Comments: No appropriate endpoint attributable to a single exposure (dose) was identified from studies including acute neurotoxicity study and developmental toxicity studies in rats and rabbits. An acute reference dose was not established for the general population including infants, children, and females age 13-49.  In the developmental toxicity study in rabbits, increased incidence of paw flexion was observed at 1000 mg/kg/day and was slightly above historical controls. Maternal toxicity, decreased fetal body weight, and incomplete ossification were also observed at this dose. Paw flexion was considered to be associated with ossification effects (i.e., all three pups that exhibited paw flexions also had incomplete ossification).  Delays in ossification and developmental delays are not typically used to set acute reference doses, therefore, paw flexion would not be used as an acute endpoint.

A.3.2	Chronic Reference Dose (cRfD)
Study Selected:  Three co-critical studies selected: Combined Chronic Toxicity/Carcinogenicity Study in Rats, 90-Day Feeding Study in Rats and Two-generation Reproduction Study in Rats.
MRID No:  48542696, 48542697 (chronic toxicity/carcinogenicity rat); 48542682 (90 day feeding rat); 48542702 (2-generation reproduction study)
Executive Summary:  See Appendix A.4.
Dose and Endpoint for Risk Assessment:  NOAEL= 16.5 mg/kg/day from both the 90-day and chronic toxicity/carcinogenicity toxicity studies in rats.  The LOAEL = 30.6 mg/kg/day from the 2-generation reproduction toxicity study. This parental LOAEL is based on effects on the adrenals (increased organ weights and histopathology), which is the target organ.
Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor)
Comments on Study/Endpoint/Uncertainty Factors:  Three studies were selected as co-critical studies for the chronic dietary endpoint. These studies are appropriate for the duration and populations of concern since there is no progression of toxicity over time. The NOAEL and LOAEL selected were based on the weight of evidence from the three studies which had similar target organ toxicities. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90-day and the chronic toxicity/carcinogenicity rat studies, which have similar NOAELs and LOAELs. The LOAEL of 30.6 mg/kg/day was selected from the 2-generation reproduction study. Although a lower NOAEL of 9.2 mg/kg/day was identified in the reproduction study (LOAEL = 30.6 mg/kg/day) this NOAEL was not selected as the POD for risk assessment since it is considered to be a function of calculated compound intake (based on food consumption) rather than a lower NOAEL/LOAEL per se.  The higher POD of 16.5 mg/kg/day selected is still protective of the effects seen at 30.6 mg/kg/day in the 2-generation reproduction toxicity study.  The POD is also protective of similar effects seen in the 28 day rat study at LOAEL of 75 mg/kg/day, the chronic mouse study at LOAEL of 537/483 mg/kg/day (M/F), and the chronic dog study at LOAEL of 300 mg/kg/day.

                        Chronic RfD =  = 0.17 mg/kg/day

A.3.3	Incidental Oral Exposure (Short- and Intermediate-Term)
Study Selected: Three co-critical studies selected: Combined Chronic/Carcinogenicity Study in Rats, 90-Day Feeding Study in Rats and Two-generation Reproduction Study in Rats
MRID No.:  48542696, 48542697 (chronic/carcinogenicity rat); 48542682 (90 day feeding rat); 48542702 (2-generation reproduction study)
Executive Summary:  See Appendix A.4.
Dose and Endpoint for Risk Assessment: NOAEL= 16.5 mg/kg/day from both the 90-day and chronic toxicity/carcinogenicity toxicity studies in rats. The LOAEL = 30.6 mg/kg/day from the 2-generation reproduction toxicity study. This parental LOAEL is based on effects on the adrenals (increased organ weights and histopathology), which is the target organ.
Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor)
Comments on Study/Endpoint/Uncertainty Factors:  There is no incidental oral exposure expected based on the current use pattern; however, an endpoint was selected during the full review of the database.

A.3.4	Dermal Exposure (Short-, Intermediate- and Long-Term)
Study Selected: None
Comments:  For short and intermediate-term dermal exposure, no appropriate endpoint was identified for risk assessment. A 28-day dermal toxicity study in rats is available; however, no adverse effects were seen at the highest dose tested of 1000 mg/kg/day. The endpoints of concern (adrenal effects) were also looked at in this study.  Although developmental/reproductive effects (not assessed in the dermal study) were observed in the developmental and reproductive toxicity studies, the effects occurred in the presence of parental toxicity.  Therefore, since no effects were observed in adults at the limit dose, no developmental or reproductive effects would be expected to occur due to parental dermal exposure.  Risk assessment for short- and intermediate, and long-term dermal exposure is not necessary.

A.3.5	Inhalation Exposure (Short-, Intermediate- and Long-Term)
Study Selected: Three co-critical studies selected: Combined Chronic/Carcinogenicity Study in Rats, 90-Day Feeding Study in Rats and Two-generation Reproduction Study in Rats
MRID No.:  48542696, 48542697 (chronic/carcinogenicity rat); 48542682 (90 day feeding rat); 48542702 (2-generation reproduction study)
Executive Summary:  See Appendix A.4.
Dose and Endpoint for Risk Assessment: NOAEL= 16.5 mg/kg/day from both the 90-day and chronic toxicity/carcinogenicity toxicity studies in rats. The LOAEL = 30.6 mg/kg/day from the 2-generation reproduction toxicity study. This parental LOAEL is based on effects on the adrenals (increased organ weights and histopathology), which is the target organ.
Uncertainty Factor:  100x (10x interspecies extrapolation, 10x intraspecies variability)
Inhalation Absorption Factor:  Equivalent to oral absorption.
Comments on Study/Endpoint/Uncertainty Factors:  The HASPOC, based on a WOE approach, determined that a subchronic inhalation toxicity study is not needed for cyflumetofen at this time (TXR# 0056691). This approach considered all of the available hazard and exposure information for cyflumetofen, including:  1) the physical/chemical properties of cyflumetofen including its low volatility (4.43 x 10[-8] mm Hg at 25 ºC); (2) its low acute inhalation toxicity; and (3) the use of an oral POD results in MOEs that are >=5,500, and above the Agency's level of concern. A route-specific inhalation toxicity study is not available for cyflumetofen, except for the acute inhalation toxicity study. Therefore, the oral toxicity study was selected for inhalation risk assessments. Three co-critical studies selected: Combined Chronic/Carcinogenicity Study in Rats, 90-Day Feeding Study in Rats and Two-generation Reproduction Study in Rats. Since an oral NOAEL was selected, the inhalation exposure component (μg ai/day) using 100% absorption rate should be converted to an equivalent oral dose (mg/kg/day) in calculating the risk for inhalation exposure.

A.4	Executive Summaries

A.4.1	Subchronic Toxicity

	870.3100	28-Day Oral Toxicity - Rat

In a 28-day feeding study (MRID 48542678), OK-5101 (99.3% a.i.) was administered to 6 Fischer rats/sex/dose in the diet at dose levels of 0, 100, 500, 1000 or 5000 ppm (0, 7.5, 37.6, 75.1 or 384 mg/kg bw/day in males, 0, 8.05, 40.8, 79.8 or 409 mg/kg bw/day in females) for 28 days.

Indications of liver dysfunction were exhibited by animals of both sexes in the 5000 ppm group and males in the 1000 ppm group with statistically significant decreases in total cholesterol and triglyceride, and statistically significant increases in absolute and relative liver weights with diffuse hypertrophy of hepatocytes.

Absolute and relative kidney weights were statistically increased in both males and females of the 5000 ppm group.  An increase in blood urea nitrogen and potassium observed in the males and a decrease in sodium levels in the females further indicate possible kidney dysfunction.

Gross pathology examinations revealed hypertrophy and white color of the adrenals in all males and females in the 5000 ppm group.  Absolute and relative adrenal weights were statistically increased in these animals.  In addition, females in the 1000 ppm group exhibited a statistical increase in relative adrenal weight.  Histopathological examinations revealed diffuse vacuolation of cortical cells in the adrenals in all 1000 and 5000 ppm animals.  The vacuolation was demonstrated to be lipid deposition.  All females in the 1000 and 5000 ppm groups also displayed diffuse hypertrophy of cortical cells in the adrenals.

Increases were detected in absolute and relative ovary weights in the 5000 ppm females.  Histopathological examinations revealed vacuolation of interstitial cells in the ovaries of these animals and the same lesions were observed in two 1000 ppm females.  Through lipid staining, the vacuolation was demonstrated to also be lipid deposition.

The LOAEL is 1000 ppm (75.1 mg/kg bw/day in males, 79.8 mg/kg bw/day in females), based on increased adrenal weight and histopathology. The NOAEL is 500 ppm (37.6 mg/kg bw/day in males, 40.8 mg/kg bw/day in females).

This 28-day toxicity study in the rat is acceptable/nonguideline for a repeat-dose oral study in rats.
      870.3100  90-Day Oral Toxicity- Rat

In a subchronic toxicity study (MRID 48542682), OK-5101 (97.6% a.i.) was administered to 10 Fischer rats/sex/dose in the diet at dose levels of 0, 100, 300, 1000 or 3000 ppm (0, 5.4, 16.5, 54.5 or 167 mg/kg bw/day in males, 0, 6.28, 19.0, 62.8 or 193 mg/kg bw/day in females) for 90 days.
Indications of liver effects were seen.  OK-5101 caused an increase in prothrombin time in high dose males.  In females, increases observed in albumin/globulin ratio in the 1000 and 3000 ppm groups were correlated to the decreases in observed globulin levels.  Organ examination revealed that liver weights were increased in both males and females at the high dose and in the 1000 ppm males.

At necropsy, all females in the 3000 ppm group had white and enlarged adrenals. In addition, adrenal weights were increased in the 1000 and 3000 ppm females.  Histopathology examinations found an increase of diffuse vacuolation and diffuse hypertrophy of cortical cells in the adrenals of all 1000 and 3000 ppm animals.

Relative kidney weights were increased in high dose males and females.  Eight of ten high dose females were observed to have vacuolation of interstitial gland cells in their ovaries.

The LOAEL is 1000 ppm (54.5 mg/kg bw/day in males, 62.8 mg/kg bw/day in females) based on the hematology and organ weight changes in the liver, organ weight and histopathology effects in the adrenals, kidneys and ovaries.  The NOAEL is 300 ppm (16.5 mg/kg bw/day in males, 19.0 mg/kg bw/day in females).

