TXR NO. 0052425 DATE: March 17, 2004 MEMORANDUM SUBJECT: AMITRAZ  1st Report of the Hazard Identification Assessment Review Committee.

FROM: Pamela M. Hurley Reregistration Branch 3 Health Effects Division ( 7509C)

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

TO: Jose Morales, Risk Assessor Reregistration Branch 3 Health Effects Division ( 7509C)

PC Code: 106201 On February 3, 2004, the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reviewed the recommendations of the toxicology reviewer for Amitraz 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. The potential for increased susceptibility of infants and children from exposure to Amitraz was also evaluated as required by the Food Quality Protection Act ( FQPA) of 1996 in accordance with the 2002 OPP 10X guidance document. The conclusions drawn at this meeting are presented in this report. 2 Committee Members in Attendance Members present were: Jess Rowland, Brenda Tarplee, Jessica Kidwell, Susan Makris, William Burnam, William Dykstra, John Liccione, P. V. Shah, Ray Kent, Pamela Hurley Member( s) in absentia: Karen Whitby, Paula Deschamp, Ayaad Assaad, Jonathan Chen, Elizabeth Mendez Data evaluation prepared by: Pamela Hurley, Reregistration Branch 3 Also in attendance were: Catherine Eiden, Chief, Reregistration Branch 3 Data Evaluation / Report Presentation Pamela M. Hurley Toxicologist 3 INTRODUCTION On February 3, 2004, the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reviewed the recommendations of the toxicology reviewer for Amitraz 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. The potential for increased susceptibility of infants and children from exposure to Amitraz was also evaluated as required by the Food Quality Protection Act ( FQPA) of 1996 in accordance with the 2002 OPP 10X guidance document.

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

2. Evidence of Neurotoxicity The HIARC concluded that there is a concern for neurotoxicity resulting from exposure to Amitraz. No neurotoxicity studies have been conducted. Evidence of neurotoxicity following exposure to Amitraz is indicated in multiple studies across species. In both the subchronic and chronic oral studies in dogs, signs of CNS depression were observed and a decrease in pulse rate and hypothermia were noted in the subchronic study. In both the subchronic and chronic oral studies in the rat, irritability, nervousness and/ or excitability were observed. In the rabbit developmental toxicity study, clinical signs that were considered to be related to treatment included langor and polypnea. These signs could be evidence of neurotoxicity.

3. Developmental Toxicity Study Conclusions a. In a developmental toxicity study ( MRID 44265902) Amitraz ( 99.7% a. i., batch/ lot # CR 20575/ 3) was administered to three groups of 24 mated female Sprague Dawley Crl: CD( SD) BR rats/ dose in 1% w/ v methyl cellulose in distilled water by gavage at dose levels of 0, 7.5, 15, or 30 mg/ kg bw/ day in 10 mL/ kg bw from days 6 through 15 of gestation. The control group was given the vehicle ( 1% w/ v methylcellulose in distilled water) only.

Maternal toxicity was manifested in the mid and high dose groups by decreases in body weight ( 5% and 8%, respectively), body weight gain ( 11% and 21%, respectively; uterine weights not taken into account) and food consumption ( high dose only, 16% less than controls). At 15 mg/ kg/ day, the decreases in body weight and body weight gain were borderline but were enough to consider 15 mg/ kg/ day as a LOAEL. The maternal LOAEL is 15.0 mg/ kg bw/ day, based on decreases in body weight and body weight gain. The maternal NOAEL is 7.5 mg/ kg bw/ day.

Dilated ureters and renal pelvic cavitation were observed in all groups, including controls. On a fetal basis, an increase in the incidence of dilated ureters was observed at 30 mg/ kg/ day ( 65% compared to 46.4% in the control group, p< 0.01). However, these were observed in 23 litters 4 versus 21 litters in the control group and are thus not considered to be toxicologically significant. Again, on a fetal basis, increases in bilateral renal pelvic cavitation at both 15 and 30 mg/ kg/ day ( 2.9% in controls versus 5.7% and 7.1% at 15 and 30 mg/ kg/ day, respectively) were observed. In this case, 6 litters were affected in the control group versus 10 and 11 litters affected at 15 and 30 mg/ kg/ day, respectively. These incidences were not statistically significant, although were likely close to an effect level. When dilated ureters and renal pelvic cavitation grouped together, the incidences are similar to those observed for dilated ureters alone. If the rats had been treated at higher dose levels, it is likely that a clear effect level would have been observed.

The developmental LOAEL is greater than 30 mg/ kg/ day. The developmental NOAEL is 30 mg/ kg/ day.

The developmental toxicity study in the rat is classified acceptable guideline and satisfies the guideline requirements for a developmental toxicity study ( OPPTS 870.3700; § 83 3a) in the rat.

b. In a developmental toxicity study ( MRID 00029959) amitraz (% a. i and, batch/ lot # not provided) was administered to 11 13 Boots Wistar rats/ dose by gavage ( assumed) in 0.4% cellulose at dose levels of 0, 1, 3, or 12 mg/ kg bw/ day from days 8 through 20 of gestation.

No treatment related maternal effects were observed; however, in a 1 generation reproduction study where rats ( same strain, laboratory and year) were administered the test material by gavage from gestation day 1 through lactation day 21, dams receiving 12 mg/ kg/ day gained 20% less weight than the control group during gestation. Utilizing data from that study ( MRID 00029960), the maternal LOAEL is 12 mg/ kg bw/ day, based on decrease in body weight gain . The maternal NOAEL is 3 mg/ kg bw/ day.

The developmental LOAEL is undetermined. The developmental NOAEL is 12 mg/ kg bw/ day ( HDT).

The developmental toxicity study in the rat is classified unacceptable guideline; and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat. Very limited data were provided, the purity of the test substance was not provided and the dosage period was from gestation days 8 20 which excludes some important gestation days.

c. In a developmental toxicity study ( MRID 00029961) amitraz (% a. i and, batch/ lot # not provided) was administered to 8 10 New Zealand White rabbits/ dose by gavage ( assumed) in 0.4% cellulose at dose levels of 0, 1, 5, or 25 mg/ kg bw/ day from days 6 through 18 of gestation.

No treatment related maternal effects were observed at either 1 or 5 mg/ kg/ day. At 25 mg/ kg/ day, the does gained less weight than the control group and 4 does aborted. The maternal LOAEL is 25 mg/ kg bw/ day, based on decrease in body weight gain and abortions. The maternal NOAEL is 5 mg/ kg bw/ day.

