UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES TXR NO. 0051578 DATE: February 19, 2003 MEMORANDUM SUBJECT: CYPERMETHRIN AND ZETA CYPERMETHRIN  5th Report of the Hazard Identification Assessment Review Committee.

FROM: Brenda Tarplee, Senior Scientist Science Information Management Branch Health Effects Division ( 7509C)

THROUGH: Jess Rowland, Co Chair and Elizabeth Doyle, Co Chair Hazard Identification Assessment Review Committee Health Effects Division ( 7509C)

TO: Yan Donovan, Risk Assessor Registration Action Branch 2 Health Effects Division ( 7509C)

PC Code: 109702 and 129064 On January 22, 2003 the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reassessed FQPA requirements in response to questions posed by the Natural Resources Defense Council ( NRDC). HIARC also reviewed the previous recommendation for a developmental neurotoxicity study in rats and subsequent need for a data base factor to account for this data gap. No new data have been reviewed and no changes were made to the toxicology endpoints previously selected for cypermethrin and zeta cypermethrin. This document revises the previous HIARC report dated January 17, 2001 ( TXR NO. 014445). 2 Committee Members in Attendance Members present were: Ayaad Assaad, William Burnam, Paula Deschamp, Elizabeth Doyle, Pamela Hurley, John Liccione, Susan Makris, Elizabeth Mendez, David Nixon, Jess Rowland, PV Shah ( for Jonathan Chen), and Brenda Tarplee ( Executive Secretary).

Member( s) in absentia were: Jonathan Chen Also in attendance were: Karen Whitby ( RAB1) and Ed Zager ( HED IO).

Meeting materials prepared by: Brenda Tarplee, Senior Scientist, SIMB 3 INTRODUCTION On November 16 and December 19, 2000, the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reviewed the recommendations of the toxicology reviewer for both cypermethrin and z cypermethrin with regard to the acute and chronic Reference Doses ( RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. This was a re evaluation of previous HIARC ( 2000 and 1997) and RfD ( 1996) Committee decisions. The December 19 meeting was a re evaluation of the dermal absorption value determined on November 16. The potential for increased susceptibility of infants and children from exposure to either cypermethrin and/ or z cypermethrin was previously evaluated on September 19, 2000 as required by the Food Quality Protection Act ( FQPA) of 1996.

On January 22, 2003 the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reassessed FQPA requirements in response to questions posed by the Natural Resources Defense Council ( NRDC). HIARC also reviewed the previous recommendation for a developmental neurotoxicity study in rats and subsequent need for a data base factor to account for this data gap. No new data have been reviewed and no changes were made to the toxicology endpoints previously selected for cypermethrin and zeta cypermethrin. This document revises the previous HIARC report dated January 17, 2001 ( TXR NO. 014445).

I. FQPA HAZARD CONSIDERATIONS 1. Adequacy of the Toxicity Data Base The HIARC concluded that the toxicology database for zeta cypermethrin is not complete for FQPA assessment.

On November 16 and December 19, 2000, the HIARC requested that a developmental neurotoxicity study in rats be conducted with zeta cypermethrin.

2. Evidence of Neurotoxicity The HIARC concluded that there is a concern for neurotoxicity resulting from exposure to zetacypermethrin The following data are available.

a. Acute Delayed Neurotoxicity  Hen ( Cypermethrin)

Cypermethrin is not an organophosphate insecticide and this study is not required. However, cypermethrin was tested in the hen following a protocol similar to the series 81 7 guideline. The dose levels tested were 0, 2500, 5000 and 10000 mg/ kg but there was no indication of the delayed type neurotoxicity noted ( MRID No.: 00070564).

b. Acute Neurotoxicity Screening Battery  Rat ( Cypermethrin)

In an acute neurotoxicity screen, cypermethrin ( 95.5/ 95.7% purity, 1: 1 cis: trans) was administered once by gavage in corn oil to four groups of 12 hour fasted Sprague Dawley rats ( 10/ sex/ group) at 4 doses of 0 ( corn oil only), 30, 100 or 200 mg/ kg. The rats were assessed at pretest, four hours after treatment and on days 7 and 14 for FOB and motor activity. After day 14, 5/ sex/ dose were prepared for neurohistopathology. ( MRID 43152001).

At 100 mg/ kg, on days 0, 1 or 2 only, ataxia ( 2 males and 2 females) and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp condition) and decreased motor activity ( 49%, p< 0.001 for males and 33%, p< 0.01 for females) resulted. In addition, some females had salivation, lacrimation and/ or soiled fur. At 200 mg/ kg, one male and two females died on day 0; the majority of the following clinical signs were noted on day 0 in one or more of 7/ 10 males and 9/ 10 females: ataxia, staggered gait, abdominogenital staining, oral discharge and decreased locomotion. Neurohistopathologically, no treatment related lesions in any of the various structures were reported. Acceptable positive control data were provided by the sponsor. The LOAEL is 100 mg/ kg based primarily on ataxia and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp conditions in addition to decreased motor activity in males and females on days 0, 1 or 2). The NOAEL is 30 mg/ kg. This study is ACCEPTABLE and satisfies the requirement for an acute neurotoxicity screen ( 81 8, 870.6200) in rats.

c. Acute Neurotoxicity Screening Battery  Rat ( Cypermethrin)

THIS EXECUTIVE SUMMARY IS BASED UPON A PUBLICATION Katherine L. McDaniel and Virginia C. Moser, " Utility of a Neurobehavioral Screening Battery for Differentiating the Effects of Two Pyrethroids, Permethrin and Cypermethrin", Neurotoxicology and Teratology 15: 71 83 ( 1993). MRID none.

The Executive Summary will include information pertaining only to cypermethrin.

Four groups of 8/ sex Charles River Long Evans rats were administered by gavage cypermethrin ( 97% a. i., 1: 1 ratios of cis and trans isomers) at single doses of 0 ( corn oil), 20, 60 or 120 ( FOB experiment)/ 100 ( motor activity) mg/ kg. Separate sets of animals were treated for the FOB and motor assessments. FOB was examined 1.5 and 3 hours post dosing. Motor activity was examined 3 hours post dosing. Both FOB and motor activity were also examined pretest as well as after 24 and 48 hours post dosing. During the FOB assessments, one male and 6 of 12 ( 8 original and 4 replacements) female rats dosed with 120 mg/ kg died. The dose was then reduced to 100 mg/ kg for the motor assessments and, at this level, two males and one female died ( symptoms prior to death not described).

Transient weight losses of 7.5 and 9% for males and females were observed 24 hours postdosing in the highest dose ( persisted to 48 hours). No body weight effects at lower doses. There were gait and muscle effects as well as choreoathetosis. Motor activity was decreased for all dose groups for males ( estimated 45%, 66% and 85% for the 20, 60 and 100 mg/ kg groups, respectively). Gait abnormalities were noted in all dose groups ( males only at 20 mg/ kg) at 1.5 hours post dosing with the 60 and 100 mg/ kg rats showing progressively higher median scores. The high dose males and females showed gait abnormalities at 24 and possibly 48 hours. Effects were reported for males 5 and females regarding the following parameters at 60 and 100 mg/ kg: salivation, urination, arousal, abnormal motor movement, forelimb or hindlimb grip strength, landing foot splay, righting reflex, touch response and tail pinch response. [ Details of these effects were not included in the DER.] Regarding body temperature, the 20 mg/ kg males had statistically significant increased temperature at 1.5 hours ( 38.5 to slightly over 39 ° C; male and female 100 mg/ kg as well as male 60 mg/ kg had temperature decreased to below 37 ° C at 1.5 hours for females and 3 hours for males; and females were still decreased after 24 and 48 hours. No histopathology or perfusion data were included.

The LOAEL for neurotoxicity was 20 mg/ kg based on decreased motor activity and gait abnormalities. The NOAEL was < 20 mg/ kg. This single dose neurotoxicity study is classified as SUPPLEMENTARY. It was in the form of a literature reprint and was not designed to meet a specific guideline protocol. [ Most of the data were presented in a semi quantitative manner and no individual animal data were presented to verify the observations.]

d. Acute Neurotoxicity Screening Battery  Rat ( z Cypermethrin)

In an acute neurotoxicity screening battery study ( MRID 44962201), male and female Long Evans rats ( 10 animals/ sex/ group) were dosed once orally by gavage with undiluted z cypermethrin ( 84.4% a. i.) at levels of 0 ( water only), 10, 50 or 250 mg/ kg. The functional observational battery ( FOB) and motor activity were evaluated prior to treatment and on study days 0, 7 and 14 postdosing At study termination, 5 animals/ sex/ dose were perfused in situ, and animals from the control and 250 mg/ kg dose groups were subjected to neuropathological examinations.

No treatment related findings were observed in the 10 mg/ kg group. Body weights, body weight gains, motor activity, gross pathology and neuropathology were unaffected by the test substance. At 50 mg/ kg, noted clinical observations included the following ( data presented as total occurrences/ number of animals): ( i) abdominogenital staining ( 1/ 1, both sexes); ( ii) oral discharge ( 1/ 1, males); ( iii) splayed hindlimbs ( 1/ 1, males); ( iv) staggered gait ( 2/ 2, males); and ( v) tremors ( 1/ 1, males). On day 0 during the homecage portion of the FOB, treatment related observations included the following: ( i) abnormal mobile posture ( 1/ 10, females); ( ii) splayed hindlimbs ( 1/ 10, females); ( iii) soiled fur ( males 2/ 10, females 1/ 10); and ( iv) unable to walk ( 1/ 10, females). All groups were comparable during the pretest evaluation and on test days 7 and 14. On day 0 during the open field portion of the FOB, treatment related observations noted in the females included the following: ( i) abnormal mobile posture ( 1/ 10); ( ii) unusual immobile posture ( 1/ 10); ( iii) severely impaired gait ( 1/ 10); ( iv) splayed hindlimbs ( 1/ 10); ( v) lands on back ( 1/ 10); ( vi) whole body tremors ( 1/ 10); and ( vii) convulsions ( 1/ 10). All female groups were comparable during the pretest evaluation and on test days 7 and 14. None of these findings were observed in the controls.

At 250 mg/ kg, one female died on the day following test substance administration ( no cause of death determined). Clinical observations included the following ( data presented as total occurrences/ number of animals): ( i) abdominal gripping ( 1/ 1, females): ( ii) abdominogenital staining ( males 6/ 4, females 4/ 3); ( iii) ataxia ( 1/ 1, females); ( iv) decreased locomotion ( males 2/ 2, 6 females 1/ 1); ( v) lacrimation ( 1/ 1, females); ( vi) loss of muscle control ( 1/ 1, females); ( vii) oral discharge ( males 3/ 3, females 2/ 1); ( viii) splayed hindlimbs ( males 2/ 2, females 3/ 2); ( ix) staggered gait ( 4/ 4, males); ( x) tremors ( 2/ 2, both sexes); ( xi) tonic clonic convulsions ( 2/ 2, females); and ( xii) vocalization ( 1/ 1, both sexes). These findings were not observed in concurrent controls. The only statistically significant ( p< 0.05) finding noted during the home cage portion of the FOB on day 0 was soiled fur in the males ( 4/ 10); this finding was not observed in any control animal. Other treatment related observations included the following: ( i) staggered gait ( 2/ 10, males); ( ii) abnormal mobile posture ( males 1/ 10, females 3/ 10); ( iii) splayed hindlimbs ( males 1/ 10, females 2/ 10); ( iv) soiled fur ( 2/ 10, females); and ( v) inability to walk ( 1/ 10, females). Treatment related effects noted on day 0 during the open field portion of the FOB included the following: ( i) abnormal mobile posture ( males 1/ 10, females 3/ 10); ( ii) unusual immobile posture ( 1/ 10, females only); ( iii) staggered gait ( males 2/ 10, females 1/ 10); ( iv) splayed hindlimbs ( males 1/ 10, females  2/ 10); ( v) slightly impaired gait ( 1/ 10, both sexes); ( vi) moderately impaired gait ( 1/ 10, males only); ( vii) severely impaired gait ( 1/ 10, females only); ( viii) dragging hindlimbs ( 1/ 10, females only); ( ix) incoordinated landing ( 1/ 10, both sexes); ( x) lands on back ( 1/ 10, females only); ( xi) whole body tremors ( 3/ 10, females only); ( vii) convulsions ( 1/ 10, females only); and ( xiii) decreased activity ( 1/ 10, both sexes). None of these findings were observed in the controls. Acceptable positive control data were provided by the sponsor.