This subchronic toxicity study in the rat is acceptable/guideline and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in the rat.

	870.3100	90-Day Oral Toxicity - Mouse

In a subchronic toxicity study (MRID 48542683), OK-5101 (97.7% a.i.) was administered to 10 SPR ICR mice/sex/dose in diet at dose levels of 0, 300, 1000, 3000 or 10000 ppm (0, 35.4, 117, 348 or 1200 mg/kg bw/day in males; 0, 45.0, 150, 447 or 1509 mg/kg bw/day in females) for 90 days.

Body weight and food consumption were decreased at >= 3000 ppm in females.  Organ weight examinations revealed increased adrenal weights in high dose males.  During necropsy, 9 of 10 male mice in the 10000 ppm exhibited enlarged adrenals.  Histopathological findings showed an increased incidence of diffuse hypertrophy of cortical cells in males at the 3000 and 10000 ppm doses.  Two and seven females exhibited diffuse vacuolation of cortical cells in the adrenals at 3000 and 10000 ppm, respectively.  The degree of severity and incidence of the lesion appeared in a dose-related manner, indicating a treatment-related effect.

The LOAEL is 3000 ppm (348 mg/kg bw/day in males; 447 mg/kg bw/day in females), based on decreased body weights in females, and diffuse hypertrophy and vacuolation of cortical cells in the adrenals in both sexes. The NOAEL is 1000 ppm (117 mg/kg bw/day in males; 150 mg/kg bw/day in females).

This subchronic toxicity study in the mouse is acceptable/guideline and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in the mouse.

	870.3150	90-Day Oral Toxicity - Dog

In a 90-day dog study (MRID 48542684), OK-5101 (98.4% a.i.) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 0, 30, 300, or 1000 mg/kg bw/day).

All animals survived until study termination.  There were no adverse compound related effects on clinical signs, hematology, clinical chemistry, urinalysis, or gross pathology.  Feces containing test substance-like material was observed in mid-and high-dose males and females.  High-dose males and females exhibited decreased body weights and body weight gains when compared to controls.  In addition, high dose males had decreased food efficiency and high dose females had slightly reduced food consumption.  A treatment-related increase in adrenal weights was observed in high-dose males.  Animals of both sex exhibited vacuolation of the adrenals associated with treatment.

The LOAEL is 1000 mg/kg bw/day, based on decreased body weight and body weight gain, increased adrenal weights (males only) and vacuolation of the adrenals. The NOAEL is 300 mg/kg bw/day.

This study in dogs is acceptable/guideline and satisfies the guideline requirement for a subchronic oral toxicity study in dogs (OPPTS 870.4100; OECD 452).

	870.3200	21/28-Day Dermal Toxicity  -  Rat

In a repeat-dose dermal toxicity study (MRID 48542686), BAS 9210 I (98.4% a.i.) was applied to the shaved skin of 10 Wistar rats/sex/dose at dose levels of 0, 100, 300 or 1000 mg/kg bw/day, 6 hours/day for 5 days/week during a 28-day period.

There were no treatment related adverse effects noted for any parameter examined in this study.

The LOAEL was not determined. The NOAEL is 1000 mg/kg bw/day.

This dermal toxicity study in the rat is acceptable/guideline and satisfies the guideline requirement for a repeat-dose dermal toxicity study (OPPTS 870.3200, OECD 410) in the rat.

	870.3465	90-Day Inhalation  -  Rat

No study was conducted.

A.4.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID 48542704), OK-5101 Technical (97.67 % a.i.) was administered to 25 female Wistar rats/dose via gavage at dose levels of 0, 50, 250 or 1000 mg/kg bw/day from days 6 through 19 of gestation.

All animals survived to scheduled termination.  Slight decreases in body weight gain and food consumption throughout the treatment period were associated with a decrease in corrected overall body weight gain (GD 6-20 and GD 0-20) at 1000 mg/kg bw/day.  Absolute left adrenal gland weight and organ to body weight ratio were increased in the mid (p<= 0.05) and high (p <=0.01) doses, while the absolute right adrenal gland weight and organ to body weight ratio were increased in the high dose only (p <=0.01).  An increase in the incidence of slight diffuse hypertrophy of the cortical cells of both adrenal glands was noted in the high dose group.  The incidence of slight or moderate bilateral diffuse cytoplasmic vacuolation of the cortical cells was also increased in the high dose group when compared to controls.

The maternal LOAEL is 250 mg/kg bw/day, based on an increase in adrenal weights and organ to body weight ratio. The maternal NOAEL is 50 mg/kg bw/day.

An increased incidence of wavy ribs was noted at 1000 mg/kg/day, while an increased incidence of incompletely ossified sternal centra was observed at the 250 and 1000 mg/kg bw/day dose levels.  There were no additional treatment related effects on developmental parameters.

The developmental LOAEL is 250 mg/kg bw/day, based on an increased incidence of incompletely ossified sternal centra. The developmental NOAEL is 50 mg/kg bw/day.

The developmental toxicity study in the rat is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID 48542706), OK-5101 Technical (97.67 % a.i.) was administered to 25 female New Zealand White rabbits/dose by gavage at dose levels of 0, 50, 250, or 1000 mg/kg bw/day from days 6 through 28 of gestation.

There were no deaths attributed to the test substance.  Body weight gains were generally slightly reduced at 250 and 1000 mg/kg bw/day, with a resulting decrease in overall body weight gain and corrected body weight gain when compared to controls.  Food consumption was generally decreased at 1000 mg/kg bw/day, resulting in decreased overall food consumption in this group during the treatment period.  Absolute liver weights were decreased in the mid- and high-dose groups and absolute weights of the left and right adrenals were decreased in the high dose group only. In the absence of body weight decrements, decreases in body weight gain (35-53%), food consumption and liver weights (marginal decrease of 8%) at the limit dose are not considered adverse effects.  As a result, no treatment related maternal adverse effects were observed. This is consistent with the range finding study where no maternal toxicity was observed.

The maternal LOAEL is not established.  The maternal NOAEL is 1000 mg/kg bw/day.

There were no abortions or premature deliveries.  No effects of treatment were noted on numbers of litters, live or dead fetuses, corpora lutea, early or late resorptions, sex ratio, or pre- or post-implantation loss.  Male, female and combined fetal body weights and combined placental weights were significantly reduced in the 1000 mg/kg bw/day dose group.  The 250 and 1000 mg/kg bw/day dose groups exhibited increased incidences in the average number of ossified pairs of ribs and thoracic vertebrae, with a concomitant decrease in the average number of ossified lumbar vertebrae when compared to controls.  The numbers of ossified xiphoid were also significantly decreased in these dose groups.  Litter and fetal incidences of angulated hyoid and incompletely ossified sternal centra were increased in the 1000 mg/kg bw/day dose group. Low incidence of ossification effects at 250 mg/kg/day were not considered an adverse effect. The only malformation attributable to treatment was a downward flexion of the forepaws (2 fetuses in one litter) and hind paws (1 fetus in one litter) in the high dose group. The incidence of downward paw flexion (litter incidence: 8%; fetal incidence: 1.4%) in the 1000 mg/kg/day group was slightly above historical controls (litter incidence: 0-5.3%; fetal incidence: 0-0.6%) and was considered treatment-related adverse effect.

The developmental NOAEL is 250 mg/kg/day; and the LOAEL is 1000 mg/kg/day based on increased incidences of ossification and paw flexion; and decreased fetal body weight.

The developmental toxicity study in the rabbit is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rabbit.

A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study, OK-5101 (97.67% a.i.) was administered to 24 Wistar rats/sex/dose in the diet at dose levels of 0, 150, 500 or 1500 ppm (0, 9.21/13.8, 30.6/46.6, or 89.4/141.1 mg/kg bw/day in males/females).  P and F1 male and female parental animals were administered test or control diet for 10 weeks prior to mating, throughout mating, gestation and lactation, and until necropsy.  A single litter was produced by each generation.  Serum LH, FSH, testosterone (males only), progesterone (females only) and 17 ß-estradiol (females only) hormone assays were conducted using blood samples collected from 10 surviving F1 adult animals/sex/dose at necropsy.

There were no treatment-related effects on parental animals of either generation for clinical signs of toxicity, mortality or food consumption.  There were no changes in body weight/body weight gain observed in any male parental animal.  At 1500 ppm, parental females exhibited a decrease in body weight gain during pre-mating weeks 1-2 (F1 generation) or 6-8 (P generation).   Absolute and relative adrenal weights were increased in P and F1 parental females at 500 ppm and above.  In parental males at 1500 ppm, absolute and relative adrenal weights were increased in the P and F1 generations.  In addition, absolute and relative ovary weights were increased in P generation females at 1500 ppm only. Following macroscopic examination, male and female parental animals of both generations exhibited white and/or enlarged adrenals at 1500 ppm.  Histopathological examination of the adrenals revealed an increased incidence of hypertrophy of the zona glomerulosa cells at 500 ppm and above in P generation females and F1 generation males and females and in P males at 1500 ppm.  Additionally in the adrenals, an increased incidence of vacuolation of the zona fasciculata cells was observed at 1500 ppm in P generation females and in both sexes of the F1 generation.  An increased incidence of vacuolation of the interstitial cells of the ovary was also noted at 1500 ppm in F1 females.

The parental LOAEL is 500 ppm (30.6/46.6 mg/kg bw/day in males/females) based on effects on the adrenals (increased organ weights and histopathology). The parental NOAEL is 150 ppm (9.21/13.8 mg/kg bw/day in males/females).

There were no treatment-related effects observed on ovarian follicle counts, sperm measurements or reproductive performance.  An increase in estrous cycle length was noted at 1500 ppm. However, the estrous cycle length is within the range of the historical controls and would not be considered an adverse effect. In addition, decreased FSH levels were noted at 500 and 1500 ppm and decreased progesterone was noted at 150 ppm and above in F1 females. Hormone changes are considered a reproductive effect.  A dose response was observed with three hormones affected at the highest dose (1500 ppm) and two hormones affected at 500 ppm.