No treatment related developmental effects were observed at either 1 or 5 mg/ kg/ day. At 25 mg/ kg/ day, decreased litter size, decreased implantations, increased postimplantation loss and decreased mean fetal body weight were observed. The developmental LOAEL is 25 mg/ kg 5 bw/ day, based on decreased litter size, decreased implantations, increased postimplantation loss and decreased mean fetal body weight. The developmental NOAEL is 5 mg/ kg bw/ day.

The developmental toxicity study in the rabbit is classified unacceptable guideline; and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat. Very limited data were provided, there is no indication that gavage dosing was used ( it is assumed), there was a limited number of litters available for analysis ( too few does) and the purity of the test substance was not provided.

d. In a developmental toxicity study ( MRID 44265901) Amitraz ( 99.7% a. i., batch/ lot # CR 20575/ 3) was administered to three groups of 16 mated female New Zealand White rabbits/ dose in 1% w/ v methyl cellulose in distilled water by gavage at dose levels of 0, 3, 6, or 12 mg/ kg bw/ day in 2 mL/ kg bw from days 7 through 19 of gestation. The control group was given the vehicle ( 1% w/ v methylcellulose in distilled water) only.

At 12 mg/ kg/ day, mortality was increased, with two does sacrificed moribund after they aborted their litters. The does lost a mean body weight of 0.06 kg or 2% of the mean body weight early in the dosing period ( between days 7 and 13) during which the control group gained 140 grams ( 4% of the mean body weight). Later in the dosing period ( between days 13 and 19, the 12 mg/ kg/ day group gained 140 grams ( 4% of the mean body weight). Although these values are small when compared to the overall mean weight of the does and no statistical analyses were conducted, it appears that the high dose induces a mild treatment related effect, especially since there is a rebound effect following the dosing period. Food consumption during the treatment period was decreased 26% when compared to controls. Clinical signs included post dosing langor ( 100% of the animals in this group displayed this finding), polypnea ( 94%) and squinting ( 75%). Three of the does totally resorbed their litters. No doe in any other group displayed a total litter resorption. At 6 mg/ kg/ day, post dosing langor ( 94%), polypnea ( 75%) and squinting ( 25%) were observed. At 3 mg/ kg/ day, the same clinical signs were observed: post dosing languor ( 75%), polypnea ( 25%) and squinting ( 13%). These clinical signs were not observed in the control group.

Deaths were observed in all groups, including controls. There was considerable gavage error. Unfortunately, maternal toxicity was confounded by indications that the animals were likely suffering from a respiratory illness throughout the study. The animals appear to have been ill from the start, even in the control group. There was a high incidence of rhinorrhea and fur staining of the paws. Necropsy results revealed a high incidence of abnormal contents in the thoracic cavity and lungs ( colored fluid, white semi solid foci on pleura, other changes) in all groups, including controls. Some of the results from these animals may be attributable to gavage administration.

The maternal LOAEL is 3.0 mg/ kg bw/ day, based on clinical signs in all treated groups. Decreases in body weight gain and food consumption were observed at the highest dose level ( 12 mg/ kg/ day). The maternal NOAEL is not established.

There were no indications of developmental toxicity; however, in two of the treated groups, there were a limited number of litters available for an adequate analysis. The number of available litters ranged from 9 to 14 for each treated and control group. An apparent increase in early resorptions and percent postimplantation loss was seen at 12 mg/ kg/ day; however, these increases were due 6 to the fact that three does at this dose totally resorbed their litters ( 88% of the early resorptions at 12 mg/ kg/ day were found in the three does which displayed total litter resorptions). Examination of body weight gain and food consumption in the animals displaying total litter resorptions indicates that the total litter resorptions were likely due to maternal toxicity rather than a direct effect on the embryo/ fetus.

The developmental LOAEL is greater than 12 mg/ kg bw/ day, the highest dose tested. The developmental NOAEL is 12 mg/ kg bw/ day.

The developmental toxicity study in the rabbit is classified unacceptable guideline and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in nonrodents. Deficiencies include: too few litters in two of the treated groups and preexisting maternal illness which may have confounded the results.

4. Reproductive Toxicity Study Conclusions a. In a 1 generation reproduction study ( MRID 00029960) BTS 27419 ( Amitraz ( purity and batch number not provided) was administered to 13 Boots Wistar rats/ sex/ dose ( 14 in the high dose) by gavage ( assumed) at dose levels of 0,1, 3 or 12 mg/ kg bw/ day in a volume of 1 ml/ 100 g body weight from gestation days 1 through lactation day 21.

At 12 mg/ kg/ day, the dams gained a mean of 20% ( p< 0.001) less weight than the control group. No maternal effects were observed in any other treated group. No information was provided on males. The maternal systemic LOAEL is 12 mg/ kg bw/ day, based on decrease in body weight gain. The maternal systemic NOAEL is 3 mg/ kg bw/ day.

At 12 mg/ kg/ day, there was a slightly lower mean litter size at birth and on lactation day 4 ( p < 0.01). By lactation day 21, mean litter size was comparable to the control group. The offspring LOAEL is 12 mg/ kg bw/ day. The offspring NOAEL is 3 mg/ kg bw/ day. Note: The NOAEL is lower than the original DER because the slightly lower mean litter sizes support the NOAEL, LOAEL and effects observed in the multi generation reproduction study ( MRID 00029962).

No reproductive effects were observed.

This study is unacceptable, non guideline and does not satisfy the guideline requirement for a multi generation reproduction study ( OPPTS 870.3800; OECD 416) in the rat. It is only one generation, only provides limited information and does not provide the purity of the test compound.

b. In a 3 generation reproduction study ( MRID 00029962) BTS 27 419 ( Amitraz ( purity not provided, batch/ lot # 2099DR) was administered to 10 male and 20 female Boots Wistar rats/ dose in the diet at dose levels of 0, 15, 50, or 200 ppm ( equivalent to 0, 1.29, 4.36, or 16.41 mg/ kg bw/ day for males and 1.58, 5.09 or 20.05 mg/ kg bw for females). One litter was produced per generation.