The acute neurotoxicity LOAEL is 50 mg/ kg based on clinical signs of toxicity and FOB findings. The acute neurotoxicity NOAEL for this study is 10 mg/ kg. This submitted study is classified as acceptable/ guideline ( 81 8[ a]; 870.6200) and satisfies the guideline requirements for an acute neurotoxicity screening battery in rats.

e. Subchronic Neurotoxicity Screening Battery  Rat ( Cypermethrin)

Cypermethrin ( 95.7% purity) was administered by dietary admix to four groups of 10/ sex Sprague Dawley strain rats at doses of 0, 500, 1300 or 1700 ppm ( mg/ kg/ day: 0, 31, 77 or 102 for males and 0, 37, 95 or 121 for females) for 90 days in a subchronic neurotoxicity study. Rats were assessed twice daily for clinical signs and mortality; FOB and motor activity were examined pretest as well as at weeks 4, 8 and 13. Neurohistopathology was performed. MRID 43152002. At 1300 ppm, females displayed the following ( number of rats with sign/ total number of rats in the group): ataxia ( 1/ 10), splayed hindlimbs ( 5/ 10), impaired gait ( 4/ 10) and decreased feces ( 4/ 10) as well as decreased body weight gain ( 41%). Males had only decreased body weight gain ( 27%) and increased landing foot splay. At 1700 ppm, males showed ataxia ( 8/ 10) and additional related symptoms; females had decreased motor activity ( 27%). No test article related neurohistopathological lesions were reported. Acceptable positive control data were included. The LOAEL is 1300 ppm ( 77 mg/ kg/ day) based on the following: males = decreased body weight gain and increased landing foot splay; females = ataxia, splayed hindlimbs, impaired gait and decreased feces as well as decreased body weight gain. The NOAEL is 500 ppm ( 31 mg/ kg/ day). This study is ACCEPTABLE and satisfies the guideline ( 82 7, 870.6200) requirements for a subchronic neurotoxicity study in rats. 7 f. Subchronic Neurotoxicity Screening Battery  Rat ( z Cypermethrin)

In this subchronic neurotoxicity screening battery, z cypermethrin, purity of 86.0% ( MRID 44962202), was administered continuously in the diet for 13 weeks to 10 Charles River Long Evans rats/ sex/ group at doses of 0, 75, 400 or 750 ppm ( equivalent to [ M/ F] 0/ 0, 5.0/ 5.9, 26.3/ 31.5, or 47.2/ 55.6 mg/ kg/ day). Five animals/ sex/ group were perfused for neurohistological examination, and the control and high dose animals were examined microscopically. Functional observational battery ( FOB) and motor activity were evaluated during the pretest interval, and following weeks 4, 8, and 13.

No treatment related deaths occurred. Clinical signs, gross pathology and neuropathology were unaffected by the test substance; furthermore, no treatment related findings were noted in the home cage observations of the FOB at any dose. No treatment related findings were observed in the 75 ppm group. In the 400 ppm males, statistically significant decreases in body weights were observed at all intervals except week 3 ( 95 8%), p # 0.05); overall ( weeks 0 13) body weight gains were also decreased relative to concurrent controls in these animals ( 915%, p # 0.05). Decreased food consumption was observed throughout the study, but statistical significance was sporadic ( 96 17%, p # 0.01 or 0.05). During the open field portion of the FOB, increased landing foot splay was observed at week 13 ( 833%, p # 0.01). In addition, mean motor activity was decreased ( p # 0.01 or 0.05) at weeks 8 ( 936%) and 13 ( 951%). At 750 ppm, one female was sacrificed in extremis on day 51 following mechanical injury; this death was considered not to be treatmentrelated Body weights were decreased throughout the study ( 912 17%, p # 0.01) in the males. In the females, body weights were decreased sporadically for the first 9 weeks of the study, and continually at weeks 10 13 ( 95 10%, p # 0.05 or 0.01). Overall ( weeks 0 13) body weight gains were decreased ( p # 0.01) in both sexes ( 928 31%) as was food consumption ( 98 29%). During the open field portion of the FOB, increased landing foot splay was observed in the males at week 13 ( 841%, p # 0.01). Mean motor activity was decreased ( p # 0.05 or 0.01) in the males at weeks 8 ( 925%) and 13 ( 942%).

The LOAEL for this study is 400 ppm for males ( equivalent to 26.3 mg/ kg/ day), based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption; and 750 ppm for females ( equivalent to 55.6 mg/ kg/ day) based on decreased body weights, body weight gains, and food consumption. The NOAEL for this study is 75 ppm for males ( equivalent to 5.0 mg/ kg/ day) and 400 ppm for females ( equivalent to 31.5 mg/ kg/ day). The submitted study is classified as acceptable/ guideline ( § 82 7[ a]; 870.6200) and satisfies the guideline requirements for a subchronic neurotoxicity screening battery in rats.

g. Evidence of neurotoxicity from studies other than the neurotoxicity studies Clinical signs of neurotoxicity ( i. e. tremors and gait abnormalities) were observed in dog ( subchronic and chronic) and rat ( subchronic, developmental, and reproduction) oral studies conducted with both cypermethrin and z cypermethrin. Similar clinical signs were also observed in the rat inhalation study conducted with cypermethrin. Increased relative brain weights were noted 8 in the z cypermethrin rat reproduction study. In the cypermethrin subchronic rat study ( 1980), electron microscopic examination of the central and peripheral nervous system revealed some possible splitting and/ or vacuolation ( not specified which tissue; 7/ 16 high dose males versus 2/ 12 control males; this was not specifically listed as a treatment related effect in the DER).

3. Developmental Toxicity Study Conclusions a. Developmental Toxicity Study, Rat ( Cypermethrin)

In a developmental toxicity study ( MRID 00056804, 92027039 or 92027061), cypermethrin ( 98.2% purity) in corn oil was administered by gavage to four groups of 25 mated CD strain Charles River rats at dose levels of 0, 17.5, 35 or 70 mg/ kg/ day on days 6 15 of gestation. The rats were sacrificed at day 21 of gestation. Dose levels of 35 ( 12%) and 70 ( 28%) mg/ kg/ day resulted in decreased body weight gain. The dams dosed with 70 mg/ kg/ day displayed neurological signs such as splayed limbs, spasms, and hypersensitivity to noise and convulsions. The maternal LOAEL is 35 mg/ kg/ day, based on decreased body weight gain. The maternal NOAEL is 17.5 mg/ kg/ day. There were no effects on either skeletal or visceral structures reported. The developmental LOAEL is > 70 mg/ kg/ day. The developmental NOAEL is > 70 mg/ kg/ day. This developmental toxicity study in the rat is classified as ACCEPTABLE and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700, 83 a).

b. Developmental Toxicity Study, Rat ( z Cypermethrin)

In a developmental toxicity study ( MRID 41776102) z cypermethrin ( 89.6% purity) in corn oil was administered by gavage to five groups of 25 Charles River Crl: CD ( SD) rats at dose levels of 0, 5, 12.5, 25 or 35 mg/ kg/ day on days 6 through 15 of gestation. Clinical signs of toxicity were observed in the 25 and 35 mg/ kg/ day groups. In the 25 mg/ kg/ day group, there was ataxia, urinestained abdominal fur and fecal stained perineal fur. In the 35 mg/ kg/ day group there was a significant ( p# 0.01) increase in ataxia, hypersensitivity, urine stained abdominal fur, emaciated appearance, excess salivation and soft or liquid feces. These symptoms started about 8 10 days after initiation of treatment and lasted through gestation. Chromorhinorrhea was observed in 0, 3, 3, 4 and 4 rats at 0, 12.5, 25 and 35 mg/ kg/ day groups. There was a decrease in body weight gains ( p# 0.01) during the dosing period in the 25 mg/ kg/ day group ( 23%) and the 35 mg/ kg/ day group ( 51%). During dosing, food consumption was also decreased ( p# 0.01) at both 25 and 35 mg/ kg/ day. There were no effects noted regarding any developmental parameters. The maternal LOAEL was 25 mg/ kg/ day based on decreased body weight gain and food consumption as well as ataxia, urine stained abdominal fur and fecal stained perineal fur. The maternal NOAEL was 12.5 mg/ kg/ day. The developmental LOAEL was > 35 mg/ kg/ day. The developmental NOAEL was 35 mg/ kg/ day. This developmental toxicity study in the rat is classified ACCEPTABLE and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700, 83 a).

c. Developmental Toxicity Study, Rabbit ( Cypermethrin) 9 In a developmental toxicity study ( MRID 00056805), cypermethrin ( 98.5% purity) in corn oil was administered to banded Dutch rabbits by gelatin capsule at dose levels of 0 ( empty capsule), 0 ( capsule plus corn oil), 3, 10 or 30 mg/ kg/ day on days 6 to 18 inclusive of gestation. There were no effects on the does of any kind reported. The maternal LOAEL is > 30 mg/ kg/ day. The maternal NOAEL is > 30 mg/ kg/ day. There were no treatment related effects on either the skeletal or visceral structures reported. The developmental LOAEL is > 30 mg/ kg/ day. The developmental NOAEL is > 30 mg/ kg/ day. This developmental toxicity study in the rabbit is classified SUPPLEMENTARY and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; 83 3b) in the rabbit. The study is not considered upgradeable because the dose levels selected are too low.

d. Developmental Toxicity Study, Rabbit ( Cypermethrin)

In a developmental toxicity study ( MRID 43776302) cypermethrin ( 94 96% pure, cis/ trans ratio approximately 1: 1) was administered to 20 New Zealand White rabbits per dose group by gavage at dose levels of 0, 100, 450 or 700 mg/ kg/ day from days 7 through 19 of gestation. The does were sacrificed on day 29 of gestation. Cypermethrin was administered as a 50% w/ v solution in corn oil at varying volumes and corn oil was administered to the control group. Body weight gain was decreased during dosing at 450 ( 25%) and 700 ( 30%) mg/ kg/ day and this was followed by compensatory increases. Exacerbation of some clinical signs such as anorexia, abdominogenital staining and decreased feces and red or pink material in the pan also resulted in the 700 mg/ kg/ day dose group and in a few does in the 450 mg/ kg/ day group. The maternal LOAEL is 450 mg/ kg/ day, based on decreased body weight gain. The maternal NOAEL is 100 mg/ kg/ day. There were no indications of developmental toxicity. The NOAEL and LOAEL for developmental toxicity are > 700 mg/ kg/ day. This developmental toxicity study in the rabbit is classified ACCEPTABLE and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; 83 3b).