The reproductive NOAEL in females is 150 ppm (13.8 mg/kg/day); and the LOAEL in females is 500 ppm (46.6 mg/kg/day) based on hormone changes (significantly decreased FSH and progesterone levels). The reproductive LOAEL is not determined in males.  The reproductive NOAEL in males is >=1500 ppm (89.4 mg/kg bw/day).

In the offspring, there were no treatment-related effects on clinical signs of toxicity, viability and measured anogenital distances.  At 1500 ppm, body weights were decreased in male and female pups of the F2 generation during LD 7-21.  Absolute and relative adrenal weights were increased at 500 ppm and above in both sexes of both generations of offspring.  An increased incidence of adrenals that were white in color was observed in both sexes of F2 pups at 1500 ppm.  Microscopic examination of the adrenals revealed an increased incidence of hypertrophy of the zona glomerulosa cells in both generations of males at 500 ppm and above and in both generations of females at 1500 ppm.  Additionally in the adrenals, an increased incidence of hypertrophy of the zona fasciculata cells was noted at 500 ppm and above in F1 males and females and F2 males, and at 1500 ppm in F2 females.   Delayed sexual maturation was observed in females (increased time to vaginal opening) at 500 ppm and above, and in males (increased time to preputial separation) at 1500 ppm. However, slight delay of sexual maturation at 500 ppm (approximately 1 day relative to the control group) would not be considered an adverse effect

The offspring LOAEL is 500 ppm (30.6/46.6 mg/kg bw/day in males/females) based on effects on the adrenals (increased organ weights and histopathology) in both sexes.  The offspring NOAEL is 150 ppm (9.21/13.8 mg/kg bw/day in males/females).

This study is acceptable/guideline and satisfies the guideline requirement for a 2-generation reproductive study (OPPTS 870.3800); OECD 416 in the rat.

A.4.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity  -  Rat

In a chronic toxicity study (MRID 48542696), OK-5101 (97.67% cyflumetofen) was administered to Fischer (F344/DuCrj) rats (50/sex/dose) in the diet at dose levels of 0, 50, 150, 500 or 1500 ppm (equivalent to 0/0, 1.90/2.31, 5.63/6.92, 18.8/23.3 or 56.8/69.2 mg/kg bw/day in males/females, respectively) for one year.  Interim sacrifices (10/sex/dose) were performed at 4, 13 and 26 weeks.  All remaining animals were sacrificed at 52 weeks.

There were no adverse treatment-related effects on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry and urinalysis parameters.  Treatment related effects were noted in the adrenals of both sexes at the high dose.  In females, absolute and relative adrenal weights were increased at all scheduled sacrifices, along with diffuse hypertrophy of adrenal cortical cells.  Effects in males were slightly different with diffuse vacuolation of the cortical cells recorded at all interim and terminal sacrifices. An increased incidence of vacuolation of ovarian interstitial gland cells was observed in high dose females from week 13 on, along with increased ovarian weights at terminal sacrifice.  An increased incidence of atrophy of the seminal vesicles and coagulating gland were recorded in high dose males at terminal sacrifice only.  There were no corresponding effects observed during histopathological examination.

The LOAEL for chronic administration of cyflumetofen in rats is 1500 ppm (equivalent to 56.8/69.2 in males/females, respectively) based on diffuse vacuolation of adrenal cortical cells and increased incidence of atrophy of the seminal vesicles and coagulating glands in males and increased adrenal weights and ovarian weights, diffuse hypertrophy of adrenal cortical cells and vacuolation of the ovarian interstitial gland cells in females.  The NOAEL is 500 ppm (equivalent to 18.8/23.3 mg/kg bw/day in males/females, respectively).

This chronic study in the rat is acceptable/guideline and satisfies the guideline requirement for a chronic oral study (OPPTS 870.4100), OECD 452 in the rat.

	870.4100a (870.4300) Chronic Toxicity  -  Rat

In a supplemental chronic toxicity study (MRID 49029701), OK-5101 (cyflumetofen, 97.82 % a.i.) was administered to SPF/VAF Fischer rats (F344/DuCrj) (50/sex/dose) in the diet at dose levels of 0 or 6000 ppm (0 or 250/319 mg/kg bw/day in males/females) for 52 weeks. Interim sacrifices (10/sex/dose) were performed at 4, 13, 26 weeks.  All remaining animals were sacrificed at 52 weeks.

There were no treatment-related deaths or effects on food consumption, food efficiency, or in the ophthalmologic assessment.  In treated females, an increased incidence of soiled fur around the external genital area and a consistent decrease in body weight and body weight gain when compared to the control group were observed throughout most of the study. Males of the 6000 ppm group had reduced body weight gain throughout the study. In treated animals of both sexes, affected hematological parameters included decreased platelet count and fibrinogen concentration and elongated prothrombin time and activated partial thromboplastin time (APTT). Blood urea nitrogen (BUN) was elevated from 26 and 52 week in males and at all sampling points in females and was slightly outside of the submitted historical control data range for the females. This observation was considered treatment-related in conjunction with increased kidney weights for the treated animals. In both sexes at 6000 ppm, absolute and relative liver, kidney and adrenal weights were increased at all sacrifice time points. Gross necropsy revealed an increase in the incidence of white colour in the adrenal gland in both sexes at 6000 ppm as well as adrenal enlargement in females. Treatment-related histological observations included effects noted in the adrenal gland such as diffuse hypertrophy of the cortical cell in treated females and diffuse cortical cell vacuolation in treated males and focal vacuolation of the cortical cell in treated females with higher incidence of these lesions by the end of the study. In treated males, gross lesions in the testis such as atrophy, softening, and spots were observed as well as an increased incidence of interstitial cell hyperplasia. Atrophy of the acinar cell of the pancreas was also noted in the treated males. In treated females, vacuolation of the interstitial gland cell of the ovary was observed.

In this supplemental study, the LOAEL was 6000 ppm (250/319 mg/kg bw/day in males/females) based on increased adrenal weights accompanied by gross pathology and histopathology lesions noted in both sexes, vacuolation of the interstitial gland cell of the ovary and hyperplasia of the interstitial cell of the testes.  A NOAEL was not set.

This chronic study in the rat is supplemental; however, when considered in conjunction with the previous study (MRID 48542696), it satisfies the guideline requirement for a chronic toxicity study (OPPTS 870.4100), OECD 452 in rats.

	870.4100b Chronic Toxicity - Dog

In a 1-year dog study (MRID 48542685), OK-5101 (cyflumetofen, 98.4% a.i.) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 0, 30, 300, or 1000 mg/kg bw/day for one year.

There were no compound related effects on mortality, body weight, body weight gain, food consumption, urinalysis, hematology, clinical chemistry, or ophthalmoscopy.  Feces containing test substance-like material was observed in both sexes at the mid-and high-dose levels.  High-dose males exhibited a treatment related increase in vomiting and soft/mucous/watery feces.  High-dose animals of both sexes exhibited decreased triglycerides.  Increased absolute and relative adrenal weights were noted in both sexes at the high dose.  In the adrenals, treatment related vacuolation, cortical degeneration, fibrosis, cell infiltration and pigmented macrophages (males only) were observed to some extent in mid- and high-dose males and females. In addition, high-dose females exhibited enlarged adrenals.

The LOAEL is 300 mg/kg bw/day, based on adrenal cortical cell vacuolation and additional adrenal histopathology findings. The NOAEL is 30 mg/kg bw/day.

This study in dogs is acceptable/guideline and satisfies the guideline requirement for a 1-year oral toxicity study in dogs (OPPTS 870.4100; OECD 452).

A.4.5	Carcinogenicity

	870.4200a Carcinogenicity - Rat

In a carcinogenicity study (MRID 48542697), OK-5101(cyflumetofen, 97.67 % a.i.) was administered to 50 Fischer rats/sex/dose in the diet at dose levels of 0, 150, 500, or 1500 ppm (0, 4.92/6.14, 16.5/20.3, 49.5/61.9 mg/kg bw/day in males/females) for 104 weeks.

There were no compound related effects on mortality, clinical signs, body weight, food consumption, hematology or gross necropsy observations.  Diffuse hypertrophy of the adrenal cortex was noted in high dose males and females in conjunction with increased adrenal weights.  In addition, luminal dilatation of the gland of the uterine horn was observed in high dose females. At the doses tested, there was no treatment related increase in tumor incidence when compared to controls.

The LOAEL is 1500 ppm (49.5/61.9 mg/kg/day for males and females) based on increased adrenal weights, hyperplasia and hypertrophy of the adrenal cortex in both sexes, and luminal dilatation of the gland in the uterine horn in females. The NOAEL is 500ppm (16.5/20.3 mg/kgkday for males and females). There was no treatment related increase in tumor incidence when compared to controls.

This carcinogenicity study in the rat is considered acceptable/guideline and satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200); OECD 451 in the rat.

	870.4200a Carcinogenicity (Supplementary) - Rat

In a supplemental carcinogenicity study, BAS 9210 I (cyflumetofen, 97.82 % a.i.) was administered to 50 Fischer rats (F344/DuCrlCrlj)/sex/dose in the diet at dose levels of 0 or 6000 ppm (0, 220/287 mg/kg bw/day in males/females) for 104 weeks.

There was no treatment-related effect on mortality and food consumption.  Treated females exhibited an increased incidence of tactile hair loss and soiled fur.  Males showed no clinical signs of toxicity. Treated males exhibited decreased final body weight and overall body weight gain, while treated females exhibited decreased body weight intermittently throughout the study period.  Decreased differential leukocyte count was observed in treated males but was unaffected in females.  Absolute and/or relative weights of the kidneys, liver, and adrenals in both sexes as well as testis weights in treated males and ovary weights in treated females were affected by treatment. Although clinical chemistry and hematological parameters were not assessed in the current study, effects were noted on these parameters in the confirmatory 1-year rat chronic toxicity study (MRID# 49029701) and were considered as corroborating findings in support of the organ weight changes in the current study.  Incidences of diffuse hypertrophy and focal vacuolation (both sexes) and diffuse vacuolation (females only) were increased in the adrenal cortical gland cells.  An increased incidence of focal atrophy of the pancreatic acinar cells was noted in treated males of the current study and was also observed in treated males in the confirmatory 1-year rat chronic toxicity study.  At necropsy, increased incidences of atrophy of the epididymis and masses in the testis were observed in treated males.  There was a treatment related increase in the incidence of Leydig cell tumours in male rats when compared to controls. Corresponding decreased incidences of softening of the testis, seminiferous tubule atrophy, and testicular interstitial cell hyperplasia were considered to be secondary to the development of testicular interstitial cell tumours in treated male rats.  In addition, treated males exhibited an increase in the incidence of thyroid C-cell tumours (combined adenomas and carcinomas).
The LOAEL for this supplementary study is 6000 ppm (220/287 mg/kg bw/day in males/females), based on effects on clinical signs of toxicity (females), decreased body weight (both sexes) and body weight gain (males), changes in hematological parameters (males), organ weights (both sexes), and histopathology findings (both sexes).  A NOAEL was not identified for this study.