At 16.41/ 20.05 mg/ kg/ day, the F0 parents gained less mean body weight than the control group 7 during the premating period ( 7% in males, 14% in females; statistically significant in females). Body weights were not reported during either the gestation or lactation periods. Body weight values were not measured at this dose level in succeeding generations because of a nearly complete loss of the high dose group during the F1 generation. No other parental effects were observed in any of the treated groups.

The parental systemic LOAEL is 200 ppm ( 16.41 mg/ kg bw/ day in males, 20.05 mg/ kg bw/ day in females), based on decreased body weight gain during the F0 premating period. The parental systemic NOAEL is 50 ppm ( 4.36 mg/ kg bw/ day in males, 5.09 mg/ kg bw/ day in females).

At 16.41/ 20.05 mg/ kg/ day, there was an almost complete loss of pups in the F1 generation during the lactation period ( 5 remaining pups versus 115 remaining pups in the control group). In addition, there was a reduction in mean litter size on day 1 ( 6.7 pups/ litter versus 7.9 pups/ litter in the control group). At 4.36/ 5.09 mg/ kg/ day, in each generation, there was a higher number of pup deaths than in the control group. By day 21, the mean litter size was smaller but was not statistically significantly smaller until the final generation ( p < 0.05).

The offspring LOAEL is 50 ppm ( 4.36/ 5.09 mg/ kg bw/ day), based on decreased survival and mean litter size during lactation. The offspring NOAEL is 15 ppm ( 1.29/ 1.58 mg/ kg bw/ day).

This study is unacceptable guideline and does not satisfy the guideline requirement for a [ 3] generation reproductive study ( OPPTS 870.3800); OECD 416 in the rat. The percent active ingredient of the test substance was not reported, very limited data were provided, mating was not 1 male to 1 female ( only 10 males used/ dose group/ generation), no data on reproductive organs were provided, litter data were only provided for a few time points, and histopathology data were not provided.

5. Additional Information from Literature Sources No additional information on developmental/ reproductive toxicity and neurotoxicity were found in the literature.

6. Pre and/ or Postnatal Toxicity The HIARC cannot conclude whether or not there is any concern for pre and/ or postnatal toxicity resulting from exposure to Amitraz because neither the rabbit developmental nor the rat reproduction studies are acceptable and they have too many deficiencies. 8 A. Determination of Susceptibility There is no evidence ( quantitative or qualitative) of increased susceptibility following pre natal exposure to rats. However, evidence for susceptibility following pre natal exposure to rabbits or following pre and/ or postnatal exposure to rats could not be ascertained due to many deficiencies in study designs and/ or study reports.

B. Degree of Concern Analysis and Residual Uncertainties There are no concerns for residual uncertainty for pre natal toxicity in the available developmental toxicity study in rats.

The HIARC determined that despite the lack of acceptable rabbit developmental and rat reproduction studies, there are no residual uncertainties for pre and/ or post natal toxicity based on the following considerations:

° Although susceptibility could not be ascertained in rabbits, the results of the two unacceptable studies show that developmental effects occurred at doses higher than the doses that caused maternal toxicity.

° At present, the endpoint of concern ( neurotoxicity) for the overall risk assessment is based on the " apparent" sensitive species ( dogs).

° A 10X database uncertainty factor ( UF DB) is required due to an incomplete database ( i. e. lack of acceptable rabbit developmental toxicity and two generation reproduction studies).

° Application of the 10X UF DB to the NOAEL ( 0.25 mg/ kg/ day) selected for the overall risk assessments yields a dose of 0.025 mg/ kg/ day which is approximately 200 fold lower than the lowest developmental NOAEL ( 5.0 mg/ kg/ day) in the unacceptable rabbit studies and 50 fold lower than the offspring NOAEL in the unacceptable three generation reproduction study.

C. Special FQPA Safety Factor( s):

Based on the above data, no special FQPA safety factor ( i. e. 1X) is required since there are no residual uncertainties for pre natal toxicity as discussed above.

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

A. Evidence that suggest requiring a Developmental Neurotoxicity study:

° The available toxicity database indicates that clinical signs of CNS toxicity are observed in rats, dogs and possibly rabbits.

B. Evidence that do not support a need for a Developmental Neurotoxicity study:

° None Based on the weight of evidence presented, the HIARC is requiring a combined 2 generation reproduction study in the rat with components assessing for potential developmental and adult neurotoxicity. The HIARC recommended that the study design for the required two generation reproduction study should be MODIFIED to include the following:

° Due to the concern for the lack of stability of the test material in the diet, treatment should be via oral ( gavage) administration.

° The potential for neurotoxicity in the developing fetuses should be evaluated according to the OPPTS Guideline § 870.6300.

° The potential for neurotoxicity in adults should be evaluated according to the OPPTS Guideline § 870.6200.

The HIARC determined that the 10X UF DB should be applied to dietary ( acute and chronic) and non dietary ( incidental oral, dermal and inhalation) risk assessments because the required studies may provide endpoints applicable for risk assessments.

II. HAZARD IDENTIFICATION 1. Acute Reference Dose ( aRfD)  General Population, including Infants and Children Study Selected: Chronic Dog Study § 870.4100 MRID No.: 00044586 Executive Summary: In a chronic toxicity study ( MRID 00044586) Amitraz (% a. i. and batch/ lot # not provided) was administered to 4 beagle dogs/ sex/ dose in gelatin capsules at dose levels of 0, 0.1, 0.25, or 1.0 mg/ kg bw/ day) for 2 years. Clinical signs were monitored; body weight and temperature, hematology, clinical chemistry, urinalysis and organ weight parameters were measured; and gross and microscopic examinations were conducted. 10 At 1.0 mg/ kg/ day, all 8 dogs had CNS depression on the first two days of dosing; however, the data on clinical signs were not submitted. There was a dose related decrease in body temperature after dosing that lasted approximately 6 hours; however, body temperatures essentially remained in the normal range. The LOAEL is 1.0 mg/ kg/ day, based on CNS depression during the first two days of dosing. The NOAEL is 0.25 mg/ kg/ day.

This chronic study in the dog is acceptable guideline and satisfies the guideline requirement for a chronic oral study [ OPPTS 870.4100, OECD 452] in the dog.

Dose and Endpoint for Establishing aRfD: NOAEL of 0.25 mg/ kg/ day based on CNS depression during the first two days of dosing at the LOAEL of 1.0 mg/ kg/ day.