4. Reproductive Toxicity Study Conclusions a. 3 Generation Reproduction Study, Rat ( Cypermethrin)

In a 3 generation ( 2 litters/ generation) reproduction study ( MRID 00090040) cypermethrin ( 98% purity) was administered to four groups of 30/ sex Wistar SPF strain rats/ sex/ dose group in their diets at dose levels of 0, 10, 100 or 500 ppm ( 0, 0.5, 5 or 25 mg/ kg/ day). The first parental group produced two litters ( F1A and F1B), the F1B litter was culled to produce the F2A and F2B litters and the F2B litter was culled to produce the F3A and F3B litters. At 25 mg/ kg/ day there was decreased parental weight gain ( i. e. about 3% for males and 7% for females for the F1 generation) and pup weight at day 21 of lactation for one or both litters of one or both sexes ( about 4% but p< 0.01). The parental LOAEL is 25 mg/ kg/ day based on decreased body weight gain. The NOAEL is 5 mg/ kg/ day. The offspring LOAEL is 25 mg/ kg/ day based on a decrease in pup body weight gain on lactation day 21 for one or both sexes of one or both litters of each generation. The offspring NOAEL is 5 mg/ kg/ day. Regarding the lactation day 21 pup body weights/ gains, there was a small but statistically significant decrease ( p< 0.01) in body weight at 100 ( 3%) and 500 ( 4%) ppm. The small decrement at 100 ppm is not considered of sufficient 10 magnitude to be included in the LOAEL as the pups in the 100 ppm dose group matured to be the parental groups and there was no statistical difference regarding the parental body weights. This reproductive study in the rat is classified as SUPPLEMENTARY and does not satisfy the guideline requirement for a 3 generation reproductive study ( OPPTS 870.3800, 83 4) in the rat. The study is in summary form only and is not supported by the individual animal data.

b. 3 Generation Reproduction Study, Rat ( Cypermethrin)

In a 3 generation ( 2 litters/ generation) reproduction study ( MRID 00112912, 42068504 and 92027040) cypermethrin ( 90.6 to 93.1% purity) was administered to four groups of 15 male and 30 female Wistar derived SPF strain rats at dose levels of 0, 50, 150 or 1000/ 750 ppm ( reduced to 750 ppm after 12 weeks because of severe neurological signs). These dose levels correspond to 0, 2.5, 7.5 or 50/ 37.5 mg/ kg/ day. Three successive generations were produced, each consisting of 2 separate breedings to produce six sets of litters. At 150 ppm ( 7.5 mg/ kg/ day), parental weight gain was decreased in males ( i. e. about 7% for F2 at week 5) and females ( i. e. about 4.5% for F0 at week 8 and about 10% for F2 at week 8). At 1000/ 750 ppm ( 50/ 37.5 mg/ kg/ day) parental body weight gain was typically 10% decreased for both males and females and there was decreased mean litter weight gain during lactation ( i. e. 12% to 21% for F1B and 12 to 17% for F1B females for days 10 to 28). At 1000 ppm ( 50 mg/ kg/ day) there were obvious clinical signs of neurotoxicity ( i. e. ataxia, increased sensitivity to sound and high stepping gait). The LOAEL is 1000/ 750 ppm ( 50/ 37.5 mg/ kg/ day) based on consistent decreased body weight gain in both sexes. The NOAEL is 150 ppm ( 7.5 mg/ kg/ day). This reproduction study is classified ACCEPTABLE and satisfies the requirement for a multigeneration reproduction study ( OPPTS 870.3800, 83 4) in the rat.

c. 2 Generation Reproduction Study, Rat ( z Cypermethrin)

In a 2 generation reproduction ( 1 litter/ generation) study ( MRID 41968204) z cypermethrin ( 89.6% purity) was administered to six groups of 30 male and 30 female Charles River Crl: CD ( SD) BR rats at dose levels of 0, 7.5, 25, 100, 375 or 750 ppm ( 750 ppm one generation only due to death of pups). For the ppm groups, approximately 0, 0.5, 1.8, 7, 27 or 45 mg/ kg/ day. At 750 ppm, two P1 females died on lactation days 18 or 21. There was no 750 ppm P2 generation due to the death of the pups. Three 750 ppm males had soft/ liquid stools. Regarding the two females which died, one or both displayed signs of emaciation, ataxia and hypersensitivity to sound as well as chromodacryorrhea or chromorhinorrhea prior to death. Hypersensitivity to sound was reported for one male ( 8 incidents) and one female ( 6 incidences) in the 375 ppm group. In P1 males, there was no decrease in body weights or weight gains in groups through 375 ppm ( 26% at 750 ppm). For P2 males, there was a slight ( 5.1%) decrease in body weight gains. For females, the only body weight differences were for gains during lactation in P1 and P2 at 375 ppm ( p< 0.01), 8.7 9.3% decrease. For males and females, food consumption was decreased 8 12% ( p< 0.05 or 0.01) in the 375 ppm groups. There was increased relative brain weight in both sexes (+ 7.8% or + 7.9%, p< 0.01) in the 375 ppm group only. There were decreases in pup body weight gains ( lactation day 21) for the F1 ( 13.4%, p< 0.01)) and the F2 ( 11.1%, p< 0.01) at 375 ppm. At 750 ppm ( F1 group only, no F2 generation), 132/ 332 pups died during lactation. The parental LOAEL is 375 ppm ( 27 mg/ kg/ day) based on a threshold for clinical signs ( hypersensitivity to sound) and decreased body weight gain in females during lactation. The parental 11 NOAEL is 100 ppm ( 7 mg/ kg/ day). The offspring LOAEL is 375 ppm ( 27 mg/ kg/ day) based on a decrease in pup weight gain during lactation. The offspring NOAEL is 100 ppm ( 7 mg/ kg/ day). This 2 generation reproduction study is classified ACCEPTABLE and satisfies the requirement for an 83 4 ( 870.3800) multigeneration reproduction study in rats.

5. Additional Information from Literature Sources None 6. Pre and/ or Postnatal Toxicity The HIARC concluded that there is not a concern for pre and/ or postnatal toxicity resulting from exposure to zeta cypermethrin.

A. Determination of Susceptibility Based on the results in a developmental toxicity study in rats and in a developmental toxicity study in rabbits, there was no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure to zeta cypermethrin.

Based on the results in a 2 generation reproduction study in rats, there was no quantitative or qualitative evidence of increased susceptibility of neonates ( as compared to adults) to zeta cypermethrin.

B. Degree of Concern Analysis and Residual Uncertainties There are no concerns or residual uncertainties for pre and/ or post natal toxicity following exposure to zeta cypermethrin.

C. Special FQPA Safety Factor( s):

The special FQPA safety factor should be 1X since there are no residual uncertainties for pre and/ or post natal toxicity.

The Special FQPA Safety Factor recommended by the HIARC assumes that the exposure databases ( dietary food, drinking water, and residential) are complete and that the risk assessment for each potential exposure scenario includes all metabolites and/ or degradates of concern and does not underestimate the potential risk for infants and children.

7. Recommendation for a Developmental Neurotoxicity Study 12 The HIARC concluded that there is a concern for developmental neurotoxicity resulting from exposure to zeta cypermethrin.

On November 16 and December 19, 2000, HIARC recommended that a developmental neurotoxicity study in rats be conducted with zeta cypermethrin based on the following considerations:

C The cypermethrins induce clinical signs of neurotoxicity in at least two species ( rats and dogs).

C There was suggestive evidence of neuropathology ( electron microscope) in a subchronic feeding study in rats conducted with cypermethrin. This study was conducted in 1980. Electron microscopy is not the usual method of examination of tissues.

C In the acute neurotoxicity study conducted with z cypermethrin, there were symptoms related to loss of muscle control, gait abnormalities, decreased motor activity, convulsions, tremors, abdominal gripping and vocalization. In the acute neurotoxicity study conducted with cypermethrin, ataxia and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp condition) and decreased motor activity were observed.

C In the subchronic neurotoxicity study conducted with z cypermethrin, there was increased landing foot splay and decreases in mean motor activity. In the subchronic neurotoxicity study with cypermethrin, ataxia, splayed hindlimbs, impaired gait, increased landing foot splay, and decreased motor activity were observed.

C The cypermethrins are members of the synthetic pyrethroid class of insecticides, which are known to induce transient tremors in mammals. Evidence to the contrary included:

C There was no indication of increased sensitivity of rats or rabbits to in utero and/ or postnatal exposure to either z cypermethrin or cypermethrin.

C With the exception of fenvalerate/ esfenvalerate in which neuropathology was cited in a literature study at dose levels close to the LD 50 , at this time, there is no indication of light microscopy neuropathology with at least 15 other pyrethroids in standard toxicity studies. Mammalian neurotoxicity testing with this group of chemicals has only recently been initiated.

C No neuropathology has been observed in either the acute or subchronic mammalian neurotoxicity studies.

C No malformations of the central nervous system were observed in the developmental and reproduction studies.

On January 22, 2003, based on the weight of evidence presented, the HIARC reaffirmed the previous conclusion that a developmental neurotoxicity ( DNT) study conducted with zetacypermethrin in rats is required. HIARC determined that a 10X database uncertainty factor ( UF DB ) is needed to account for the lack of the DNT since the available data provide no basis to support reduction or removal of the default 10X factor. The following points were considered in this determination: ° It is assumed that the DNT study will be conducted at dose levels similar to those used in the rat reproduction study with zeta cypermethrin ( 0.5, 1.8, 7, 27, 45 mg/ kg/ day) wherein the offspring NOAEL / LOAEL was 7 / 27 mg/ kg/ day, 13 respectively. ° It is possible that the results of the DNT study could impact the current selected regulatory doses since the NOAELs used for risk assessment endpoints ( e. g., 10 mg/ kg/ day for acute and 6 mg/ kg/ day for chronic) are approximately the same order of magnitude as the offspring NOAEL in the rat reproduction study conducted with zeta cypermethrin ( 7 mg/ kg/ day).

Therefore, a UF DB of 10X will be applied to account for the lack of the DNT study with zetacypermethrin

II. HAZARD IDENTIFICATION 1. Acute Reference Dose ( RfD)  General Population, Including Infants and Children Study Selected: Acute rat neurotoxicity study with z cypermethrin § 870.6200 MRID No.: 44962201 Executive Summary: In an acute neurotoxicity screening battery study ( MRID 44962201), male and female Long Evans rats ( 10 animals/ sex/ group) were dosed once orally by gavage with undiluted z cypermethrin ( 84.4% a. i.) at levels of 0 ( water only), 10, 50, or 250 mg/ kg. The functional observational battery ( FOB) and motor activity were evaluated prior to treatment and on study days 0, 7 and 14 post dosing. At study termination, 5 animals/ sex/ dose were perfused in situ, and animals from the control and 250 mg/ kg dose groups were subjected to neuropathological examinations.