Treatment with cyflumetofen was associated with an increase in thyroid C-cell tumours (carcinomas, as well as adenomas and carcinomas combined) in males as well as an increase in the incidence of testicular interstitial cell tumours.  There was no treatment related increase in tumor incidence in females when compared to controls.

This carcinogenicity study in the rat is supplemental; however, when considered in conjunction with the previous study (MRID# 48542697), it satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200); OECD 451 in rats.

	870.4200b Carcinogenicity - Mouse

In a carcinogenicity study (MRID 48542698), OK-5101(cyflumetofen, 97.67 % a.i.) was administered to 52 CD-1 mice/sex/dose in the diet at dose levels of 0, 150, 500, 1500 or 5000 ppm (0, 15.5/14.3, 54.3/48.1, 156/144, 537/483 mg/kg bw/day in males/females) for 78 weeks.

There were no compound-related effects on mortality, clinical signs, body weight, food consumption, hematology or gross necropsy observations at any dose level.  Diffuse adrenal cortical cell vacuolation was noted in 5000 ppm males and females, with a corresponding increase in adrenal weight in males. At the doses tested, there has no treatment related increase in tumor incidence when compared to controls.

The LOAEL is 5000 ppm, based on an increased incidence of diffuse adrenal cortical cell vacuolation in males and females, and an increase in adrenal weight in males. The NOAEL is 1500 ppm. There was no treatment related increase in tumor incidences when compared to controls.

This carcinogenicity study in the mouse is acceptable/guideline and satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200); OECD 451 in mice.

      870.4200b Carcinogenicity (Supplementary) - Mouse

In a supplemental carcinogenicity study (MRID 49209101), BAS 9210 I (cyflumetofen, 97.82 % a.i.) was administered to SPF ICR (Crj:CD1) mice (52/sex/dose) in the diet at dose levels of 0 or 10,000 ppm (0, 1143/1132  mg/kg bw/day in males/females) for 78 weeks.

There were no compound-related effects on mortality, body weight, food consumption, or hematology parameters at the dose tested. Diffuse adrenal cortical cell vacuolation and deposition of brown pigment in the cortico-medullary junction of the adrenals was observed in treated animals of both sexes.  Treated females exhibited a significant increase in the incidence of pale-colored skin and pale-colored eye/eyelid, increased adrenal weights, enlarged spleen and an increased incidence of extramedullary hematopoiesis in the spleen.

The LOAEL for this confirmatory study is 10,000 ppm, based on clinical signs of toxicity, increased adrenal weights, enlarged spleen and an increased incidence of extramedullary hematopoiesis in the spleen of treated females and an increased incidence of diffuse adrenal cortical cell vacuolation and deposition of brown pigment in the cortico-medullary junction of the adrenals in both sexes.  A NOAEL was not identified for this study.

At the dose tested, there was no treatment-related increase in tumor incidence when compared to controls. Dosing was considered adequate as animals were dosed above the limit dose of 1000 mg/kg bw/day.

This carcinogenicity study in the mouse is supplemental; however, when considered in conjunction with the previous study (MRID 48542698), it satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200); OECD 451 in mice.

A.4.6	Mutagenicity

Cyflumetofen, two metabolites (B-1 and B-3) and one impurity (AB-13) were evaluated in a comprehensive battery of Genetic Toxicology assays.  The data indicate that neither the parent compound nor metabolite B-1 were mutagenic in bacteria.  However, metabolite B-3 induced a weak but reproducible and concentration-related mutagenic response (1.7- 2.2 fold increases at 3330 and 5000 ug/plate) in Salmonella typhimurium TA100; the effect was, nevertheless, abolished in the presence of exogenous metabolic activation. There was also evidence of a mutagenic response in the L5178Y mouse lymphoma assay that was induced by the parent and the two metabolites.  The response was the strongest in the parent compound (90 ug/mL  - S9 vs. the limit concentration for the two metabolites).  However, for both the parent and metabolite B-1, mutagenic activity was only seen at severely cytotoxic concentration (i.e., ≈10% survival); consequently, these results are not considered sufficient evidence of a mutagenic response in this test system.  For metabolite B-3, the 4.3-fold increase in the mutation frequency at 1891 ug/mL (equivalent to the limit concentration of 10 mM) was confined to this level and not observed in the S9-activated portion of the assay.

For the remaining genetic endpoints, the parent and the two metabolites were not clastogenic in Chinese hamster lung cells (parent in two studies performed by independent laboratories) or peripheral human lymphocytes (metabolites B-1 and B-3).  Similarly, cyflumetofen was not clastogenic or aneugenic in mouse bone marrow cells up to the limit dose.  Finally, neither the parent nor the two metabolites induced a genotoxic response in hepatocytes harvest from male rats orally exposed up to the limit dose (parent and metabolite B-1) or an overtly toxic level for the test animals (metabolite B-3).

Studies performed on an impurity of cyflumetofen (AB-13) showed negative results for reverse gene mutations in bacteria (S. typhimurium TA 1535, TA 1537, TA 98 or TA 100 or Escherichia coli WP2 uvrA), forward gene mutations in mammalian cells (L5178Y mouse lymphoma cells), and chromosome aberrations in mammalian cells (human peripheral lymphocytes).

Overall, the data indicate that while there was some evidence of a mutagenic response from in vitro assays, the responses were confined to severely cytotoxic concentrations, abolished in the presence of exogenous metabolic activation, or were not expressed in whole animal studies.   Based on these considerations, there is no concern for mutagenicity for the parent or the metabolites.  Similarly, the impurity was uniformly negative; hence, there is also no concern for mutagenicity. All assays were well-conducted, acceptable and satisfy FIFRA test guidelines for mutagenicity testing.  Consequently, mutagenicity can be ruled out as a possible mode of action for tumor formation.  Results from these assays are summarized below:

Parent

Cyflumetofen was negative in bacteria in two independent trials using the pre-incubation method at concentrations of 20.6 to 5000 ug/plate +/-S9 (MRID 48542687).

In the mouse lymphoma forward gene mutation assay, concentrations of 20 to 90 ug/mL  - S9 or 10 to 140 ug/mL +S9 for 3 hours.  Although increases in the total mutation frequencies (MF) occurred at 90 ug/mL  - S9 (3.2-fold) and at 140 ug/mL +S9 (6.1-fold), these concentrations were insoluble and severely cytotoxic (relative suspension growth (RSG) was 10% at 90 ug/mL  - S9 and 12% at 140 ug/mL +S9).  These results are, therefore, not considered sufficient evidence of a mutagenic response in this test system (MRID 48542692).

In an in vitro chromosome aberration study, Chinese hamster lung fibroblasts (V79) cells were exposed to 6.25 to 50 ug/mL  - S9 and 25 to 200 ug/mL +S9 for 6 hours and allowed an 18-hour recovery period.  Cells were also continuously treated with 3.75 to 30 ug/mL  - S9 for 24 or 48 hours  and harvested at the end of treatment.  Compound precipitation was seen at >=200 ug/mL +S9.   Less than 50% of the cells were available for analysis at the highest dose tested with or without S9 activation.  There were however, and no significant increases in cells with structural or numerical chromosome aberrations (MRID 48542689).

In a second in vitro chromosome aberration study, Chinese hamster lung fibroblasts (V79) cells were exposed to 2.5 to 80 ug/mL  - S9 and 10 to 160 ug/mL +S9 for 4 hours and allowed a 14-hour recovery period.  Due to severe cytotoxicity, the assay was repeated with 3.1 to 10 ug/mL  - S9.  Cells were also continuously treated with 3.1 to 40 ug/mL  - S9 for 18 hours and harvested or allowed an additional 10 hour recovery.  With S9, cells were dosed with 20-320 ug/mL for 4 hours and harvested after a 24-hour recovery period. Compound precipitation was seen at >=120 ug/mL.  Less than 50% of the cells were available for analysis at >=160 ug/mL +S9, >=20 ug/mL-S9 (18-hour exposure), or 40 ug/mL-S9 (18-hour exposure with 10-hour recovery).  There were however, and no significant increases in cells with structural or numerical chromosome aberrations (MRID 48542691).

In the mouse bone marrow micronucleus assay, levels up to the limit dose were not overtly toxic to the test animals, cytotoxic to the target cells or induce an aneugenic or a clastogenic response (MRID 48542694).

In an in vivo unscheduled DNA synthesis (UDS) assay in male Wistar rats, metabolite B-1 was not overtly toxic to the test animals or genotoxic in the hepatocytes harvested 2-4 or 12-16 hours after oral administration of levels up to the limit dose of 2000 mg/kg (MRID 48542695).

Metabolite B-1

Metabolite B-1 was negative in bacteria in two independent trials using the plate incorporation method at concentrations of 3 to 5000 ug/plate +/-S9 (MRID 48542710).

In the mouse lymphoma forward gene mutation assay, concentrations of 1 to 1901 ug/mL +/ - S9 (1901 ug/mL is equivalent to the limit concentration of 10 mM) were tested using a 3-hour exposure.  A second assay was performed with comparable nonactivated concentrations and a 24-hour exposure and S9-activated levels of 3-1910 ug/mL with a 3-hour exposure.  The nonactivated assay was repeated for the 24-hour exposure with 3- 1910 ug/mL.  The 3-hour exposure with or without S9 activation was negative up to the highest dose tested (HDT).  Although marked increases in the total MF occurred at the HDT without S9 activation after the 24-hour treatment in both the initial (8.2-fold) and repeat trials (7-fold), these concentrations were severely cytotoxic (RSG was 13 or 9%, respectively).  Consequently, these results are not considered sufficient evidence of a mutagenic response in this test system (MRID 48542712).