Uncertainty Factor ( UF): 1000 ( 10x for interspecies extrapolation, 10x for intraspecies variations and 10x for data gaps.)

Comments about Study/ Endpoint/ Uncertainty Factor: This study is appropriate for an acute dietary endpoint because CNS effects were observed three hours after administration of a single dose. This endpoint is supported by similar clinical signs observed in humans following an acute exposure ( TXR No. 011110) .

2. Chronic Reference Dose ( cRfD)

Study Selected: Chronic Dog Study § 870.4100 MRID No.: 00044586 Executive Summary: See Section II. 1. Acute Reference Dose ( aRfD)

Dose and Endpoint for Establishing cRfD: NOAEL of 0.25 mg/ kg/ day based on CNS depression during the first two days of dosing at the LOAEL of 1.0 mg/ kg/ day.

Uncertainty Factor( s): 1000 ( 10x for interspecies extrapolation, 10x for intraspecies variations and 10x for data gaps.)

Comments about Study/ Endpoint/ Uncertainty Factor: Although effects were observed early on in the study and were not observed later in the study, this study is appropriate for a chronic dietary endpoint because the dogs were exposed to the test material for 2 years. Additionally, the dose ( 0.25 mg/ kg/ day) would address the concerns for systemic effects seen in mice ( liver, spleen and stomach lesions) and rats ( clinical signs and decrease in body weight gain), following long term oral administration at higher doses. Acute RfD = 0.25 ( NOAEL ) mg/ kg/ day = 0.00025 mg/ kg/ day 1000 ( UF ) 11 3. Incidental Oral Exposure: All Durations ( 1  30 days and 1 6 Months)

Study Selected: Chronic Dog Study § 870.4100 MRID No.: 00044586 Executive Summary: See Section II. 1. Acute Reference Dose ( aRfD)

Dose and Endpoint for Risk Assessment: NOAEL of 0.25 mg/ kg/ day based on CNS depression during the first two days of dosing at the LOAEL of 1.0 mg/ kg/ day.

Comments about Study/ Endpoint: This study is appropriate for the population of concern ( infants and children). This dose/ endpoint is appropriate for both short and intermediate term exposure because the effects were observed early in the study ( i. e. first two days of dosing), dogs are the most sensitive species and it would address the concern for effects seen via the oral route in other species.

4. Dermal Absorption Dermal Absorption Factor: 8%

Ten male rats were dosed via the dermal route with the M82 formulation of amitraz diluted in water at a dose of 91 micrograms/ cm2 a. i. ( MRID 42133501). The application site was shaved and washed with acetone 24 hours before dosing. After dosing the site was protected with a nonocclusive device and the animals were placed individually in metabolism cages for collection of total urine and feces. After ten hours of exposure, the application site of each animal was washed quantitatively with soap and water and the animals were returned to metabolism cages. At 24 hours post dosing, 5 animals were euthanized and the application site skin, digestive tract and the remaining carcass were collected for analysis. The remaining five animals were carried for five days postdosing, with total urine and fecal samples for each 24 hour period, and then terminated as above. The mean percent of dose available for risk assessment purposes is shown in the following table.

Dermal Absorption Study in Rats: Mean Percent of Dose Available for Risk Assessment 24 Hours (%) 120 Hours (%)

Treatment Site 2.98 1.41 Total Absorbed 3.69 6.56 Total 6.67 7.79 Chronic RfD = 0.25 ( NOAEL ) mg/ kg/ day = 0.00025 mg/ kg/ day 1000 ( UF ) 12 5. Dermal Exposure: All Durations ( 1  30 days, 1 6 Months and > 6 Months)

Study Selected: Chronic Dog Study § 870.4100 MRID No.: 00044586 Executive Summary: See Section II. 1. Acute Reference Dose ( aRfD)

Dose and Endpoint for Risk Assessment: NOAEL of 0.25 mg/ kg/ day based on CNS depression during the first two days of dosing at the LOAEL of 1.0 mg/ kg/ day.

Comments about Study/ Endpoint: The HIARC noted that a 21 day dermal toxicity study in rabbits is available and shows CNS depression at the lowest dose tested, 50 mg/ kg/ day; a NOAEL was not established. The Committee determined that this study is not suitable for use for risk assessments due to many deficiencies with the conduct of the study. The deficiencies noted were testing of too few animals ( 4/ sex/ dose), concurrent infections, lack of test article characterization and limited histopathological evaluation of the required tissues. Therefore, an oral NOAEL from the chronic dog study was selected for dermal risk assessments. Although the endpoint of concern ( CNS depression) was seen after a few exposures, it is appropriate for all time periods ( i. e., short, intermediate and long term) since the effects were seen in the most sensitive species ( dogs) and the selected dose ( 0.25 mg/ kg/ day) would address the concerns of systemic toxicity seen in mice and rats following oral administration. Additionally, the use of an 8% dermal absorption value with the 0.25 mg/ kg/ day oral dose yields a dermal equivalent dose of 3.1 mg/ kg/ day ( 0.25 ÷ 0.08) which is comparable to an extrapolated NOAEL of 5.0 mg/ kg/ day ( 50.0 ÷ 10 UF for use of a LOAEL) from the 21 day dermal toxicity study.

6. Inhalation Exposure: All Durations ( 1  30 days, 1 6 Months and > 6 Months)

Study Selected: Chronic Dog Study § 870.4100 MRID No.: 00044586 Executive Summary: See Section II. 1. Acute Reference Dose ( aRfD)

Dose/ Endpoint for Risk Assessment: NOAEL of 0.25 mg/ kg/ day based on CNS depression during the first two days of dosing at the LOAEL of 1.0 mg/ kg/ day.

Comments about Study/ Endpoint: The HIARC noted that a 21 day inhalation toxicity study in rats is available with a NOAEL of 0.42 mg/ kg/ day and a LOAEL of 4.2 mg/ kg/ day. These values are based on the conversion of nominal values and therefore, are considered to be gross estimates of the actual values. The Committee determined that this study is not suitable for risk assessments due to many deficiencies with the conduct of the study. There were limited individual animal data, analytical exposure concentrations were not measured and the study reports were incomplete in terms of study protocol and environmental conditions. Therefore, an oral NOAEL from the chronic dog study was selected for dermal risk assessments. Although the endpoint of concern ( CNS depression) was seen after a few exposures, it is appropriate for all 13 time periods ( i. e., short, intermediate and long term) since the effects were seen in the most sensitive species ( dogs) and the selected dose ( 0.25 mg/ kg/ day) would address the concerns of systemic toxicity seen in mice and rats following oral administration.