No treatment related findings were observed in the 10 mg/ kg group. Body weights, body weight gains, motor activity, gross pathology and neuropathology were unaffected by the test substance. At 50 mg/ kg, noted clinical observations included the following ( data presented as total occurrences/ number of animals): ( i) abdominogenital staining ( 1/ 1, both sexes); ( ii) oral discharge ( 1/ 1, males); ( iii) splayed hindlimbs ( 1/ 1, males); ( iv) staggered gait ( 2/ 2, males); and ( v) tremors ( 1/ 1, males). On day 0 during the homecage portion of the FOB, treatment related observations included the following: ( i) abnormal mobile posture ( 1/ 10, females); ( ii) splayed hindlimbs ( 1/ 10, females); ( iii) soiled fur ( males 2/ 10, females 1/ 10); and ( iv) unable to walk ( 1/ 10, females). All groups were comparable during the pretest evaluation and on test days 7 and 14. On day 0 during the open field portion of the FOB, treatment related observations noted in the females included the following: ( i) abnormal mobile posture ( 1/ 10); ( ii) unusual immobile posture ( 1/ 10); ( iii) severely impaired gait ( 1/ 10); and ( iv) convulsions ( 1/ 10). All female groups were comparable during the pretest evaluation and on test days 7 and 14. None of these findings were observed in the controls. At 250 mg/ kg, one female died on the day following test substance administration ( no cause of death determined). Clinical observations included the following ( data presented as total occurrences/ number of animals): ( i) abdominal gripping ( 1/ 1, females); ( ii) abdominogenital staining ( males 6/ 4, females 4/ 3); ( iii) ataxia ( 1/ 1, females); ( iv) decreased locomotion ( males 2/ 2, females 1/ 1); ( v) lacrimation ( 1/ 1 females);( vi) loss of muscle control ( 1/ 1, females); ( vii) oral 14 discharge ( males 3/ 3, females 2/ 1); ( viii) splayed hindlimbs ( males 2/ 2, females 3/ 2); ( ix) staggered gait ( 4/ 4, males); ( x) tremors ( 2/ 2, both sexes); ( xi) tonic clonic convulsions ( 2/ 2, females); and ( xii) vocalization ( 1/ 1, both sexes). These findings were not observed in concurrent controls. The only statistically significant ( p< 0.05) finding noted during the home cage portion of the FOB on day 0 was soiled fur in the males ( 4/ 10); this finding was not observed in any control animal. Other treatment related observations included the following: ( i) staggered gait ( 2/ 10, males); ( ii) abnormal mobile posture ( males 1/ 10, females 3/ 10); ( iii) splayed hindlimbs ( males 1/ 10, females 2/ 10); ( iv) soiled fur ( males  2/ 10, females  2/ 10); and ( v) inability to walk ( 1/ 10, females). Treatment related effects noted on day 0 during the open field portion of the FOB included the following: ( i) abnormal mobile posture ( males 1/ 10, females 3/ 10); ( ii) unusual immobile posture ( 1/ 10, females only); ( iii) staggered gait ( males 2/ 10, females 1/ 10); ( iv) splayed hindlimbs ( males 1/ 10, females 2/ 10); ( v) slightly impaired gait ( 1/ 10, both sexes); ( vi) moderately impaired gait ( 1/ 10, males only); ( vii) severely impaired gait ( 1/ 10, females only); ( viii) dragging hindlimbs ( 1/ 10, females only); ( ix) uncoordinated landing ( 1/ 10, both sexes); ( x) lands on back ( 1/ 10, females only); ( xi) whole body tremors ( 3/ 10, females only); ( xii) convulsions ( 1/ 10, females only); and ( xiii) decreased activity ( 1/ 10, both sexes). None of these findings were observed in the controls. Acceptable positive control data were provided by the sponsor.

The acute neurotoxicity LOAEL is 50 mg/ kg based on clinical signs of toxicity and FOB findings. The acute neurotoxicity NOAEL for this study is 10 mg/ kg. The submitted study is classified as acceptable/ guideline ( 81 8[ a]; 870.6200) and satisfies the guideline requirements for an acute neurotoxicity screening battery in rats.

Dose and Endpoint for Establishing RfD: 10 mg/ kg based on clinical signs of neurotoxicity and changes in the FOB in the acute neurotoxicity study observed at 50 mg/ kg.

Uncertainty Factor ( UF): 1000 ( 10x for interspecies extrapolation, 10x for intraspecies variations, and 10x for an incomplete database for lack of developmental neurotoxicity study).

Comments about Study/ Endpoint/ Uncertainty Factor: In 1997, the HIARC selected the acute dietary endpoint for z cypermethrin and cypermethrin from a chronic dog study conducted with cypermethrin, in which the test article was administered in corn oil via capsules. The observed effects were an increased incidence of loose stools, starting on the first week of the study at 5 mg/ kg/ day with a NOAEL of 1 mg/ kg/ day. Since 1997, an acute neurotoxicity study was conducted with z cypermethrin. The current HIARC determined that the new acute neurotoxicity study is more appropriate because loose stools in the dog study with capsules as the route of administration are of questionable regulatory significance to the acute dietary endpoint and because one can definitively state that the observed effects in the neurotoxicity study are due to a single dose. In addition, the acute neurotoxicity study is conducted with z cypermethrin, an enriched isomer of cypermethrin and is thus anticipated to be protective of any effects observed following acute dietary exposure to cypermethrin.

Acute RfD = NOAEL: 10 mg/ kg = 0.01 mg/ kg UF: 1000 15 2. Chronic Reference Dose ( cRfD)

Study Selected: 53 Week chronic toxicity [ feeding]  dog  cypermethrin § 870.4100 MRID No.: 44536801 Executive Summary: In a chronic toxicity study ( MRID 44536801), cypermethrin ( 95.7% a. i.) in corn oil was administered to beagle dogs ( 4/ sex/ dose) in the diet at dose levels of 0, 100, 200, 600, or 1100 ppm ( achieved doses 0/ 0, 2.9/ 3.3, 6.0/ 5.7, 20.4/ 18.1, or 33.9/ 38.1 mg/ kg/ day [ M/ F], respectively) for 12 months. One 600 ppm male died and two 1100 ppm males were sacrificed moribund during the study interval.

At 600 ppm, one male exhibited tremors, irregular gait, and excessive salivation on two occasions each prior to death ( day 133). A second male exhibited irregular gait and tremors during weeks 39 or 44 ( 1 or 2 incidents). Females had reduced body weights ( 91 16%, not statistically significant [ NS]) beginning at week 9 and reduced body weight gains throughout the study ( week 52: 0, 100, 200, 600 and 1100 ppm = 2.0, 1.8, 2.6, 0.7 and  0.2 kg).

In the 1100 ppm group, two males were sacrificed moribund on day 276 or 324. Males exhibited the following clinical signs: tremors in four males during weeks 16 51 ( 47/ 276, 54/ 324, 6/ 368, or 53/ 367 incidents); irregular gait in four males during weeks 11 52 ( 47/ 276, 90/ 324, 2/ 368, or 94/ 367 incidents); excessive salivation in one male during week 8 ( 1/ 368 incidents); prostration in one male during week 27 ( 3/ 368 incidents); uncoordination, characterized by difficulty in supporting own weight, in one male during weeks 37 40 ( 6/ 276 incidents); decreased activity in one male during week 39 ( 1/ 276 incidents); and clonic convulsions in one male during week 32 ( 1/ 324 incidents). Two females exhibited the following clinical signs: tremors during weeks 33 54 ( 63/ 368 or 132/ 372 incidents); irregular gait during weeks 33 54 ( 93/ 368 or 140/ 372 incidents); unthrifty coat during weeks 23 52 ( incidents could not be deduced from data provided); and moderate alopecia during weeks 15 52 ( incidents could not be deduced from data provided). One female also exhibited excessive salivation during week 27 ( 1/ 372 incidents). Females had progressively reduced mean body weights throughout the study ( 92 24%, p# 0.05 during weeks 43 47), with maximum decreases beginning at week 31 ( 917 24%) and reduced mean body weight gains throughout the study ( week 52 body weight gains in kg for 0, 100, 200, 600 and 1100 ppm = 2.0, 1.8, 2.6, 0.7 and  0.2).

When compared to concurrent controls, no treatment related changes were noted regarding food consumption, ophthalmoscopic abnormalities, hematological, clinical chemistry, or urinalysis parameters, organ weights, or gross or microscopic pathological findings. No neoplastic tissue was observed in dogs from any test group.

The LOAEL is 600 ppm ( equivalent to 20.4/ 18.1 mg/ kg/ day [ M/ F]), based on mortality and abnormal clinical signs in males, and decreased body weights and body weight gains in females. The NOAEL is 200 ppm ( equivalent to 6.0/ 5.7 mg/ kg/ day [ M/ F]). 16 This study is classified acceptable ( § 83 1b; 870.4100) and satisfies the guideline requirements for a chronic toxicity study in dogs.

Dose and Endpoint for Establishing RfD: 6.0/ 5.7 mg/ kg/ day based on mortality and abnormal clinical signs in males, and decreased body weights and body weight gains in females at 20.4/ 18.1 mg/ kg/ day ( LOAEL).

Uncertainty Factor( s): 1000 ( 10x for interspecies extrapolation, 10x for intraspecies variations, and 10x for an incomplete database for lack of developmental neurotoxicity study).

Comments about Study/ Endpoint/ Uncertainty Factor: In 1997, the HIARC selected the chronic dietary endpoint for z cypermethrin from a chronic dog study conducted with cypermethrin, in which the test article was administered in corn oil via capsules. The NOAEL was 1 mg/ kg/ day based on an increased incidence of loose stools, starting on the first week of the study at 5 mg/ kg/ day. Since 1997, a dog chronic feeding study was conducted with cypermethrin. The current HIARC determined that the new chronic feeding study in the dog is more appropriate for the chronic dietary endpoint because dietary exposure is more relevant for the expected exposure and the gastrointestinal effects in the capsule dog study may be due to focal exposure ( bolus dose with corn oil). Although no chronic studies are available on z cypermethrin which is anticipated to be protective of any effects observed following chronic dietary exposure to cypermethrin, the parental NOAEL and LOAEL for the 2 generation reproduction study conducted with zcypermethrin are 7 and 27 mg/ kg/ day, respectively, which are comparable to the parental NOAEL ( 7.5 mg/ kg/ day) and LOAEL ( 50/ 37.5 mg/ kg/ day) observed with the acceptable rat reproduction study conducted with cypermethrin. The NOAEL/ LOAEL ( 7.5/ 75 mg/ kg/ day) in the chronic rat study conducted with cypermethrin provide additional support to the critical study selected. In addition, the endpoint ( clinical signs of neurotoxicity) is of particular relevance to pyrethroid toxicity.

3. Incidental Oral Exposure: Short Term ( 1 30 days)

Study Selected: Acute neurotoxicity study in the rat z cypermethrin § 870.6200 MRID No.: 44962201 Executive Summary: See acute dietary endpoint Dose and Endpoint for Risk Assessment: 10 mg/ kg based on clinical signs of neurotoxicity and changes in the FOB observed at 50 mg/ kg. Chronic RfD = NOAEL: 6 mg/ kg/ day = 0.006 mg/ kg/ day UF: 1000 17 Comments about Study/ Endpoint: Although the endpoint is selected from a single dose study, it is supported by the developmental rat study conducted with z cypermethrin with a maternal NOAEL of 12.5 mg/ kg/ day based on ataxia, urine stained abdominal fur, fecal stained perineal fur, decreased food consumption and decreased body weight gain at 25 mg/ kg/ day. This endpoint is appropriate for the population ( toddlers) of concern and is considered to be protective of any effects observed following short term oral exposure to cypermethrin.

