biliary metabolite in both males (29.3%) and females (27.4%). Metabolite I (parent compound) was not detected in the bile. Each of the other biliary metabo
    • The metabolic fate of [(14)C]-methyl-(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate (azoxystrobin) was determined in the male and female rat following a single oral dose of 1 and 100 mg x kg(-1) and in surgically prepared, bile duct-cannulated rats following a single oral dose of 100 mg x kg(-1). 2. Azoxystrobin was extensively metabolized with at least 15 metabolites. There was a sex difference, with females producing more metabolites than males. 3. The two principal metabolic pathways were hydrolysis of the methoxyacid followed by glucuronic acid conjugation and glutathione conjugation of the cyanophenyl ring followed by further metabolism leading to the mercapturic acid. There were also several other minor pathways.[Laird WJ et al; Xenobiotica 33 (6): 677-90 (2003)] **PEER REVIEWED** PubMed Abstract

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    Tsca Test Submissions

    • None found

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    Footnotes

    1 Source: the NTP's CEBS database.

    2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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