7. 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 100 100 100 Inhalation 100 100 100 Residential ( Non Dietary) Exposure Oral 1000 1000 N/ A Dermal 1000 1000 1000 Inhalation 1000 1000 1000 For Occupational exposure: This is based on the conventional uncertainty factor of 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation)

For Residential exposure: This is based on the conventional uncertainty factor of 100X ( 10X for intraspecies extrapolation and 10X for interspecies variation) plus an additional 10X database uncertainty factor for lack of acceptable developmental rabbit and rat reproduction studies.

8. 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 short, intermediate and long term aggregate exposure risk assessments, the oral, dermal and inhalation routes can be combined because of the common study endpoint used for these routes ( i. e., oral equivalent doses were selected for the dermal and inhalation routes). 14 III. CLASSIFICATION OF CARCINOGENIC POTENTIAL 1. Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No. 00044585 Executive Summary: In a combined chronic / carcinogenicity study ( MRID 00044585) BTS 27 419 ( 97.8 99.8 % a. i, batch/ lot #' s 2093DH, 2099DH) was administered to 40 Ash Wistar SPF rats/ sex/ dose in the diet at dose levels of 0, 15, 50, or 200 ppm ( equivalent to 0, 0.77/ 0.97, 2.5/ 3.13 or 10.18/ 12.59 mg/ kg bw/ day, males/ females, respectively) for 2 years.

There was no treatment related effect on survival. The number of rats reported as excitable, nervous or aggressive was increased in the 50 ( females) and 200 ppm groups ( males and females); the females were more frequently affected. Body weight gain was decreased in the 200 ppm group at weeks 0 12 for both males and females, weeks 12 24 for females, and weeks 24 36 and 0 104 for males. Food consumption was reduced in both the males and females in the 200 ppm group at the beginning of treatment but then was comparable to the control group. There were no treatment related effects on clinical pathology parameters or necropsy findings. The incidence of tumors was comparable between the treated and control groups. The LOAEL is 200 ppm ( males, 10.18 mg/ kg/ day based on clinical signs and decreased body weight gain) and 50 ppm ( females, 3.13 mg/ kg/ day based on clinical signs). The NOAEL is 50 ppm ( males, 2.5 mg/ kg/ day) and 15 ppm ( females, 0.97 mg/ kg/ day).

At the doses tested, there were no treatment related increases in tumor incidence when compared to controls. Dosing was considered adequate based on clinical signs and decreased body weight gain.

This chronic/ carcinogenicity study in the rat is acceptable guideline and satisfies the guideline requirement for a chronic/ carcinogenicity study OPPTS 870.4300); OECD 453] in the rat.

Discussion of Tumor Data: At the doses tested, there were no treatment related increases in tumor incidence when compared to controls.

Adequacy of the Dose Levels Tested: Dosing was considered adequate based on clinical signs of neurotoxicity and decreased body weight gain.

2. Carcinogenicity Study in Mice MRID No. 00139552 Executive Summary: In a carcinogenicity study ( MRID 00139552) Amitraz ( 88.2 100.8% a. i., batch #' s 34732Y, 52221, 56105) was administered to 100 control and 75 treated B6C3F1 mice/ sex/ dose in the diet at dose levels of 0, 25, 100 or 400 ppm ( equivalent to 0, 2.31/ 2.63, 9.61/ 10.77, or 44.65/ 50.13 mg/ kg bw/ day) for 104 weeks. 15 At 2.31/ 2.63 mg/ kg/ day and above, a dose related increase in the incidence of hyperplastic nodules, basophilic and telangiectatic foci was observed in the liver of females, accompanied by an increased incidence of stomach hyperkeratosis and spleen hematopoiesis in males.

At 9.61/ 10.77 mg/ kg/ day and above, hyperactivity and aggressive behavior were observed in males during the first 12 weeks of the study. Cutaneous lesions, as evidence of fighting were also observed. By week 52, mean body weight gain was reduced by 29% in males and 32% in females ( p< 0.01). A 6% decrease in food consumption was observed in males during weeks 1 12 at both the mid and high dose levels ( p< 0.05) and during weeks 13 25 at the mid dose level ( p< 0.01). An increase in food consumption was recorded at the high dose level in males during weeks 26 104 ( 9 13%). In females, 5 11% decreases in food consumption were observed during weeks 1 19 ( p< 0.05), followed by increases in food consumption during weeks 31 58 and 93 104. The bone marrow myeloid/ erythroid ratio was significantly reduced ( p< 0.001) in females ( 22% and 26% at the mid and high dose levels, respectively).

At 44.65/ 50.13 mg/ kg/ day, piloerection and hunched posture were observed in males during weeks 2 4. Food utilization was lower for both sexes during the first 24 weeks of the study ( approximately 35% 42% lower). Mean body weight gain was reduced by week 52 in males and females ( 29% and 32%, respectively, p< 0.01). The bone marrow myeloid/ erythroid ratio was significantly reduced ( p< 0.001) in males ( 24%).

Males had a significant positive trend in mortality with incremental doses of amitraz.

The LOAEL is 2.31/ 2.63 mg/ kg/ day, based on a dose related increase in the incidence of hyperplastic nodules, basophilic and telangiectatic foci in the liver of females, accompanied by an increased incidence of stomach hyperkeratosis and spleen hematopoiesis in males. The NOAEL is less than 2.31/ 2.63 mg/ kg/ day.

In females there were significant dose related positive trends in hepatocellular adenomas, carcinomas and in combined adenomas/ carcinomas. Females also had a significant increase in the pair wise comparison of controls and the highest dose group in hepatocellular adenomas, carcinomas and in combined adenomas and/ or carcinomas. Males had a significant dose related positive trend in lung adenomas. In addition, males had a significant increase in the pair wise comparison of controls and the highest dose group in lung adenomas. Reduction in body weight gain and a significant positive trend in mortality in male mice suggest that the highest dose tested was excessive. In females, however, the highest dose was high but not excessive since it was not life threatening.

This carcinogenicity study in the mice is acceptable guideline and satisfies the guideline requirement for a carcinogenicity study [ OPPTS 870.4200; OECD 451] in mice.