4. Incidental Oral Exposure: Intermediate Term ( 1  6 Months)

Study Selected: Subchronic neurotoxicity study in the rat  z cypermethrin § 870.6200 MRID No.: 44962202 Executive Summary: In this subchronic neurotoxicity screening battery, z cypermethrin, purity of 86.0% ( MRID 44962202), was administered continuously in the diet for 13 weeks to 10 Charles River Long Evans rats/ sex/ group at doses of 0, 75, 400 or 750 ppm ( equivalent to [ M/ F] 0/ 0, 5.0/ 5.9, 26.3/ 31.5, or 47.2/ 55.6 mg/ kg/ day). Five animals/ sex/ group were perfused for neurohistological examination, and the control and high dose animals were examined microscopically. Functional observational battery ( FOB) and motor activity were evaluated during the pretest interval, and following weeks 4, 8, and 13.

No treatment related deaths occurred. Clinical signs, gross pathology and neuropathology were unaffected by the test substance; furthermore, no treatment related findings were noted in the home cage observations of the FOB at any dose. No treatment related findings were observed in the 75 ppm group. In the 400 ppm males, statistically significant decreases in body weights were observed at all intervals except week 3 ( 95 8%), p # 0.05); overall ( weeks 0 13) body weight gains were also decreased relative to concurrent controls in these animals ( 915%, p # 0.05). Decreased food consumption was observed throughout the study, but statistical significance was sporadic ( 96 17%, p # 0.01 or 0.05). During the open field portion of the FOB, increased landing foot splay was observed at week 13 ( 833%, p # 0.01). In addition, mean motor activity was decreased ( p # 0.01 or 0.05) at weeks 8 ( 936%) and 13 ( 951%). At 750 ppm, one female was sacrificed in extremis on day 51 following mechanical injury; this death was considered not to be treatmentrelated Body weights were decreased throughout the study ( 912 17%, p # 0.01) in the males. In the females, body weights were decreased sporadically for the first 9 weeks of the study, and continually at weeks 10 13 ( 95 10%, p # 0.05 or 0.01). Overall ( weeks 0 13) body weight gains were decreased ( p # 0.01) in both sexes ( 928 31%) as was food consumption ( 98 29%). During the open field portion of the FOB, increased landing foot splay was observed in the males at week 13 ( 841%, p # 0.01). Mean motor activity was decreased ( p # 0.05 or 0.01) in the males at weeks 8 ( 925%) and 13 ( 942%).

The LOAEL for this study is 400 ppm for males ( equivalent to 26.3 mg/ kg/ day), based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption; and 750 ppm for females ( equivalent to 55.6 mg/ kg/ day) based on decreased body weights, body weight gains, and food consumption. The NOAEL for this study is 75 ppm for males ( equivalent to 5.0 mg/ kg/ day) and 400 ppm 18 for females ( equivalent to 31.5 mg/ kg/ day). The submitted study is classified as acceptable/ guideline ( § 82 7[ a]; 870.6200) and satisfies the guideline requirements for a subchronic neurotoxicity screening battery in rats.

Dose and Endpoint for Risk Assessment: 5.0 mg/ kg/ day based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption observed in males at 26.3 mg/ kg/ day.

Comments about Study/ Endpoint: The subchronic neurotoxicity study is considered to be appropriate for the intermediate term incidental exposure endpoint and the population ( toddlers) of concern because it is of an appropriate route of administration and duration of exposure. See the comments under the chronic dietary endpoint as to why the chronic capsule dog study was not selected for this endpoint. In addition, it is recognized that the NOAEL of 5.0 mg/ kg/ day selected for this endpoint is less than the NOAEL of 6.0 mg/ kg/ day selected for the chronic dietary endpoint. This is due to dose selection and spacing.

5. Dermal Absorption Dermal Absorption Factor: 2.5%

There is no series 85 2 dermal penetration/ absorption study available. In 1997, the HIARC estimated a dermal absorption rate of 25% based on the 6 45% dermal absorption observed with the structurally related pyrethroids permethrin ( 22 45%), deltamethrin ( 15%) and tralomethrin ( 6 25%). A range of dermal absorption factors was presented for permethrin and tralomethrin, but not for deltamethrin because the studies indicated higher absorption at lower exposure doses. Since no study was available with either cypermethrin or z cypermethrin, a value of 25% was assumed. In the case of z cypermethrin, the current HIARC estimated a dermal absorption value by comparing the developmental rat study with the 21 day dermal study in the rat and determined that the dermal absorption rate would probably be an order of magnitude less. Using a comparison of the maternal LOAEL of 25 mg/ kg/ day from the developmental study in the rat and the NOAEL ( highest dose tested) of 1000 mg/ kg/ day from the 21 day dermal study in the rat, dermal absorption would be estimated to be less than 2.5%. Since there was no common endpoint because no effects were observed in the 21 day dermal study in the rat, this is considered to be a worst case estimate ( i. e. the dose level of 1000 mg/ kg/ day was considered to be the LOAEL).

6. Dermal Exposure: Short Term ( 1 30 days)

Study Selected: None MRID No.: None Executive Summary: None Dose and Endpoint for Risk Assessment: Not Applicable 19 Comments about Study/ Endpoint: No hazard has been identified to support quantitation of risk. No systemic effects were observed in the 21 day dermal study in the rat at dose levels up to 1000 mg/ kg/ day. In addition, no developmental effects were observed in any of the available developmental studies.

For the dermal risk assessments, HIARC determined the following:

The observed systemic effects in the 21 day dermal study conducted with cypermethrin in rabbits ( focal necrosis of the liver, decrease in testicular weights and body weight loss ( females)) were noted only in animals with abraded skin. No effects were observed in animals with nonabraded skin up to the highest dose tested ( 200 mg/ kg/ day). These effects are discounted because 1) the method does not simulate actual exposure, 2) the test conditions are compromised, 3) there would be physiological differences between the abraded and nonabraded animals and 4) the rat is the more sensitive species for z cypermethrin in the oral studies ( comparison of maternal toxicity in the developmental studies). However, the dermal study in the rat was not selected because no systemic toxicity was seen at the limit dose.

7. Dermal Exposure: Intermediate Term ( 1 6 months)

Study Selected: None MRID No.: None Executive Summary: None Dose/ Endpoint for Risk Assessment: Not applicable Comments about Study/ Endpoint: No hazard has been identified to support quantitation of risk.

8. Dermal Exposure: Long Term (> 6 months)

Selected: 53 Week chronic toxicity [ feeding]  dog  cypermethrin § 870.4100 MRID No.: 44536801 Executive Summary: See chronic dietary endpoint Dose and Endpoint for Risk Assessment: 6.0/ 5.7 mg/ kg/ day based on mortality and abnormal clinical signs in males, and decreased body weights and body weight gains in females. The estimated percent dermal absorption value will be 2.5% ( see dermal absorption section).

Comments about Study/ Endpoint: See comments under chronic dietary endpoint.

9. Inhalation Exposure: All Durations 20 Study Selected: 21 Day Inhalation Study in the Rat ( Cypermethrin) § 870.3465 MRID No.: 43507101 Executive Summary: In a 21 day subchronic inhalation toxicity study ( MRID 43507101) cypermethrin ( 87.1% purity, 1: 1 cis: trans) was administered to five Alpk: Apfsd, Wistar derived rats/ sex/ dose group by nose only exposure at concentrations of 0, 0.01, 0.05 or 0.25 mg/ L for six hours per day, 5 days per week for a total of 15 exposures. The analytical concentrations were 0, 0.0096, 0.0463, 0.229 mg/ L/ day. Additional satellite groups of 5/ sex were included for recovery assessment and analysis of cypermethrin in the brain. The MMAD was determined to be 2.63 to 2.86 µ M. At 0.05 mg/ L/ day there was slight but consistently statistically significant (< 5% body, p< 0.05) body weight loss also reflected as a 16% decrease in body weight gain. All males and 4 females had occasional salivation. At 0.25 mg/ L, clinical signs were evident from day 10 on ( particularly including decreased activity, salivation, lacrimation, tail erection, head and/ or paw flicking and tip toe gait and others, see results). Changes in RBC parameters were slight and equivocal. Cypermethrin was not detected in the brain at day 10 or 22. The LOAEL is 0.05 mg/ L/ day based mainly on body weight decrease and salivation. The NOAEL is 0.01 mg/ L/ day. This study is classified as ACCEPTABLE.

Dose/ Endpoint for Risk Assessment: 0.01 mg/ L ( 2.7 mg/ kg/ day) based on decreases in bodyweight and salivation at 0.05 mg/ L/ day.

Comments about Study/ Endpoint: This is an appropriate study and route of exposure for this endpoint. The target MOE's are 100 for short and intermediate term exposure and 300 for longterm exposure. Based on the inhalation study, it appears that the most sensitive route of administration is inhalation. The additional 3x for long term exposure is for the lack of an alternative study on which to make an endpoint selection. If one uses an oral study and conducts a route to route estimation, the result would be a less protective endpoint.

10. Margins of Exposure Summary of target Margins of Exposure ( MOEs) for risk assessment.

Route Duration Short Term ( 1 30 Days) Intermediate Term ( 1  6 Months) Long Term (> 6 Months)

Occupational ( Worker) Exposure Dermal NA NA 100 Inhalation 100 100 300 21 Residential ( Non Dietary) Exposure Oral 1000 1000 1000 Dermal NA NA 1000 Inhalation 1000 1000 1000 For Occupational and Residential exposure: short term ( 1 day to 1 month) and intermediate term ( 1 to 6 months) dermal quantitative risk assessments are not required since no systemic effects were observed at 1000 and there are no developmental concern. MOE is not applicable ( NA)

For Occupational exposure: short term ( 1 day to 1 month) and intermediate term ( 1 to 6 months) inhalation risk assessments, and for long term ( longer than 6 months) dermal exposure risk assessments, a MOE of 100 is required. This is based on the conventional uncertainty factor of 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation).

For occupational exposure: long term ( longer than 6 months) inhalation risk assessment, a MOE of 300 is required. This requirement is due to lack of an alternative study on which to make an endpoint selection: inhalation appears to be the most sensitive endpoint and using the existing oral studies with a route to route extrapolation would result in a less protective endpoint. For Residential incidental oral exposure: short term ( 1 day to 1 month) and intermediateterm ( 1 to 6 months) risk assessments, a MOE of 1000 is required. This is based on the conventional uncertainty factor of 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation) and 10X for an incomplete database ( lack of developmental neurotoxicity study).

For Residential exposure: short term ( 1 day to 1 month), intermediate term ( 1 to 6 months) inhalation risk assessments and long term ( longer than 6 months) dermal and inhalation risk assessments, a MOE of 1000 is required. This is based on the conventional uncertainty factor of 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation) and 10X for an incomplete database ( lack of developmental neurotoxicity study).

11. Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated as follows. For the acute and chronic dietary aggregate risks, the recommendation is food plus water. For short and intermediate term aggregate risk, the recommendation is food plus water, incidental oral, and inhalation ( dermal is not required for these scenarios). For long term aggregate risk, the recommendation is food plus water, dermal and inhalation exposure. The ARI method needs to be 22 employed because the target MOEs are different for intermediate dermal and inhalation exposure scenarios.

III. CLASSIFICATION OF CARCINOGENIC POTENTIAL 1. Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID Nos. 00112910 and 9202741 Executive Summary: In a chronic toxicity/ carcinogenicity study ( MRID 00112910), cypermethrin ( 88 93% purity, 55% cis and 45% trans) was administered to 5 groups of 52/ sex Wistar derived Alderley Park SPF strain rats at dose levels of control 1, control 2, 20, 150 or 1500 ppm ( corresponding to 0, 0, 1, 7.5 or 75 mg/ kg/ day) for 2 years. Satellite groups of 12/ sex were sacrificed after one year of dosing. Definite signs of toxicity were evident at 75 mg/ kg/ day and these consisted of body weight gain decrease throughout the study ( i. e. about 10% for males and 13% for females at week 13), slight effects on several hematological parameters ( both red and white cells), slight effects on clinical chemistry parameters ( decreased cholesterol and triglycerides and glucose and increased urea). Decreases in urine volume, pH and an increase in specific gravity were noted. Liver weight was increased in females. The LOAEL is 1500 ppm ( 75 mg/ kg/ day) based on decreases in body weight gains. The NOAEL is 150 ppm ( 7.5 mg/ kg/ day). This chronic toxicity/ carcinogenicity study is classified ACCEPTABLE and satisfies the guideline requirement for a chronic oral feeding/ carcinogenicity study in rats.

Discussion of Tumor Data: Cypermethrin was not considered to be carcinogenic in this study.

Adequacy of the Dose Levels Tested: The dose levels were adequate for testing of carcinogenicity. Body weight gains were reduced 10 13% ( both sexes).

2. Carcinogenicity Study in Mice MRID No. 00112911 and 92027038 Executive Summary: In a carcinogenicity study ( MRID 00112911 and 92027038), cypermethrin ( 53 54% cis and 46 47% trans) was administered to groups of 70/ sex Swiss derived Alderley Park strain SPF mice at dose levels of control 1, control 2, 100, 400 and 1600 ppm ( corresponding to 0, 0, 14, 57 or 229 mg/ kg/ day) for 97 weeks for males and 101 weeks for females. Liver weight was increased at 57 mg/ kg/ day ( 20% absolute weight) and above in males and for females at the high dose only ( 15% for relative weight) at the interim sacrifice but not at the terminal. Other systemic effects noted at 229 mg/ kg/ day included reduction in RBC parameters ( hemoglobin, hematocrit and RBC count in males, mean cell volume and hemoglobin) and platelet counts ( for males at interim but not terminal sacrifice) and neutrophils and body weight gain ( i. e. about 9% at week 6 for males and 22% for females at week 11). The LOAEL is 57 mg/ kg/ day based on increased liver weight. The NOAEL is 14 mg/ kg/ day. This study was determined to be positive for induction of benign lung adenomas. This carcinogenicity study is classified 23 ACCEPTABLE and satisfies the guideline requirement for a carcinogenicity study ( 83 2) in mice.

Discussion of Tumor Data: Cypermethrin produced a statistically significant increase in lung adenomas, and in adenomas plus carcinomas combined, in female mice at the highest dose level ( 1600 ppm, 229 mg/ kg/ day) tested. There were also significant positive dose related trends for these tumor combinations in female mice. No significant increases in carcinomas were observed. The Cancer Peer Review Committee ( 1988) noted the following additional information in regard to the increased lung tumorigenic response in female mice: ( a) most of the adenomas were observed at terminal sacrifice and there was no decrease in latency for the time to tumor occurrence ( tumors were first seen at week 53 in the control females and at weeks 52 to 53 in the high dose females); ( b) the incidences of lung tumors produced at the highest dose level of cypermethrin exceeded the historical control incidences for lung adenomas ( mean = 9.6%, range = 0 to 15.7), and adenomas/ carcinomas combined ( mean 11.3%, range = 0 to 15.7%), in several contemporary studies conducted in female Swiss Alderley Park mice at ICI Laboratories between 1977 to 1985; no compound related nonneoplastic changes were observed in the lungs of treated female mice; ( d) alveolar adenoma is a relatively common tumor in mice; ( e) there were more malignant lung tumors in the control female mice than there were in the treated female mice ( i. e. 2 carcinomas occurred in controls vs. 1 carcinoma in the treated groups); and ( f) the highest dose level of cypermethrin tested ( i. e. 1600 ppm) was considered, based on weight gain decrements, to approximate ( but not to exceed) a MTD level in both male and female mice.

Adequacy of the Dose Levels Tested: Adequacy of dosing for carcinogenicity is based upon decreases in body weight gains typically of 9% in males and 12% in females.

Classification of Carcinogenic Potential: The Committee classified cypermethrin as a category C oncogen ( possible human carcinogen). The evidence ( common tumor, one species ( mice), one sex ( female), no increase in the proportion of malignant tumors or decrease in the time to tumor occurrence, and lack of mutagenic activity) was not considered strong enough to warrant a quantitative estimation of human risk ( Cancer Peer Review Committee, 1988).

IV. MUTAGENICITY Z cypermethrin is considered a possible weak mutagen under the conditions of the Ames assay. There was no evidence of mutagenicity in any of the other assays. Cypermethrin tested negatively in all of the assays available to the Agency.

Z Cypermethrin SALMONELLA/ MAMMALIAN ACTIVATION GENE MUTATION ASSAY 24 Doses: 0, 100, 333, 1000, 3333, 5000 and 10000 µ g/ plate. FMC 56701 gave a very weak positive response ( 2 fold increase in revertants/ plate) in S. typhimurium strain TA100 at 10000 µ g/ plate without S 9 activation in two separate experiments. Doses of 3333 and 5000 µ g/ plate gave 1.5 and 1.6 fold increases in revertants/ plate, respectively. Strains TA98, TA1535, TA1537 and TA1538 treated in the presence and absence of mammalian S 9 activation were not affected. FMC 56701 is, therefore, considered a possible weak mutagen under the conditions of this assay. ( MRID 41968205)

IN VITRO MAMMALIAN GENE MUTATION ASSAY Doses: 0, 1, 10, 25, 50, 100, 400, 700 and 1000 µ g/ ml in the absence and presence of S 9 activation. Doses were administered to Chinese hamster ovary cells ( CHO K1 BH 4 , subclone D1). No evidence of increased forward mutation rate at the HGPRT locus was observed at any dose tested under the conditions of these assays. The solubility limit of the test compound in culture media was about 100 µ g/ ml. ( MRID 41968206)

MOUSE LYMPHOMA IN VITRO ASSAY Doses: 12.5, 25, 50, 100 and 150 µ g/ ml in vitro with/ without metabolic activation. The study demonstrates that cypermethrin is not mutagenic in the mouse lymphoma assay ( L5178Y cell line) at the above doses with or without metabolic activation. ( MRID 41551101)

CHROMOSOME ABERRATIONS IN VIVO IN RAT BONE MARROW Doses: 0, 31.25, 62.5 and 125 mg/ kg in corn oil. No evidence of structural chromosomal aberrations was demonstrated at either 6, 18 or 30 hours post dosing. ( MRID 42758601)

UNSCHEDULED DNA SYNTHESIS ASSAY IN MALE RAT PRIMARY HEPATOCYTE CELLS Doses: 14, 45, 140, 450, 1400 and 4500 µ g/ ml. No unscheduled DNA synthesis was observed at any dose level up to 4500 µ g/ ml in male rat ( Fischer 344) liver primary hepatocyte cultures under the conditions of this assay. Minimal cytotoxicity was observed at the highest doses. Incomplete solubility of the test compound in culture media was observed, particularly at higher doses. ( MRID 41968207)

Cypermethrin SALMONELLA/ MAMMALIAN ACTIVATION GENE MUTATION ASSAY Doses: 4, 20, 100, 500 or 2500 ug/ plate. No evidence of bacterial mutations in S. typhimurium strains TA 1535, TA 1537, TA 1538, TA 98 or TA 100 with and without metabolic activation ( S 9) at dose levels of 4, 20, 100, 500 or 2500 ug/ plate. Strains of yeast ( S. cerevisiae) also assessed and negative. ( MRIDs 00090037, 92027042, and 92027062; 00090036 and 00126834)

IN VITRO MAMMALIAN GENE MUTATION ASSAY In an in vitro gene mutation assay, Chinese hamster ovary cells ( CHO K1 BH 4 subclone D1) were 25 exposed to dose levels of 0, 1, 10, 25, 50 100, 400, 700 or 1000 ug/ ml in the presence or absence of S9 activation medium. No evidence of increased forward mutation rate at the HGPRT locus was observed at any dose tested under the conditions of these assays. The solubility limit of cypermethrin s in the culture media was about 100 ug/ ml. ( MRID 41968206)

CHROMOSOME ABERRATIONS IN VIVO IN CHINESE HAMSTER BONE MARROW There was no evidence of increased chromosome aberrations in chinese hamster bone marrow cells following gavage dosing with 0, 20 or 40 mg/ kg. ( MRID 00090038 and 92027043)

DOMINANT LETHAL ASSAY IN MALE MICE There was no evidence of dominant lethal activity in CD 1 strain mice at dose levels of control, 2.5, 5, 7.5 or 10 mg/ kg/ day for five consecutive days. An initial observation of a possible effect in a preliminary experiment with animals dosed at 2.5 or 5 mg/ kg for 5 days was not repeated at higher doses. ( MRID 00090039)

UNSCHEDULED DNA SYNTHESIS  RAT PRIMARY HEPATOCYTES IN VIVO No evidence of induction of unscheduled DNA synthesis in vivo at dose levels of 100 and 200 mg/ kg by gavage in corn oil) in Alpk: APfSD strain rats ( males only) assessed 4 and 12 hours post dosing. The 200 mg/ kg dose was considered near the MTD and displayed toxic behavioral reactions. ( MRID 41599801)

V. HAZARD CHARACTERIZATION With the exception of some of the acute toxicity studies and the developmental neurotoxicity study, the toxicology database for z cypermethrin, when bridged with cypermethrin, is complete and there are no data gaps. The scientific quality is relatively high and the toxicity profile of z cypermethrin can be characterized for all effects, including potential developmental, reproductive and neurotoxic effects. The data provided no indication of increased susceptibility of rats or rabbits to in utero and/ or postnatal exposure to the cypermethrins. At the present time, there does not appear to be increased susceptibility to the synthetic pyrethroids as a whole. Exceptions include cyfluthrin and fenvalerate and esfenvalerate ( at dose levels approaching the LD 50 ).

Z Cypermethrin is moderately acutely toxic via the oral route ( Category II). No other acute toxicity studies are available on technical z cypermethrin. Acute toxicity studies conducted with cypermethrin indicate that it is also Category II via the oral route; however, it is not very toxic via the dermal and inhalation routes ( Categories III and IV). It is mildly irritating to the eyes and skin and is a dermal sensitizer.