In an in vitro chromosome aberration study, peripheral human lymphocytes were exposed to 333 to 1901 ug/mL +/ - S9 (1901 ug/mL is equivalent to the limit concentration of 10 mM) for 3 hours and allowed a 21-hour recovery period.  Cells were also continuously treated with 100 to 1000 ug/mL  - S9 for 24 or 48 hours and harvested at the end of exposure.  With S9, cells were dosed with 333-1901 ug/mL for 3 hours and harvested after 48 hours. There were no significant increases in cells with structural chromosome aberrations without S9 activation up to concentrations that caused a >=50% decrease in relative suspension growth (>= 750 ug/mL, prolonged 24-hour exposure or (>= 560 ug/mL, prolonged 48-hour exposure).  Similarly, no evidence of a clastogenic response was seen after exposure for 3 hours with or with S9 up to the limit dose (MRID 48542711).

In an in vivo unscheduled DNA synthesis (UDS) assay in male Wistar rats, metabolite B-1 was not overtly toxic to the test animals or genotoxic in the hepatocytes harvested 2-4 or 12-16 hours after oral administration of levels up to the limit dose of 2000 mg/kg (MRID 48542713).

Metabolite B-3 [2-(trifluoromethyl)benzamide]

Metabolite-3 induced a reproducible and dose-related increase in mutant colonies of Salmonella typhimurium TA100.  Fold increases were 1.7 and 1.9-fold at 3330 and 5000 ug/plate  - S9 in Trial 1 and 1.7 and 2.2-fold at 3330 and 5000 ug/plate  - S9 in Trial 2.  The response was, however, abolished in the presence of S9 activation and was not seen in any other Salmonella strain or in Escherichia coli WP2 uvrA (MRID 48542715).

In the mouse lymphoma forward gene mutation assay, concentrations of 1 to 1891 ug/mL +/ - S9 (1891 ug/mL is equivalent to the limit concentration of 10 mM) were tested using a 3-hour exposure.  A second assay was performed with comparable nonactivated concentrations and a 24-hour exposure and comparable S9-activated concentrations with a 3-hour exposure.  The 3-hour exposure with or without S9 activation was negative up to the highest dose tested (HDT).  A marked increase in the total MF occurred at the HDT without S9 activation (4.3-fold) following the prolonged and in the absence of severe cytotoxicity.  However, the response was confined to this concentration and not observed when S9 activation was incorporated into the reaction mixture (MRID 48542717).

In an in vitro chromosome aberration study, peripheral human lymphocytes were exposed to 333 to 1891 ug/mL +/ - S9 (1891 ug/mL is equivalent to the limit concentration of 10 mM) for 3 hours and allowed a 21-hour recovery period.  Cells were also continuously treated with 100 to 1891 ug/mL  - S9 for 24 hours or 33 to 1891 ug/mL  - S9 for 48 hours.  Cells were harvested at the end of the prolonged exposures.  With S9, cells were dosed with 333-1891 ug/mL for 3 hours and harvested after 48 hours. There were no significant increases in cells with structural chromosome aberrations with or without S9 up to the limit concentrations (MRID 48542716).

In an in vivo unscheduled DNA synthesis (UDS) assay in male Wistar rats, metabolite B-3 was toxic to the test animals at 350 mg/kg but was not genotoxic in the hepatocytes harvested 2-4 or 12-16 hours after oral administration of 0, 175 or 350 mg/kg (MRID 48542718).

Impurity AB-13

Impurity AB-13 was negative in bacteria in two independent trials using the plate incorporation method up to insoluble concentrations (>=333 ug/plate +/-S9) (MRID 48542688).

In the mouse lymphoma forward gene mutation assay, concentrations of 0.03 to 100 ug/mL +/ - S9 were tested using a 3-hour exposure.  A second assay was performed with similar concentrations and a 24-hour exposure for the nonactivated phase of testing and with a 3-hour exposure for the S9-activated concentrations.  The 3-hour exposure with or without S9 activation was negative up to the highest dose tested. Compound precipitation was seen at 100 ug/mL +/ - S9.  RSG was generally similar to the control at all concentrations and exposure intervals.  There was no appreciable increase in the MF at any nonactivated or S9-activated concentration (MRID 48849413).
In an in vitro chromosome aberration study, peripheral human lymphocytes were exposed continuously to 10 to 333 ug/mL  - S9 for 24 or 48 hours and harvested at the end of the prolonged exposures.  With S9, cells were dosed with 10 to 333 ug/mL for 3 hours and harvested after 48 hours.  Compound precipitation was noted at >=100 ug/mL.  There were no adverse effects on the mitotic indices or significant increases in cells with structural chromosome aberrations with or without S9 up to insoluble levels (MRID<PHONE_NUMBER>0).

A.4.7	Neurotoxicity

	870.6200 Acute Neurotoxicity Screening Battery- Rat

In an acute neurotoxicity study (MRID 48542707), groups of young adult Wistar rats (10/sex) were given a single gavage dose of BAS 9210 I (97.08% a.i.) in 1% carboxymethylcellulose at doses of 0, 125, 500, 2000 mg/kg bw. Rats were observed for 14 days.

Neurobehavioral assessments (functional observation battery and motor activity testing) were performed in 10 animals/sex/group 7 days before dosing, the day of dosing, and 7 and 14 days post-dosing. At study termination, 5 animals/sex/group were euthanized and perfused for neuropathological examination. Of the perfused animals, 5/sex from the control and high dose groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues. Brains weights were taken for 5 animals/sex/group.

No treatment-related effects were noted on mortality, clinical signs, body weight, brain weight, gross pathology or histologic neuropathology. FOB and motor activity testing revealed no treatment-related effects.

The NOAEL is 2000 mg/kg bw, the highest dose tested. No LOAEL was established. No evidence of neurotoxicity.

The study is classified as acceptable/guideline as an acute neurotoxicity study in rats (870.6200).

	870.6200 Subchronic Neurotoxicity Screening Battery -Rat

In a subchronic neurotoxicity study (MRID 48542708), BAS 9210 I (97.08% cyflumtofen) was administered to 10 Wistar rats/sex/group in the diet for 91 days at doses of 0, 500, 1500, and 5000 ppm (equivalent to 0/0, 30/41, 89/99, and 293/353 mg/kg bw in males/females). Neurobehavioral assessments (functional observation battery and motor activity testing) were performed in all animals one week before dosing commenced and also 1, 22, 50, and 85 days after the start of dosing. At study termination, 5 animals/sex/group were euthanized and perfused for neuropathological examination and the brain weights of these animals were measured. Of the perfused animals, only the control and high dose groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues. The remaining 5 animals/sex/group were sacrificed by decapitation, subjected to gross necropsy, and the adrenal gland of each animal was weighed and examined microscopically. Body weights and food consumption for all animals on study were measured weekly.

There were no treatment related effects on mortality, clinical signs, body weight, food consumption, brain weight or neuropathology. Food consumption was elevated in 500 ppm females, and these animals also exhibited increased body weights and body weight gains. Consequently, due to the increased body weights, absolute brain weights were elevated in 500 ppm females while relative brain weights remained comparable to controls. Since these findings were restricted to the low dose and no dose-response was observed, increased food consumption, body weight, and the corresponding increase in absolute brain weights are not considered treatment-related in 500 ppm females.

FOB testing revealed no treatment-related effects. Slightly decreased motor activity was observed in all treated males and in high dose females on Day 1, and this finding is considered to be potentially treatment-related. However, due to a lack of any other indications of neurotoxicity in this study (altered FOB parameters, clinical observations or neuropathy) a slight depression of motor activity is likely not indicative of a neurotoxic effect. Although potentially treatment-related, the slight decrease in motor activity in males at the low dose was not considered sufficiently adverse to be considered for the determination of the LOAEL.

Absolute and relative adrenal weights were statistically significantly increased in 1500 ppm females and 5000 ppm males and females. Upon gross necropsy, the adrenal cortex of all 5000 ppm animals was discoloured to light beige and it was moderately enlarged in 5000 ppm females. Microscopic evaluation revealed diffuse vacuolation of the adrenal cortex in 1500 and 5000 ppm animals of both sexes. The severity of vacuolation appeared to increase with dose.

A NOAEL of 500 ppm (30/41 mg/kg bw/day in males/females) was selected based on the increased adrenal weights in females and the altered adrenal histopathology of both sexes observed at the LOAEL of 1500 ppm (89/99 mg/kg bw/day). No evidence of neurotoxicity.

The study is classified as acceptable/guideline as a subchronic neurotoxicity study in rats (870.6200; OECD 424).

A.4.8	Metabolism

	870.7485	Metabolism - Rat

In a series of metabolism studies, [14]C-cyflumetofen (>98% radiochemical purity), labeled either on the benzene ring in the 4-tert-butylphenyl group (A-ring) or on the benzene ring in the α,α,α-trifluoro-o-tolyl group (B-ring), was administered via gavage in aqueous hydroxypropyl cellulose to 3-4 Fischer rats/sex/dose/radiolabel position at dose levels of 3 or 250 mg/kg bw.  Rats were sacrificed either at Tmax (1 or 2 hours post-dosing), or at 24, 48 or 72 hours after dosing. The [14]C-time course in plasma; the [14]C-excretion in urine, feces and bile; and the distribution to organs and tissues were examined. In addition, the profile of the metabolites in urine, feces and bile was determined.

[14]C-cyflumetofen was rapidly absorbed following administration of the low dose, with plasma levels of radioactivity peaking at 1 hour post-dosing. Absorption was slightly slower following administration of the high dose, with peak plasma levels attained at 2-4 hours post-dosing.  At the high dose, females demonstrated higher Cmax and AUC values than males for both radiolabels.  The AUC values at the high dose were approximately 15-16 and 36-38 times the AUC at the low dose for males and females, respectively; these values are much lower than the 83-fold difference in dose levels, indicating saturation of absorption. The half-lives of elimination from plasma ranged from 12 to 22 hours, with no consistent pattern in terms of differences related to sex, dose or radiolabel position.  The half-lives of elimination from whole blood, kidney and liver were comparable to the elimination rates from plasma, but longer elimination half-lives were calculated for bone marrow (14-30 hours) and adipose tissue (19-43 hours).