Discussion of Tumor Data: In females there were significant dose related positive trends in hepatocellular adenomas, carcinomas and in combined adenomas/ carcinomas. Females also had a significant increase in the pair wise comparison of controls and the highest dose group in hepatocellular adenomas, carcinomas and in combined adenomas and/ or carcinomas. Males had a significant dose related positive trend in lung adenomas. In addition, males had a significant increase in the pair wise comparison of controls and the highest dose group in lung adenomas. 16 Adequacy of the Dose Levels Tested Reduction in body weight gain and a significant positive trend in mortality in male mice suggest that the highest dose tested was excessive. In females, however, the highest dose was high but not excessive since it was not life threatening.

3. Classification of Carcinogenic Potential:

The HED Cancer Peer Review Committee met on October 31, 1990 and determined that Amitraz should be classified as a Group C, possible human carcinogen. The Q 1* was calculated to be 5.0 x 10 2, based upon the combined hepatocellular adenomas and carcinomas in female mice. A 2/ 3' s/ day cross species scaling factor was utilized for the calculation. On February 11, 2004, a revised Q 1* of 2.83 x 10 2 in human equivalents was estimated using the 3/ 4' s scaling factor, reflecting the change in Agency policy in1994.

IV. MUTAGENICITY The HIARC concluded that there is not a concern for mutagenicity resulting from exposure to Amitraz.

Amitraz: Results of Mutagenicity Studies Study Type Results Salmonella reverse gene mutation ( Ames) Negative up to 10 mg/ plate, w/ wo metabolic activation. MRID 00161009 Forward Gene Mutation Assay ( mouse L5178Y lymphoma cells) Negative at 0.06 20

g/ ml w/ wo activation. HDT is highest non cytotoxic dose. MRID 00161008 In vitro Structural Chromosome Aberration Assay ( human lymphocytes) Negative up to cytotoxic and/ or insoluble concentrations. MRID 41795101 Unscheduled DNA Synthesis ( human embryonic lung fibroblast) Negative up to cytotoxic concentrations, w/ wo activation. MRID 00161011 Morphological Transformation ( C3H/ 10T1/ 2 cells derived from mouse embyro fibroblast) Negative up to cytotoxic concentrations, w/ wo activation. MRID 00161010 V. HAZARD CHARACTERIZATION Amitraz has a low acute toxicity by the oral, dermal and inhalation routes in a wide number of species. It has been tested in mice, rats, guinea pigs, rabbits, dogs, baboons and domestic pigs by the oral, dermal and inhalation routes of exposure. In the Registration Standard ( TXR 005633), a pharmacotoxic profile suggests a depression of hypothalmic function. Clinical signs of toxicity include central nervous system 17 depression, ataxia, ptosis, emesis, labored respiration, muscular weakness, tremors, hypothermia and bradycardia. These signs varied in severity depending upon the species. The dog appears to be the most sensitive species with the baboon approximately 2.5 times less sensitive, followed by the rat and guinea pig ( 5 times less sensitive). The mouse appears to be the least sensitive ( 15 times less sensitive). Metabolism studies in humans indicate clinical signs similar to those observed in animals. These signs were reported within 90 to 160 minutes after ingestion and included sedation, dry mouth, disorientation, bradycardia, hypertension and hypothermia persisting up to 12 hours after dosing.

Metabolism studies have been conducted in the mouse, rat, cat, dog, baboon and man. The major metabolites of amitraz include N( 2,4 dimethylphenyl) N methylformamidine; 2,4 dimethylformanilide; 2,4 dimethylaniline; 4 amino 3 methylbenzoic acid; 4 formamido 3 methyl benzoic acid; 4 acetamido 3 methyl benzoic acid; and N, N bis 2,4 dimethylphenylformamidine. 2,4 dimethylaniline is included in the tolerance expression along with the parent.

Clinical signs of neurotoxicity and decreased body weights appear to be the major targets for amitraz. A comparison of the subchronic and chronic studies indicates that there does not appear to be any issues of cumulative toxicity ( i. e. no increased toxicity with a longer term of exposure). The dog is the most sensitive species, although the clinical signs appear early in the chronic study and do not reappear.

There is no indication of developmental toxicity in the rat in either of two available studies ( one unacceptable study and an acceptable repeat study). Two studies are available in the rabbit; however, niether are acceptable due to deficiencies in either the study designs and/ or the studies themselves. In the first rabbit study, at a dose level where decreased body weight gains and abortions were observed in the does, decreased litter size, decreased implantations, increased postimplantation loss, abortions and decreased mean fetal body weight had been observed. However, the study needed to be repeated because there were too few litters available for analysis, limited data available in the report and an unclear method of dosing. No developmental toxicity was observed in the second rabbit study; however this study is not acceptable due to too few available litters in the two treated groups and pre existing maternal respiratory infections. In addition, this study was not tested at as high a dose as in the first study. In the repeat study, an apparent increase in early resorptions and percent postimplantation loss was seen at the highest dose tested; however, these increases were due to the fact that three does at this dose totally resorbed their litters ( 88% of the early resorptions were found in the three does which displayed total litter resorptions). It might be possible that developmental toxicity could be observed at a higher dose if a new study were conducted. In summary, there is no evidence ( quantitative or qualitative) of increased susceptibility following pre natal exposure to rats. However, evidence for susceptibility following pre natal exposure to rabbits could not be ascertained due to deficiencies in either the study designs and/ or study reports.

Two reproduction studies are available, a 1 generation and a 3 generation study. In the 1 generation reproduction study, at the same LOAEL, the parents exhibit a mean decrease in body weight gain whereas the pups exhibit a lower mean litter size at birth and on lactation day 4. In the 3 generation reproduction study, the parents exhibit a mean decrease in body weight gain during the F0 premating period at the LOAEL. At the parental NOAEL, the pups exhibit decreased survival and mean litter size during lactation. Unfortunately, neither study is unacceptable for regulatory purposes. In the 1 generation study, the animals are not tested over at least two generations, only limited information were 18 provided and the purity of the test compound was not available. In the 3 generation reproduction study, again, limited data were provided, mating was not 1 male to 1 female, no data on reproductive organs were provided, litter data only provided for a few time points, and histopathology data were not provided. In summary, evidence for susceptibility following pre and/ or postnatal exposure to rats could not be ascertained due to many deficiencies in study designs and/ or study reports.