The database on z cypermethrin ( including cypermethrin) indicates one major target for this chemical: the neuromuscular system. The liver also appears to be affected ( rabbits ( focal necrosis, abraded animals only) and mice ( may only be an adaptive response)). The neuromuscular effects ( tremors, gait abnormalies and 26 decreases in activity) occur mainly in oral studies in the dog and the rat, but similar effects were also observed in an inhalation study conducted with cypermethrin. There appears to be a dose response for these effects. In the subchronic feeding studies, the rat appears to be the most sensitive species; however, in the chronic feeding studies, the dog appears to be more sensitive to the neuromuscular effects. In general, neither sex is more sensitive; however, in both the rat 90 day neurotoxicity study and the 1 year feeding study in the dog, the male appears to be more sensitive to these effects. As with other pyrethroids, the tremors do not appear to increase in severity with increasing duration of exposure. They appear to be more of a transient acute effect as opposed to an effect which appears after an accumulated dose.

No dermal penetration/ absorption studies are available for z cypermethrin. A dermal absorption value of 2.5% may be estimated by comparing the maternal LOAEL of 25 mg/ kg/ day from the developmental study in the rat and the NOAEL ( highest dose tested) of 1000 mg/ kg/ day from the 21 day dermal study in the rat. Since there was no common endpoint because no effects were observed in the 21 day dermal study in the rat, this is considered to be a worst case estimate.

The data demonstrated no indication of increased sensitivity or susceptibility of rats or rabbits to in utero and/ or postnatal exposure to either z cypermethrin or cypermethrin. In the prenatal developmental toxicity studies in rats and rabbits with both cypermethrin and z cypermethrin, there was no evidence of developmental toxicity at the highest dose tested. In the multi generation reproduction studies in rats conducted with both of these chemicals, offspring toxicity was observed either at the same treatment level which resulted in parental systemic toxicity or at higher dose levels than the dose levels which induced parental toxicity.

There is no evidence that z cypermethrin induces any endocrine disruption.

Cypermethrin has been classified as a Category C, possible human carcinogen, based on an increased incidence of lung adenomas and adenomas plus carcinomas combined in female mice. The evidence was not considered strong enough to warrant a quantitative estimation of human risk. Cypermethrin has not been classified under the more current, Proposed Guidelines for Carcinogen Risk Assessment ( April 10, 1996). Z Cypermethin is considered a weak mutagen under the conditions of the Salmonella typhimurium ( Ames) assay; however, cypermethrin was negative in all mutagenicity studies available to the Agency. Structure activity comparisons with the other pyrethroids reveal indications of lung tumors in mice with 3 other pyrethroids.

Cypermethrin and z cypermethrin are type II pyrethroids ( i. e. it has a cyano group at the " carbon position of the alcohol moiety and it is more effective when the ambient temperature is raised). Ware states, " pyrethroids initially stimulate nerve cells to produce repetitive discharges and eventually cause paralysis. Such effects are caused by their action on the sodium channel, a tiny hole through which sodium ions are permitted to enter the axon to cause excitation. These effects are produced in insect nerve cord, which contains ganglia and synapses, as well as in giant nerve fiber axons. The stimulating effect of pyrethroids is much more pronounced than that of DDT. The exact sites of action of pyrethroids at synapses are not known. It is probable that the toxic action of pyrethroids is primarily due to its blocking action on the nerve axon since this action shows a negative temperature coefficient. But because the cockroach ganglion is affected by pyrethroid concentrations many fold less than are required to block conduction in giant fibers, 27 its also seems likely that pyrethroids act on some aspect of synaptic function. The fast knockdown of flying insects could be the result of rapid muscular paralysis, suggesting that the ganglia of the insect central nervous system are affected."

VI. DATA GAPS / REQUIREMENTS z Cypermethrin Acute dermal toxicity study ( 81 2, 870.1200) Acute inhalation toxicity study ( 81 3, 870.1300) Primary eye irritation study ( 81 4, 870.2400) Primary dermal irritation study ( 81 5, 870.2500) Dermal sensitization study ( 81 6, 870.2600) Developmental neurotoxicity study ( 83 6, 870.6300)

Cypermethrin None 28 VII. ACUTE TOXICITY Acute Toxicity of z Cypermethrin and Cypermethrin Guideline No. Study Type MRIDs # Results Toxicity Category 870.1000 Acute Oral  z Cypermethrin 41776115 LD50 ( M): 134.4 mg/ kg ( F): 86.0 mg/ kg Clinical signs of neurotoxicity observed. II 870.1000 Acute Oral  Cypermethrin 00056800 LD50 ( M): 247 mg/ kg ( F): 309 mg/ kg females Deaths: $ 150 mg/ kg, usually in first day. Clinical signs of neurotoxicity, gait abnormalities; some persisting to 14 days. II 870.1100 Acute Dermal Rats  Cypermethrin Rabbits  Cypermethrin 00056800 00056800 LD50 > 4920 mg/ kg/ day. Clinical signs of neurotoxicity.

Abraded skin: LD50 > 2460 mg/ kg. Lacrimation, discharge from the eye and " nervous and shaking". III III 870.1200 Acute Inhalation  Cypermethrin 42395702 LC50: % ( not calculated but higher than &) LC50: & 2.5 ( 1.6 3.4) mg/ L. Clinical signs of neurotoxicity. IV 870.2400 Primary Eye Irritation  Cypermethrin 00056800 Slight redness of conjunctivae, chemosis & discharge. Persisted to day 7. III 870.2500 Primary Skin Irritation  Cypermethrin 00056800 Slight to mild erythema on intact & abraded skin. Regressed by 48 hours. Primary Irritation Index: 0.71 IV 870.2600 Dermal Sensitization  Cypermethrin 00056800 40377701 Not a sensitizer in Buehler assay. Moderate sensitizer in Magnusson Kligman Maximization method. N/ A VIII. SUMMARY OF TOXICOLOGY ENDPOINT SELECTION 29 Summary of Toxicology Endpoint Selection for Cypermethrin and Zeta cypermethrin Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( General Population including infants and children) NOAEL = 10 mg ai/ kg UF = 1000 Acute RfD = 0.01 mg/ kg/ day FQPA SF = 1X aPAD = acute RfD FQPA SF = 0.01 mg/ kg/ day Acute mammalian neurotoxicity study Clinical signs of neurotoxicity and changes in the FOB at the LOAEL of 50 mg/ kg.

Chronic Dietary ( All populations) NOAEL = 6 mg ai/ kg/ day UF = 1000 Chronic RfD = 0.006 mg/ kg/ day 1X cPAD = chronic RfD FQPA SF = 0.006 mg/ kg/ day Chronic feeding study  dog Clinical signs of neurotoxicity and mortality in males, and decreased body weights and body weight gains in females at the LOAEL of 20.4 mg/ kg/ day.

Short Term Incidental Oral ( 1 30 days) NOAEL= 10 mg ai/ kg/ day Residential MOE = 1000 Occupational = NA Acute mammalian neurotoxicity study Clinical signs of neurotoxicity and changes in the FOB at the LOAEL of 50 mg/ kg.

Intermediate Term Incidental Oral ( 1 6 months) NOAEL= 5 mg ai/ kg/ day Residential MOE = 1000 Occupational = NA Subchronic mammalian neurotoxicity study Decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption at the LOAEL of 26.3 mg/ kg/ day.

Short Term Dermal ( 1 30 days) None Residential MOE = NA Occupational MOE = NA None  No systemic effects observed at 1000. No developmental concern. No hazard identified to support a quantitation of risk.

Intermediate Term Dermal ( 1 6 months) None Residential MOE = NA Occupational MOE = NA None  No systemic effects observed at 1000. No developmental concern. No hazard identified to support a quantitation of risk.

Long Term Dermal (> 6 months) Oral NOAEL= 6 mg ai/ kg/ day with 2.5% dermal absorption factor. Residential MOE = 1000 Occupational MOE = 100 Chronic feeding study  dog Clinical signs of neurotoxicity and mortality in males, and decreased body weights and body weight gains in females at the LOAEL of 20.4 mg/ kg/ day. Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects 30 Short Term Inhalation ( 1 30 days) Inhalation NOAEL= 0.01 mg/ L Residential MOE = 1000 Occupational MOE = 100 21 day inhalation study with cypermethrin Decrease in bodyweight gain, salivation.

Intermediate Term Inhalation ( 1 6 months) Inhalation NOAEL= 0.01 mg/ L Residential MOE = 1000 Occupational MOE = 100 21 day inhalation study with cypermethrin Decrease in bodyweight gain, salivation.

Long Term Inhalation (> 6 months) Inhalation NOAEL= 0.01 mg/ L Residential MOE = 1000 Occupational MOE = 300 21 day inhalation study with cypermethrin Decrease in bodyweight gain, salivation.

Cancer ( oral, dermal, inhalation) Classification: Category C ( possible human carcinogen) No quantitation required.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * NOTE: The Special FQPA Safety Factor recommended by the HIARC assumes that the exposure databases ( dietary food, drinking water, and residential) are complete and that the risk assessment for each potential exposure scenario includes all metabolites and/ or degradates of concern and does not underestimate the potential risk for infants and children.


SIP SUBMITTAL COMPLETENESS CRITERIA CHECKLIST ( in accordance with 40 CFR Part 51  App. V)

SIP Submitted by: Maryland Department of the Environment Date Submitted: October 31, 2005 Subject: Clarification of the Definition of " interruptible gas service" Revision # 05 07)

Completeness Review Completed by: Helene Drago Date Completed:

Administrative Materials ACCEPTABLE EPA REQUIREMENT STATE SUBMITTAL ( X)

1. A formal letter of submittal from the Governor or his designee, requesting EPA approval of the plan or revision thereof. 1. Letter dated October 31, 2005 from Kendl P. Philbrick,

Secretary, Maryland Department of the Environment, to Donald Welsh, Regional Administrator, EPA Region III. Yes 2. Evidence that the State has adopted the plan in the State code or body of regulations; or issued the permit, order,

consent agreement in final form. That evidence shall include the date of adoption or final issuance as well as the effective date of the plan, if different from the adoption/ issuance date. 2. The regulations were adopted on August 23, 2005 and published in the Maryland Register on September 2, 2005 with an effective date of September 12, 2005. Yes 3. Evidence that the State has the necessary legal authority under State law to adopt and implement the plan. 3. Environmental Article, Title 2, Annotated Code of Maryland. Yes Administrative Materials EPA REQUIREMENT STATE SUBMITTAL ( X)

2 4. A copy of actual regulation, or document submitted for approval and incorporation by reference into the plan,

including indication of the changes made to the existing approved plan, where applicable. The submittal shall be a copy of the official State regulation/ document signed, stamped,

dated by the appropriate State official indicating that it is fully enforceable by the State. The effective date of the regulation/ document shall, whenever possible, be indicated in the document itself. 4. A copy of the proposed rule published in the Maryland Register on June 10, 2005, and the final rule published in the Maryland Register on September 2, 2005 with an effective date of September 12, 2005. Yes 5. Evidence that the State followed all of the procedural requirements of the State's laws and constitution in conducting and completing the adoption/ issuance of the plan. 5. Letter dated October 31, 2005, from Kendl P. Philbrick,

Secretary, Maryland Department of the Environment. Yes 6. Evidence that public notice was given of the proposed change consistent with procedures approved by EPA, including the date of publication of such notice. 6. Copy of hearing notices in Maryland Register, The Baltimore Sun, Washington Post, The Frederick News Post,

The Cumberland Times News, The Salisbury Daily and Sunday Times, and the Gazette Newspaper. Copy of hearing transcripts, attendance sign in sheets. Yes 7. Certification that public hearings were held in accordance with the information provided in the public notice and the State's laws and constitution, if applicable. 7. Letter dated October 31, 2005, from Kendl P. Philbrick,

Secretary, Maryland Department of the Environment. Certified transcript of public hearing with attendance sign in sheets. Yes 8. Compilation of public comments and the State's response thereto. 8. Certified transcript of Public Hearings with copies of public comments and state response to comments Yes Technical Materials EPA REQUIREMENT STATE SUBMITTAL ( X)

3 1. Identification of all regulated pollutants affected by the plan. 1. Not applicable 2. Identification of the locations of affected sources including the EPA attainment/ nonattainment designation of the locations and the status of the attainment plan for the affected area( s). 2. Not applicable 3. Quantification of the changes in plan allowable emissions from the affected sources; estimates of changes in current actual emissions from affected sources or, where appropriate,

quantification of changes in actual emissions from affected sources through calculations of the differences between certain baseline levels and allowable emissions anticipated as a result of the revision. 3. Not applicable.