The absorption rates for the A-ring group were higher for the low dose group (68% and 71% in males and females, respectively) than for the high dose group (46% for both males and females).  For the B-ring groups, the absorption rate was higher in females (78%) than in males (69%) at the low dose, but higher in males (44%) than in females (35%) at the high dose.

At 72 hours post-dosing, the total radioactivity recovered in tissues and carcass accounted for approximately 0.4-2.5% of the administered dose, with lower proportions recovered in tissues from rats in the high dose group than in the low dose group. For all dose groups, the gastrointestinal tract, carcass, and liver and kidney contained the highest proportions of radioactivity.  The remaining tissues generally contained 0.002% of the administered dose or less at 72 hours.

For the low dose groups, biliary, urinary and fecal excretion accounted for approximately 25-37%, 29-51% and 6-17% of the administered dose, respectively. For the high dose groups, biliary, urinary and fecal excretion accounted for approximately 18-32%, 11-24% and 34-41% of the administered dose, respectively.  Most of the radioactivity excreted in urine from low dose rats (90-96%) was eliminated within 24 hours after dosing, whereas at the high dose, excretion was slower with only 74-88% of the radioactivity excreted in urine being eliminated with 24 hours of dosing.  At both low and high doses, 60-89% of the radioactivity excreted in feces was eliminated within 24 hours of dosing.

The unchanged parent was not detected in the urine of any test group. For both radiolabels, metabolite AB-3 was identified as a major metabolite in the urine of female rats but was a minor urinary metabolite in males. For the A-ring label, metabolite A-18 was a major metabolite common to both males and females administered low and high doses, while metabolite A-21 was detected at high levels in the urine of both sexes in the low dose group and males from the high dose group, but was minimal in the urine of females from the high dose group. Minor metabolites common to males and females from the low and high dose groups administered the A-ring label included A-20, AB-2, and [A-6]-GA. For the B-ring label, metabolites [B-1]-TLA, B-1, and [B-1]-MA were major components in urine of both males and females from both the low and high dose groups. Metabolite AB-2 was a minor metabolite in urine of all test groups except females from the low dose group, in which residues for this metabolite reached 4% of the administered dose.

In feces, the unchanged parent and metabolites A-20 and A-12 were detected in the low dose groups administered the A-ring label, each accounting for approximately 2-4% of the administered dose. However, in the corresponding high dose groups, unchanged parent was detected in feces at 62-63% of the administered dose while metabolites A-12 and A-20 were detected at approximately 1%.  Following administration of the B-ring label, the unchanged parent detected in feces accounted for approximately 2% of the administered dose  for the low dose groups, but increased at the high dose to 66% and 54% of the administered dose for males and females, respectively. The only metabolite detected in feces was metabolite B-1, which was detected at much higher levels in the low dose groups than the high dose groups.

The major metabolites detected in the bile from all test groups were the glucuronic acid conjugates of metabolites AB-1 and AB-3. Metabolite AB-2 was also detected at lower levels in the bile from all test groups. Unique metabolites identified in the bile of rats administered the A-ring or B-ring label included the glucuronic acid conjugate of A-6 and the glutathione conjugate of B-1, respectively.

14C-cyflumetofen was metabolized in the rat primarily by hydrolytic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B-1 (trifluoromethylbenzoic acid) and A-18.   Another minor pathway included successive hydroxylation of the tert-butyl side chain.

This series of metabolism studies in the rat is classified as acceptable/guideline and satisfies the guideline requirement for a metabolism study (OPPTS 870.7485; OECD 417) in rats.

	870.7600	Dermal Absorption - Rat

In a dermal absorption study (MRID 48542724), a dermal absorption of [14]C-BAS 9210 (cyflumetofen) was examined in vivo in male rats after a single dermal application at 2, 20 or 2000 ug/cm2 doses. A 100 ul of each dose was applied to10 cm[2] skin area to groups of 4 animals each. Each dose was washed after 8h of exposure and groups of animals were sacrificed at 8h, 24h or 120h. An additional skin wash before sacrifice was given to groups monitored for 24h or 120h.  The dermal absorption, as % of applied radioactive dose, increased over monitored time of 5 days; but decreased with increase in dose. The dermal absorption, as sum of excreta, blood and carcass, was 4.93% (8h), 6.48% (24h) and 8.02% (120h) in 2 ug/cm2 dose groups; 0.63% (8h), 1.27% (24h) and 2.20% (120h) in 20 ug/cm2 dose groups; and 0.26% (8h), 0.53% (24h) and 0.96% (120h) in at 2000 ug/cm2 dose groups. Recovery of the applied dose (mass balance) was acceptable at all dose levels (93 -108 %).  The majority of the administered dose was recovered in first skin wash after 8h of exposure at all dose levels (85 -95%).  The amount of radioactivity recovered in non-occlusive protective cover was small for mid and high dose groups and up to 25.52% in low dose groups. The amount retained at the application sites was 5.18% (8h), 1.44 % (24h) and 1.00 %(120h) in 2 ug/cm2 dose groups; 4.88% (8h), 2.13 %(24h) and 1.32 % (120h) in 20 ug/cm2 dose groups;  6.48% (8h), 2.24 %(24h) and 0.45  %(120h) in 2000 ug/cm2 dose groups.  Small amounts were also detected in skin surrounding the test site and in skin strips. As the residues at the application site skin and in skin strips were absorbed over 5 days, they were included in the total estimate of dermal absorption (Table 3). The residues in the surrounding skin samples were variable, but were lower in 120h groups compared to 8h groups. Therefore, these residues were also included in the estimate. Thus, the total amount of test substance absorbed over time by each animal was estimated as the sum of the quantity found in the excreta (urine, feces and cage wash), blood  (cells + plasma), carcass and skin (at the application site + surrounding skin + skin strips). The estimated dermal absorption were: 11.33% (8h), 10.86% (24h) or 9.5% (120h) in low dose (2 ug/cm2) groups; 7.74 %(8h), 6.09 % (24h) and 3.9 % (120h) in 20 ug/cm2 groups; and  7.28 %(8h), 3.02% (24h) and 1.63% (120h) in 2000 ug/cm2 groups.

The test substance doses and exposure time were selected based on the application rate of the concentrated and spray diluted product expected in the field in actual use conditions. Given the uncertainty regarding actual deposition under field conditions and worker exposure time frame, it is considered appropriate to derive an estimate of dermal absorption based on the results from the low dose group (2 ug/cm2) sacrificed at 8 hr after a skin wash, as the percent dermal absorption was highest in  this dose group. Thus, the estimated dermal absorption is 11%.  This value is considered conservative as the residues retained at the skin site and surrounding skin as well as residues found in the skin strips was included in this estimate and it is possible that all of the skin residues may not become systemically available.

This study is classified as acceptable/guideline and satisfies the guideline requirement for a dermal absorption study (OPPTS 870.7600) in rats.

A.4.9	Immunotoxicity

	870.7800	Immunotoxicity- Rat

In an immunotoxicity study (MRID 48542726), BAS 9210 I (97.08% a.i.) was administered to 8 female Wistar rats/dose in the diet at dose levels of 0, 500, 1500, or 5000 ppm (0, 33, 107, or 349 mg/kg bw/day) for 28 days.  An additional group of 8 female rats was dosed with cyclophosphamide monohydrate in drinking water at a dose level of 4.5 mg/kg bw/day to serve as positive control.  Systemic toxicity parameters were evaluated, and immunotoxicity was investigated by performing an enzyme-linked immunoabsorbant assay (ELISA) to measure serum IgM responses to sheep red blood cells (sRBC) following immunization with SRBC.

A statistically significant increase (p<=0.01) in absolute and relative adrenal weights was observed in the 1500 and 5000 ppm dose groups.  Correlating histopathology was noted as vacuolation of adrenal cortical cells, with severity increasing with dose.  In addition, light discolouration and enlargement of the adrenals was noted in the 1500 and 5000 ppm dose groups.  There were no treatment related effects on mortality, clinical signs, body weights, body weight gains, or food consumption at any dose level.

The LOAEL for systemic toxicity was 1500 ppm (107 mg/kg bw/day) based upon increased adrenal weights and correlating histopathology. The NOAEL for systemic toxicity is 500 ppm (33 mg/kg bw/day) in female rats.

There was no evidence of immunotoxicity.  No effects of treatment were observed on the humoral immune response as measured by the primary serum IgM antibody response to the T-dependent antigen, sheep erythrocytes.  Spleen and thymus weights were unaffected by treatment. Positive control rats demonstrated an 81% decrease (p<=0.01) in serum titer compared to concurrent controls, demonstrating the ability of this ELISA to detect suppression of the humoral immune response.

The LOAEL for immunotoxicity was not established. The NOAEL for immunotoxicity is 5000 ppm (349 mg/kg bw/day) in female rats.

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the rat.