In rats, there is no indication of potential carcinogenicity for amitraz; however, in female mice amitraz induces significant dose related positive trends in hepatocellular adenomas, carcinomas and in combined adenomas/ carcinomas. Females also had a significant increase in the pair wise comparison of controls and the highest dose group in hepatocellular adenomas, carcinomas and in combined adenomas and/ or carcinomas. Male mice had a significant dose related positive trend in lung adenomas. In addition, males had a significant increase in the pair wise comparison of controls and the highest dose group in lung adenomas. Amitraz is classified as a Group C, possible human carcinogen. The Q 1* has been calculated to be 2.83 x 10 2 in human equivalents using the 3/ 4' s scaling factor, reflecting the 1994 Agency policy. Amitraz has not been shown to induce gene mutations in either bacterial or mammalian cells, is not clastogenic, either in vivo or in vitro, does not induce unscheduled DNA synthesis in mammalian cells, and does not induce cell transformations in C3H/ 10T1/ 2 cells derived from mouse embyro fibroblasts under the conditions in which the studies were conducted.

VI. DATA GAPS / REQUIREMENTS ° Prenatal developmental toxicity study in rabbits ( 870.3700)

° A two generation reproduction study which should be MODIFIED to include the following:

° Due to the concern for the lack of stability of the test material in the diet, treatment should be via oral ( gavage) administration.

° The potential for neurotoxicity in the developing fetuses should be evaluated according to the OPPTS Guideline § 870.6300.

° The potential for neurotoxicity in adults should be evaluated according to the OPPTS Guideline § 870.6200.

The HIARC determined that the 10X UF DB should be applied to dietary ( acute and chronic) and nondietary ( incidental oral, dermal and inhalation) risk assessments because the required studies may provide endpoints applicable for risk assessments.

° A 28 day inhalation study which should follow the OPPTS Guidance 870.3465, with cessation of exposure at 28 days. 19 VII. ACUTE TOXICITY Acute Toxicity of Amitraz Guideline No. Study Type MRID #( s) Results Toxicity Category 81 1 Acute Oral 00041539 LD 50: 531 mg/ kg ( M) 515 mg/ kg ( F) III 81 2 Acute Dermal 00040862 LD 50: > 200 mg/ kg II 81 3 Acute Inhalation 00029963 LC 50: 2.4 mg/ L III 81 4 Primary Eye Irritation 00040861 Non irritating IV 81 5 Primary Skin Irritation 00040862 Non irritating IV 81 6 Dermal Sensitization  G. Pigs 00029965 Not a sensitizer under conditions of study N/ A 20 VIII. SUMMARY OF TOXICOLOGY ENDPOINT SELECTION Summary of Toxicological Dose and Endpoints for Amitraz 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 = 0.25 mg/ kg/ day UF = 1000 Acute RfD = 0.00025 mg/ kg/ day FQPA SF = 1 aPAD = acute RfD FQPA SF = 0.00025 mg/ kg/ day Chronic oral study in the dog ( capsule) LOAEL = 1.0 mg/ kg/ day based on CNS depression during the first two days of dosing.

Chronic Dietary ( All populations) NOAEL= 0.25 mg/ kg/ day UF = 1000 Chronic RfD = 0.00025 mg/ kg/ day FQPA SF = 1 cPAD = chronic RfD FQPA SF = 0.00025 mg/ kg/ day Chronic oral study in the dog ( capsule) LOAEL = 1.0 mg/ kg/ day based on CNS depression during the first two days of dosing.

Short and Intermediate  Term Incidental Oral ( 1 30 days and 1 6 months) NOAEL= 0.25 mg/ kg/ day Residential LOC for MOE = 1000 Occupational = NA Chronic oral study in the dog ( capsule) LOAEL = 1.0 mg/ kg/ day based on CNS depression during the first two days of dosing.

Dermal ( All Durations) Oral NOAEL= 0.25 mg/ kg/ day ( dermal absorption rate 8%) Residential LOC for MOE = 1000 Occupational LOC for MOE = 100 Chronic oral study in the dog ( capsule) LOAEL = 1.0 mg/ kg/ day based on CNS depression during the first two days of dosing.

Inhalation ( All Durations) Oral NOAEL= 0.25 mg/ kg/ day ( inhalation absorption rate = 100%) Residential LOC for MOE = 1000 Occupational LOC for MOE = 100 Chronic oral study in the dog ( capsule) LOAEL = 1.0 mg/ kg/ day based on CNS depression during the first two days of dosing.

Cancer ( oral, dermal, inhalation) Q1* = 2.83 x 10 2 Group: C Combined hepatocellular adenomas and carcinomas in female mice.

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 21 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.


[Federal Register Volume 86, Number 63 (Monday, April 5, 2021)]
[Proposed Rules]
[Pages 17571-17572]
[FR Doc No: 2021-06926]

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

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 141

[EPA-HQ-OW-2021-0255; FRL 10022-33-OW]
RIN 2040-AF15

Lead and Copper Rule (LCRR) Virtual Engagements

AGENCY: Environmental Protection Agency (EPA).

ACTION: Announcement of events; request for public comment.

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

SUMMARY: The Environmental Protection Agency (EPA) will host virtual
engagements beginning in April 2021. The goal of the events is to
obtain further public input on EPA's revision to the Lead and Copper
rule (LCRR), particularly from individuals and communities that are
most at-risk of exposure to lead in drinking water. For more
information on each event, visit EPA's drinking water website:
www.epa.gov/safewater. For more information, go to the SUPPLEMENTARY
INFORMATION section of this document.

DATES: Public listening sessions will be held on April 28, 2021 and May
5, 2021, from 10 a.m. to 10 p.m., eastern daylight time. Should
additional dates and times be required, EPA will provide updates on our
website: www.epa.gov/safewater. If you are unable to attend any of the
events, you will be able to submit comments at http://www.regulations.gov: enter Docket ID No. EPA-HQ-OW-2021-0255 until June
30, 2021.
    EPA will host virtual community-focused roundtables starting in May
2021. Virtual roundtables with stakeholder groups including drinking
water utilities, environmental organizations, environmental justice
organizations, public health organizations, and consumer associations
will be held starting in June 2021. EPA also intends to host a national
co-regulator meeting in July 2021 to discuss the feedback received from
communities. Details and times for these engagements will be posted on
EPA's drinking water website at: www.epa.gov/safewater.