4. The State's demonstration that the national ambient air quality standards, prevention of significant deterioration increments, reasonable further progress demonstration, and visibility, as applicable, are protected if the plan is approved and implemented. 4. Not applicable 5. Modeling information required to support the proposed revision, including input data, output data, models used,

ambient monitoring data used, meteorological data used,

justification for use of offsite data ( where used), modes of models used, assumptions, and other information relevant to the determination of adequacy of the modeling analysis. 5. Not applicable.

6. Evidence, where necessary, that emission limitations are based on continuous emission reduction technology. 6. Not applicable. Technical Materials EPA REQUIREMENT STATE SUBMITTAL ( X)

4 7. Evidence that the plan contains emission limitations, work practice standards and recordkeeping/ reporting requirements,

where necessary, to ensure emission levels. 7. Not applicable 8. Compliance/ enforcement strategies, including how compliance will be determined in practice. 8. Not applicable.

9. Special economic and technological justifications required by any applicable EPA policies. ( If a policy is not appropriate,

explain why.) 9. Not applicable .

10. A Section 107 request must be accompanied by a maintenance plan demonstrating maintenance to the relevant NAAQS for at least 10 years after redesignation. 10. Not applicable


[Federal Register: August 19, 2009 (Volume 74, Number 159)]
[Notices]
[Page 41916]
[DOCID:fr19au09-73]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0664]

Methodologies for Post-Approval Studies of Medical Devices;
Public Workshop

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public workshop.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing a public
workshop entitled ``Methodologies for Post-Approval Studies of Medical
Devices.'' The purpose of the workshop is to facilitate discussion
among FDA, industry, academia, professional societies, clinical
investigators and other interested parties on issues related to
methodologies for post-approval studies of medical devices. The target
audiences for this workshop are Epidemiologists, Statisticians,
Clinicians and Regulatory Affairs Specialists.
    Dates and Times: The workshop will be held on September 9, 2009,
from 9 a.m. to 5 p.m. and September 10, 2009, from 9 a.m. to 5 p.m.
Participants are encouraged to arrive early to ensure time for parking
and security screening before the meeting. Security screening will
begin at 8 a.m., and registration will begin at 8:30 a.m. Please pre-
register for the workshop by following the instructions in this
document.
    Location: The workshop will be held at the FDA White Oak Campus,
10903 New Hampshire Ave., Silver Spring, MD 20993.
    Contact Persons: Daniel Ca[ntilde]os, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., WO66/Room 4120, Silver Spring, MD 20993,<PHONE_NUMBER>,
<EMAIL_ADDRESS>; or Ellen Pinnow, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., WO66/Room 4106, Silver Spring, MD 20993,<PHONE_NUMBER>,
<EMAIL_ADDRESS>    Registration: To register for the conference please visit the
following Web site: https://medsun2.S-3.net/FDAPASWkshpSep09. There is
no fee to attend the workshop, but attendees must register in advance.
The registration process will be handled by Social and Scientific
Systems, which has extensive experience in planning, executing, and
organizing educational meetings. Although the facility is spacious,
registration will be on a first-come, first-served basis. In-person
attendance is limited to 120 participants. You may also register to
attend the meeting via webcast. Non-U.S. citizens are subject to
additional security screening, and they should register as soon as
possible. If you need special accommodations because of a disability,
please contact Daniel Ca[ntilde]os (see Contact Persons) at least 7
days before the public workshop.

SUPPLEMENTARY INFORMATION:

I. Why Are We Holding This Public Workshop?

    The purpose of the public workshop is to facilitate discussion
among FDA and other interested parties on methodological issues related
to Post-Approval Studies for medical devices.

II. What Are the Topics We Intend To Address at the Public Workshop?

    We hope to discuss a large number of issues at the workshop,
including, but not limited to:
     Regulatory requirements for conducting Post-Approval
Studies for medical devices;
     Using existing infrastructure (e.g., registries) to
facilitate Post-Approval Studies;
     Using innovative study design strategies and advanced
epidemiologic methods to enhance and facilitate Post-Approval Studies;
     Review important measurement considerations inherent to
Post-Approval Studies;
     Clinical research organizations, industry, academia, and
other clinical trial consultant's perspectives on all of the previous
issues related to Post-Approval Study methodologies for medical
devices.

III. Where Can I Find Out More About This Public Workshop?

    Background information on the public workshop, registration
information, the agenda, information about lodging, and other relevant
information will be posted, as it becomes available, on the Internet at
http://www.fda.gov/cdrh/meetings.html.

    Dated: August 12, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. 09-19904 Filed 8-18-09; 8:45 am]

BILLING CODE 4160-01-S


[Federal Register Volume 80, Number 40 (Monday, March 2, 2015)]
[Notices]
[Pages 11243-11244]
[FR Doc No: 2015-04184]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-74358; File No. SR-DTC-2015-01]

Self-Regulatory Organizations; The Depository Trust Company;
Notice of Filing of Proposed Rule Change To Discontinue the Prospectus
Repository System Service

February 24, 2015.
    Pursuant to Section 19(b)(1) \1\ of the Securities Exchange Act of
1934 (``Act'') and Rule 19b-4 \2\ thereunder, notice is hereby given
that on February 13, 2015, The Depository Trust Company (``DTC'') filed
with the Securities and Exchange Commission (``Commission'') the
proposed rule change as described in Items I, II and III below, which
Items have been prepared by DTC. The Commission is publishing this
notice to solicit comments on the proposed rule change from interested
persons.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
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I. Clearing Agency's Statement of the Terms of Substance of the
Proposed Rule Change

    The proposed rule change consists of a proposal to discontinue the
Prospectus Repository System Service (``PRS'') and delete the PRS Terms
of Use (``Terms of Use'') from DTC's Rules and Procedures (``Rules''),
as more fully described below.\3\
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    \3\ Terms not otherwise defined herein have their respective
meanings set forth in the Rules.
---------------------------------------------------------------------------

II. Clearing Agency's Statement of the Purpose of, and Statutory Basis
for, the Proposed Rule Change

    In its filing with the Commission, DTC included statements
concerning the purpose of and basis for the proposed rule change and
discussed any comments it received on the proposed

rule change. The text of these statements may be examined at the places
specified in Item IV below. DTC has prepared summaries, set forth in
sections A, B, and C below, of the most significant aspects of such
statements.

(A) Clearing Agency's Statement of the Purpose of, and Statutory Basis
for, the Proposed Rule Change

1. Purpose
    The purpose of the proposed rule change is to discontinue PRS.
    PRS was implemented in 2003 and enables DTC Participants
(``Participants'') and DTC-authorized third parties (Participants and
such DTC-authorized third parties, collectively referred to as
``Users'') \4\ to access prospectuses and official statements relating
to new issues of corporate and municipal securities (``Documents'')
available in electronic format from a DTC-maintained Web site.\5\ Due
to the fact that PRS currently has few Users and many of the Documents
made available via PRS are available to the public via electronic
sources outside of DTC, it is no longer necessary or cost-effective for
DTC or the industry to have DTC continue to maintain PRS. Therefore,
DTC proposes to discontinue PRS and delete the Terms of Use from the
Rules.
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    \4\ Third-party Users of PRS include syndicate members,
correspondent banks, paying agents, transfer agents, and certain
legal counsel and financial advisors. Individual investors do not
have access to PRS.
    \5\ Securities Exchange Act Release No. 47410 (February 26,
2003); 68 FR 10558 (March 5, 2003) (SR-DTC-2002-13).
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Effective Date
    The effective date of the proposed rule change would be announced
via a DTC Important Notice.
2. Statutory Basis
    The proposed rule change would discontinue an underutilized service
and eliminate the associated costs to DTC of maintaining it. Therefore,
by precluding the need for DTC to allocate resources in this regard,
the proposed rule change is consistent with the provisions of: (i)
Section 17A(b)(3)(F) \6\ of the Act which requires that the rules of
the clearing agency be designed, inter alia, to promote the prompt and
accurate clearance and settlement of securities transactions, and (ii)
Rule 17Ad-22(d)(6) \7\ promulgated under the Act which requires, inter
alia, that a clearing agency establish, implement, maintain and enforce
written policies and procedures reasonably designed to, as applicable,
be cost-effective in meeting the requirements of participants while
maintaining safe and secure operations.
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    \6\ 15 U.S.C. 78q-1(b)(3)(F).
    \7\ 17 CFR 240.17Ad-22(d)(6).
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(B) Clearing Agency's Statement on Burden on Competition

    DTC does not believe that the proposed rule change would have any
impact, or impose any burden, on competition.

(C) Clearing Agency's Statement on Comments on the Proposed Rule Change
Received From Members, Participants, or Others

    Written comments relating to the proposed rule change have not yet
been solicited or received. DTC will notify the Commission of any
written comments received by DTC.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    Within 45 days of the date of publication of this notice in the
Federal Register or within such longer period up to 90 days (i) as the
Commission may designate if it finds such longer period to be
appropriate and publishes its reasons for so finding or (ii) as to
which the self-regulatory organization consents, the Commission will:
    (A) By order approve or disapprove such proposed rule change, or
    (B) institute proceedings to determine whether the proposed rule
change should be disapproved.

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File Number SR-DTC-2015-01 on the subject line.

Paper Comments

     Send paper comments in triplicate to Brent J. Fields,
Secretary, Securities and Exchange Commission, 100 F Street NE.,
Washington, DC 20549-1090.

All submissions should refer to File Number SR-DTC-2015-01. This file
number should be included on the subject line if email is used. To help
the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street NE.,
Washington, DC 20549, on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of the filing also will be available
for inspection and copying at the principal office of DTC and on DTCC's
Web site (http://dtcc.com/legal/sec-rule-filings.aspx). All comments
received will be posted without change; the Commission does not edit
personal identifying information from submissions. You should submit
only information that you wish to make available publicly. All
submissions should refer to File Number SR-DTC-2015-01 and should be
submitted on or before March 23, 2015.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\8\
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    \8\ 17 CFR 200.30-3(a)(12).
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Jill M. Peterson,
Assistant Secretary.
[FR Doc. 2015-04184 Filed 2-27-15; 8:45 am]
BILLING CODE 8011-01-P