A.5	Summary of Toxicological Doses and Endpoints for Cyflumetofen

Table A.5.  Summary of Toxicological Doses and Endpoints for Cyflumetofen
                              Exposure/ Scenario
                              Point of Departure
                                 Uncertainty/
                              FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (All populations)
An acute reference dose has not been established for either the general population or for Females 13-49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for these populations.
Chronic Dietary (All Populations)
NOAEL =
16.5 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x

Chronic RfD = 0.17 mg/kg/day

cPAD = 0.17
mg/kg/day
Three co-critical studies:
90-day feeding study in rats
LOAEL = 1000 ppm (54.5/62.8 mg/kg/day in M/F) based on hematology and organ weight changes in the liver, adrenal, kidney and ovaries; and histopathology effects in the adrenals and the ovaries. NOAEL=300 ppm (16.5/19 mg/kg/day in males/females)

Chronic toxicity/carcinogenicity study in rats
LOAEL = 1500 ppm (49.5/61.9  mg/kg/day in M/F) based on increased adrenal weights and histopathology. NOAEL=500 ppm (16.5/20.3 mg/kg/day in males/females)

Two generation reproduction study in rats
Parental: LOAEL = 500 ppm (30.6/46.6  mg/kg/day in M/F) based on increased organ weight and histopathology in adrenals. NOAEL=150 ppm (9.2/13.8 mg/kg/day in males/females)
Incidental Oral (Short- and Intermediate-Term)
NOAEL =
16.5 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x

Residential LOC for MOE = 100
Same as chronic dietary endpoint
Dermal
(Short-, Intermediate- and Long-Term)
No dermal hazard was identified. No appropriate endpoint was selected for risk assessment.
Inhalation (Short-, Intermediate- and Long-Term)
NOAEL =
16.5 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x

Occupational and Residential LOC for MOE = 100
Same as chronic dietary endpoint
Cancer (oral, dermal, inhalation)
CARC Classification: Suggestive Evidence of Carcinogenic Potential.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

Appendix B. Metabolism Summary Table

B.1	Structures of Cyflumetofen Metabolites

Table B.1.     Cyflumetofen and Metabolite Structures
                              Common Names / Code
                             Chemical Name (IUPAC)
                              Chemical Structure
Cyflumetofen
BAS 9210 I
OK-5101
2-methoxyethyl (RS)-2-(4-tert-butylphenyl)-2-cyano-3-oxo-3-(α,α,α-trifluoro-o-tolyl)propionate

CAS: 2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-β-oxo-2-(trifluoromethyl) benzenepropanoate

A-1

2-methoxyethyl (RS)-(4-tert-butylphenyl) cyanoacetate

A-2

(4-tert-butylphenyl) acetonitrile

A-12

4-tert-butylbenzoic acid

A-18
(4-tert-butylphenyl) cyanoacetic acid

B-1

o-trifluoromethylbenzoic acid

B-3

CAS: 2-(trifluoromethyl) benzamide

AB-1

(RS)-2-(4-tert-butylphenyl)-3-oxo-3-(α,α,α-tifluoro-o-tolyl) propiononitrile

AB-6

AB-7

AB-11

AB-15

                                      CF
3
O
NC
O
O
OH
AB-1 Dimer

AU-16

AU-17

B.2	Tabular Summary of Metabolites and Degradates

Table B.2.  Tabular Summary of Cyflumetofen Metabolites and Degradates
                         Metabolite Name and Structure
                                    Matrix
                              Percent TRR (PPM)

                             A Label (Butylphenyl)
                               B Label (Benzoyl)

                     Matrices - Major Residue (>10%TRR)
                     Matrices - Minor Residue (<10%TRR)
                     Matrices - Major Residue (>10%TRR)
                     Matrices - Minor Residue (<10%TRR)
Cyflumetofen

Apple
                                 61.0% (Day 1)
                                 78.2% (Day 7)
                                53.2% (Day 30)

                                 58.4% (Day 1)
                                 83.8% (Day 7)
                                64.9% (Day 30)

Eggplant
                                 95.0% (Day 1)
                                 66.9 (Day 7)
                                 62.2 (Day 14)

                                 91.2% (Day 1)
                                 70.7% (Day 7)
                                42.4% (Day 14)

Mandarin
                                 89.8% (Day 1)
                                 82.6% (Day 7)
                                54.0% (Day 30)

                                 88.4% (Day 1)
                                 78.9% (Day 7)
                                43.9% (Day 30)

Rotational Crops

Ruminant
                                 Feces - 45.6%

                           Fat (abdominal)  -  19.6%
                            Fat (kidney)  -  21.0%
                                Feces  -  7.4%

Rat[1]
                           Feces  -  3.3%  -  63.5%

                            Feces  -  2.5% - 65.7%

B-1
(2-trifluoromethylbenzoic acid)

Apple

                                 1.2% (Day 7)
                                 1.8% (Day 30)

Eggplant

                                 10.6% (Day 7)
                                14.8% (Day 14)
                         16.2% (Conjugate  -  Day 14)
                                 2.5% (Day 1)

Mandarin

                                11.2% (Day 30)
                                 4.7% (Day 1)
                                 6.6% (Day 7)

Rotational Crops

                                    0.2%[2]

Ruminant

                                Liver  -  32.0%
                               Kidney  -  53.9%
                            Muscle (leg)  -  50.5%
                            Muscle (back)  -  46.5%
                                Urine  -  47.0%
                                Feces  -  63.9%
                                Bile  -  22.4%
                           Fat (abdominal)  -  40.2%
                            Fat (kidney)  -  21.0%
                                 Milk  -  4.5%

Rat[1]

                            Feces  -  6.0% - 27.0%
              Urine  -  1.4% - 13.5% (mercapturic acid conjugate)
              Urine  -  4.3% - 20.2% (thiolactic acid conjugate)
                             Urine  -  2.6% - 9.7%
AB-6

Apple

                                 1.3% (Day 7)
                                 5.1% (Day 30)

                                 5.3% (Day 30)

Eggplant

                                 8.8% (Day 7)
                                 5.1% (Day 14)

                                 3.0% (Day 7)
                                 3.4% (Day 14)

Mandarin

                                 1.0% (Day 1)
                                 2.1% (Day 7)
                                 7.5% (Day 30)

                                 1.0% (Day 1)
                                 2.5% (Day 7)
                                 8.6% (Day 30)

Rotational Crops

Ruminant

Rat[1]

Apple

AB-7
Apple

                                 6.3% (Day 30)

                                 5.4% (Day 7)
                                 5.3% (Day 30)

Eggplant

                                 4.8% (Day 7)
                                 5.1% (Day 14)

                                 2.9% (Day 7)
                                 3.6% (Day 14)

Mandarin

                                 0.7% (Day 1)
                                 1.6% (Day 7)
                                 7.1% (Day 30)

                                 0.5% (Day 1)
                                 2.0% (Day 7)
                                 8.5% (Day 30)

Rotational Crops

Ruminant

Rat[1]

Notes:
-For plant metabolism studies, rinsate and extract values were summed prior to inclusion in this table.
-Due to rounding of some values with very low residues, accountabilities may be slightly different from those reported in earlier tables.
[1]For the rat metabolism study, a range is given from the low dose to the high dose groups
[2]B-1 was seen in the benzoyl labeled spring wheat grain only (30 day PBI) at <0.001ppm

Appendix C.  Physical/Chemical Properties

Table C.1.  Physicochemical Properties of the Technical Grade Cyflumetofen
Parameter
Value
Reference
Molecular weight (g/mole)
447.45
MRIDs 48542735-41
Physical state (21.5°C)
White solid (powder)

Melting point (°C)
77.9

pH
NA

Density (g/cm[3]) (23°C)
1.229

Water solubility ( mg/L at 20°C)
0.0277

Solvent solubility (g/L at 20°C)
n-Hexane  5.16
Toluene  >500
Dichloromethane  >500
Acetone  >500
Methanol   98.7
Ethyl acetate   >500

Vapor pressure (mm Hg)
4.43 x 10[-8] at 25 ºC

Dissociation constant (pKa)
The structural formula does not indicate dissociation in the relevant pH region (2 to12). The pKa was calculated to be - 4.19.

Octanol/water partition coefficient - Log(KOW)
4.3

Appendix D.  Review of Human Research

This risk assessment relies, in part, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re-entry Task Force (ARTF) database; and the Residential SOPs (Residential Handler) are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at: http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Appendix E.  Residue Summary Table

Table E.1.  Summary of Residues from Field Trials with Cyflumetofen
                                 Crop Matrix
                                    Analyte
                                 Applic. Rate
                                 (lb ai/acre)
                                  PHI (days)
                                     n[*]
                                Residues (ppm)

                                   Min.[†]
                                   Max.[†]
                                    LAFT[*]
                                    HAFT*
                                   Median[*]
                                    Mean[*]
                                     SD[*]
Citrus
Orange fruit
                                 Cyflumetofen
                                0.355  -  0.366
                                       7
                                      12
                                     0.010
                                     0.159
                                     0.010
                                     0.116
                                     0.073
                                     0.070
                                     0.035
Grapefruit fruit
                                 Cyflumetofen
                                0.357  -  0.364
                                       7
                                       6
                                   <0.010
                                     0.077
                                     0.010
                                     0.072
                                     0.038
                                     0.037
                                     0.021
Lemon fruit
                                 Cyflumetofen
                                  0.349-0.358
                                       7
                                       5
                                   <0.010
                                     0.141
                                     0.010
                                     0.135
                                     0.021
                                     0.054
                                     0.054
Pome Fruits
Apple fruit[1]
                                 Cyflumetofen
                                  0.349-0.375
                                      6-8
                                      12
                                   <0.010
                                     0.248
                                     0.015
                                     0.163
                                     0.080
                                     0.092
                                     0.048
Pear fruit
                                 Cyflumetofen
                                  0.349-0.375
                                      6-8
                                       5
                                     0.032
                                     0.265
                                     0.049
                                     0.160
                                     0.106
                                     0.098
                                     0.045
Tree Nuts
Pecan Nutmeat
                                 Cyflumetofen
                                  0.350-0.365
                                      7-8
                                       5
                                   <0.010
                                   <0.010
                                   <0.010
                                   <0.010
                                     0.010
                                     0.010
                                       0
Almond Nutmeat
                                 Cyflumetofen
                                  0.354-0.356
                                       7
                                       5
                                   <0.010
                                   <0.010
                                   <0.010
                                   <0.010
                                     0.010
                                     0.010
                                       0
Almond Hulls
                                 Cyflumetofen
                                  0.354-0.356
                                       7
                                       5
                                     0.339
                                     2.046
                                     0.352
                                     1.871
                                    0.0534
                                     0.830
                                     0.610
Strawberry
Strawberry
                                 Cyflumetofen
                                  0.351-0.362
                                       1
                                       8
                                     0.038
                                     0.437
                                     0.042
                                     0.365
                                     0.154
                                     0.171
                                     0.098
Tomato
Tomato[2]
                                 Cyflumetofen
                                  0.345-0.364
                                       3
                                      16
                                   <0.010
                                     0.161
                                     0.013
                                     0.148
                                     0.038
                                     0.053
                                     0.038
Tomato[3]
                                 Cyflumetofen
                                  0.345-0.364
                                       3
                                      16
                                   <0.019
                                     0.298
                                     0.023
                                     0.274
                                     0.070
                                     0.097
                                     0.071
Grape
Grape
                                 Cyflumetofen
                                  0.350-0.361
                                      14
                                      12
                                     0.014
                                     0.439
                                     0.023
                                     0.423
                                     0.156
                                     0.175
                                     0.103
† Values based on total number of samples.  Includes samples from decline trials at proposed PHI.
[*] Values based on per-trial averages.  LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard Deviation.  For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the LOQ.
[1] Apple fruit trials consisted of four treated samples (two replicates, one dilute and one concentrate) at each field trial site.     	Summary statistics are calculated by using the per-trial average of all four samples.
[2] Uncorrected residues of cyflumetofen from tomato field trials.
[3] Corrected residues of cyflumetofen for residue loss during freezer storage.


Mark Collatz, Adhesives and Sealants Council<PHONE_NUMBER>

6/21/2007

Tel. log

Question about the May 30, 2007 proposal:

When would adhesives users have to stop using?  When a final rule is effective—60 days after final, sometime next year, most likely.

Raise issues of how long to convert—Mr. Collatz will check with his constituents to see if there is likely to be an issue with the timeframe.


[Federal Register Volume 88, Number 243 (Wednesday, December 20, 2023)]
[Notices]
[Pages 88060-88061]
[FR Doc No: 2023-27986]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 2417-067]

Northern States Power Company; Notice of Application Tendered for
Filing With the Commission and Soliciting Additional Study Requests and
Establishing Procedural Schedule for Relicensing and Deadline for
Submission of Final Amendments

    Take notice that the following hydroelectric application has been
filed with the Commission and is available for public inspection.
    a. Type of Application: Subsequent Minor License.
    b. Project No.: 2417-067.
    c. Date Filed: November 30, 2023.
    d. Applicant: Northern States Power Company (Northern States
Power).
    e. Name of Project: Hayward Hydroelectric Project (Hayward
Project).
    f. Location: The Hayward Project is located on the Namekagon River
in the City of Hayward in Sawyer County, Wisconsin.
    g. Filed Pursuant to: Federal Power Act 16 U.S.C. 791(a)-825(r).
    h. Applicant Contact: Donald Hartinger, Director of Renewable
Operation-Hydro, Xcel Energy, 414 Nicollet Mall, 2, Minneapolis, MN
55401; phone<PHONE_NUMBER>; or Matthew Miller, Environmental Analyst,
Xcel Energy, 1414 W Hamilton Ave., P.O. Box 8, Eau Claire, WI 54702-
0008; phone<PHONE_NUMBER>.
    i. FERC Contact: Laura Washington<PHONE_NUMBER>,
[email protected].
    j. Cooperating Agencies: Federal, state, local, and tribal agencies
with jurisdiction and/or special expertise with respect to
environmental issues that wish to cooperate in the preparation of the
environmental document should follow the instructions for filing such
requests described in item l below. Cooperating agencies should note
the Commission's policy that agencies that cooperate in the preparation
of the environmental document cannot also intervene. See, 94 FERC ]
61,076 (2023).
    k. Pursuant to section 4.32(b)(7) of 18 CFR of the Commission's
regulations, if any resource agency, Indian Tribe, or person believes
that an additional scientific study should be conducted in order to
form an adequate factual basis for a complete analysis of the
application on its merit, the resource agency, Indian Tribe, or person
must file a request for a study with the Commission not later than 60
days from the date of filing of the application, and serve a copy of
the request on the applicant.
    l. Deadline for filing additional study requests and requests for
cooperating agency status: January 29, 2024.
    The Commission strongly encourages electronic filing. Please file
additional study requests and requests for cooperating agency status
using the Commission's eFiling system at http://www.ferc.gov/docs-filing/efiling.asp. For assistance, please contact FERC Online Support
at [email protected],<PHONE_NUMBER> (toll free), or (202)
502-8659 (TTY). In lieu of electronic filing, you may submit a paper
copy. Submissions sent via the U.S. Postal Service must be addressed
to: Kimberly D. Bose, Secretary, Federal Energy Regulatory Commission,
888 First Street NE, Room 1A, Washington, DC 20426. Submissions sent
via any other carrier must be addressed to: Kimberly D. Bose,
Secretary, Federal Energy Regulatory Commission, 12225 Wilkins Avenue,
Rockville, Maryland 20852. The first page of any filing should include
docket number P-2417-067.
    m. This application is not ready for environmental analysis at this
time.
    n. The existing Hayward Project consists of the following existing
facilities: (1) a 246.9-acre reservoir; (2) a 442-foot-long the
concrete overflow dam; (3) a 18-foot-wide, 24-foot long powerhouse with
intake channel containing one S. Morgan Smith vertical Francis-Type
turbine with a total installed capacity of 0.168 megawatts;

(4) a tailrace; (5) a 150-foot-long underground transmission line.
Northern States Power is not proposing any changes to project
facilities or operation.
    o. A copy of the application can be viewed on the Commission's
website at http://www.ferc.gov using the ``eLibrary'' link. Enter the
docket number excluding the last three digits in the docket number
field to access the document. For assistance, contact FERC at
[email protected] or call toll-free,<PHONE_NUMBER> or (202)
502-8659 (TTY).
    You may also register online at http://www.ferc.gov/docs-filing/esubscription.asp to be notified via email of new filings and issuances
related to this or other pending projects. For assistance, contact FERC
Online Support.
    The Commission's Office of Public Participation (OPP) supports
meaningful public engagement and participation in Commission
proceedings. OPP can help members of the public, including landowners,
environmental justice communities, Tribal members and others, access
publicly available information and navigate Commission processes. For
public inquiries and assistance with making filings such as
interventions, comments, or requests for rehearing, the public is
encouraged to contact OPP at<PHONE_NUMBER> or [email protected].
    p. Procedural Schedule: The application will be processed according
to the following preliminary schedule. Revisions to the schedule will
be made as appropriate.

------------------------------------------------------------------------
                Milestone                           Target date
------------------------------------------------------------------------
Issue Deficiency Letter (if necessary)..  February 2024.
Request Additional Information (if        February 2024.
 necessary).
Issue Scoping Document 1 for comments...  May 2024.
Issue Acceptance Letter.................  June 2024.
Request Additional Information (if        July 2024.
 necessary).
Issue Scoping Document 2 (if necessary).  August 2024.
------------------------------------------------------------------------

    Final amendments to the application must be filed with the
Commission no later than 30 days from the issuance date of the notice
of ready for environmental analysis.

    Dated: December 14, 2023.
Debbie-Anne A. Reese,
Deputy Secretary.
[FR Doc. 2023-27986 Filed 12-19-23; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 84, Number 102 (Tuesday, May 28, 2019)]
[Notices]
[Pages 24575-24576]
[FR Doc No: 2019-10982]

-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

[SEC File No. 270-447, OMB Control No. 3235-0504]

Proposed Collection; Comment Request

Upon Written Request, Copies Available From: Securities and Exchange
Commission, Office of FOIA Services, 100 F Street NE, Washington, DC
20549-2736.

Extension:
    Rule 19b-4(e) and Form 19b-4(e).

    Notice is hereby given that pursuant to the Paperwork Reduction Act
of 1995 (44 U.S.C. 3501 et seq.) the Securities and Exchange Commission
(``Commission'') is soliciting comments on the existing collection of
information provided for in Rule 19b-4(e) (17 CFR 240.19b-4(e)) under
the Securities Exchange Act of 1934 (15 U.S.C 78a et seq.) (the
``Act''). The Commission plans to submit this existing collection of
information to the Office of Management and Budget (``OMB'') for
extension and approval.
    Rule 19b-4(e) permits a self-regulatory organization (``SRO'') to
list and trade a new derivative securities product without submitting a
proposed rule change pursuant to Section 19(b) of the Act (15 U.S.C.
78s(b)), so long as such product meets the criteria of Rule 19b-4(e)
under the Act. However, in order for the Commission to maintain an
accurate record of all new derivative securities products traded on the
SROs, Rule 19b-4(e) requires an SRO to file a summary form, Form 19b-
4(e), to notify the Commission when the SRO begins trading a new
derivative securities product that is not required to be submitted as a
proposed rule change to the Commission. Form 19b-4(e) should be
submitted within five business days after an SRO begins trading a new
derivative securities product that is not

required to be submitted as a proposed rule change. In addition, Rule
19b-4(e) requires an SRO to maintain, on-site, a copy of Form 19b-4(e)
for a prescribed period of time.
    This collection of information is designed to allow the Commission
to maintain an accurate record of all new derivative securities
products traded on the SROs that are not deemed to be proposed rule
changes and to determine whether an SRO has properly availed itself of
the permission granted by Rule 19b-4(e). The Commission reviews SRO
compliance with Rule 19b-4(e) through its routine inspections of the
SROs.
    The respondents to the collection of information are SROs (as
defined by the Act), all of which are national securities exchanges. As
of March 29, 2019 there are twenty-two entities registered as national
securities exchanges with the Commission. The Commission receives an
average total of 5,122 responses per year, which corresponds to an
estimated annual response burden of 5,122 hours. At an average hourly
cost of $71, the aggregate related internal cost of compliance with
Rule 19b-4(e) is $363,662 (5,122 burden hours multiplied by $71/hour).
    Compliance with Rule 19b-4(e) is mandatory. Information received in
response to Rule 19b-4(e) shall not be kept confidential; the
information collected is public information.
    Written comments are invited on: (a) Whether the proposed
collection of information is necessary for the proper performance of
the functions of the Commission, including whether the information
shall have practical utility; (b) the accuracy of the Commission's
estimate of the burden of the collection of information; (c) ways to
enhance the quality, utility, and clarity of the information collected;
and (d) ways to minimize the burden of the collection of information on
respondents, including through the use of automated collection
techniques or other forms of information technology. Consideration will
be given to comments and suggestions submitted in writing within 60
days of this publication.
    An agency may not conduct or sponsor, and a person is not required
to respond to, a collection of information under the PRA unless it
displays a currently valid OMB control number.
    Please direct your written comments to: Charles Riddle, Acting
Director/Chief Information Officer, Securities and Exchange Commission,
c/o Candace Kenner, 100 F Street NE, Washington, DC 20549 or send an
email to<EMAIL_ADDRESS>
    Dated: May 21, 2019.
Eduardo A. Aleman,
Deputy Secretary.
[FR Doc. 2019-10982 Filed 5-24-19; 8:45 am]
 BILLING CODE 8011-01-P