ADDRESSES: Individuals, including those that attend and provide oral
statements, are encouraged to send written statements, identified by
Docket ID EPA-HQ-OW-2021-0255, by the following method:
     Federal eRulemaking Portal: https://www.regulations.gov/
(our preferred method). Follow the online instructions for submitting
comments.
    Instructions: All submissions received must include the Docket ID
No. EPA-HQ-OW-2021-0255 for this EPA engagements. Comments received may
be posted without change to https://www.regulations.gov/, including any
personal information provided. For detailed instructions on sending
comments and additional information on the rulemaking process, see the
``Public Participation'' heading of the SUPPLEMENTARY INFORMATION
section of this document.

FOR FURTHER INFORMATION CONTACT: Christina Wadlington, USEPA, 1200
Pennsylvania Avenue NW, Washington, DC 20460; telephone number: 202-
566-1859; email address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Public Participation

    A. Written Comments--No.
    B. Submit your comments, identified by Docket ID EPA-HQ-OW-2021-
0255, at https://www.regulations.gov. Once submitted, comments cannot
be edited or removed from the docket. The EPA may publish any comment
received to its public docket. Do not submit electronically any
information you consider to be Confidential Business Information (CBI)
or other information whose disclosure is restricted by statute.
Multimedia submissions (audio, video, etc.) must be accompanied by a
written comment. The written comment is considered the official comment
and should include discussion of all points you wish to make. EPA will
generally not consider comments or comment contents located outside of
the primary submission (i.e., on the web, cloud, or other file sharing
system). For the full EPA public comment policy, information about CBI
or multimedia submissions, and general guidance on making effective
comments, please visit https://www.epa.gov/dockets/commenting-epa-dockets.
    C. Details about Participating in the Listening Session:
    The public is invited to speak during the April 28, 2021 or May 5,
2021 listening sessions. Those interested in speaking can sign up for a
3-minute time slot on EPA's website at https://www.epa.gov/safewater.
EPA will send an email to each speaker to confirm their speaking time
and date. EPA intends to make each session available for viewing to
those who are not participating but are interested in listening. EPA
will be posting additional event details on www.epa.gov/safewater, as
they become available.
    D. Details about Participating in the Community Roundtable:
    EPA intends to host community virtual roundtables during which
local organizations can participate in a discussion of LCRR related
topics and provide their unique perspective to EPA. These roundtables
will focus on communities that are disproportionately impacted by the
challenges of lead in drinking water. EPA requests that communities
that would like to be considered for a roundtable submit their
nomination letter to EPA via email to<EMAIL_ADDRESS>not later than April
23, 2021. Nomination letters should include the following information:
     Name of location,
     Primary point of contact and contact information,
     A description of how your community has been underserved
or experienced disproportionate impacts from drinking water lead
exposure, and
     A list of no more than 25 recommended community
participants and/or local organizations.
    EPA recommends that the list of participants/organizations that are
submitted be representative of all interests in their community
including, but not limited to, local government entities, public water
utilities, community-organized groups, environmental groups and elected
officials. EPA intends to make each roundtable available for viewing to
those who are not participating but are interested in listening. EPA
will be posting meeting materials and additional event details on
www.epa.gov/safewater, as they become available.
    E. Details about Participating in Stakeholder Roundtables:
    EPA intends to host stakeholder roundtables where representatives
of national organizations (e.g., environmental, industry, consumer,
intergovernmental) can participate in a discussion of LCRR related
topics and provide their perspective to the Agency. EPA requests that
organizations that would like to participate in a roundtable submit
their nomination letter to EPA via email to<EMAIL_ADDRESS>not later than
April 23, 2021. Nomination letters should include the following
information:
     Name of organization,
     Primary point of contact and contact information, and
     Why your organization should be considered as a
participant.

    EPA intends to make each roundtable available for viewing to those
who are not participating but are interested in listening. EPA will be
posting meeting materials and additional event details on www.epa.gov/safewater, as they become available.
    F. Details of National Co-Regulator Meeting:
    EPA will be reaching out directly to primacy agencies (e.g.,
states, tribes, territories) with a specific date, time, and details of
this meeting in the coming months. EPA will be posting meeting
materials and additional event details on www.epa.gov/safewater, as
they become available.

II. Revised LCR Extension

    On March 12, 2021, EPA announced that it is extending the effective
date of the Revised Lead and Copper Rule (LCRR) so that the agency can
seek further public input, particularly from communities that are most
at-risk of exposure to lead in drinking water. To accomplish this goal,
EPA published in the Federal Register two rules regarding the revised
LCR as follows: Final Rule delay of effective date (86 FR 14003, March
12, 2021); and Proposed Rule delay of effective and compliance dates
(86 FR 14063, March 12, 2021).
    The first is a final rule that announced an extension of the
effective date for the revised LCR from March 16, 2021 until June 17,
2021. The purpose of this initial extension of the effective date is to
enable EPA to take public comment on a second action that would provide
a longer extension of the effective date to allow EPA to undertake its
review of the rule in a deliberate and thorough manner, consistent with
the public health purposes of the Safe Drinking Water Act, President
Biden's Executive Order on Protecting Public Health and the Environment
and Restoring Science to Tackle the Climate Crisis, the President's
Chief of Staff's Regulatory Freeze Pending Review Memorandum, and in
consultation with affected stakeholders. The second action is a
proposed rulemaking to extend the effective date until December 16,
2021, and also proposes a corresponding extension of the revised LCR's
compliance deadline to September 16, 2024. This action would provide
time for EPA to complete its review and obtain additional stakeholder
input but would also ensure that drinking water systems and primacy
states continue to have adequate time as provided by the Safe Drinking
Water Act to take actions needed to assure regulatory compliance. The
request for public comment on these extensions, which closes on April
12, is separate from the stakeholder meetings EPA is announcing in this
action.

Yu-Ting Guilaran,
Acting Director, Office of Ground Water and Drinking Water.
[FR Doc. 2021-06926 Filed 4-2-21; 8:45 am]
BILLING CODE 6560-50-P


[Federal Register Volume 78, Number 52 (Monday, March 18, 2013)]
[Notices]
[Pages 16738-16740]
[FR Doc No: 2013-06157]

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

SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-69123; File No. SR-ISE-2013-21]

Self-Regulatory Organizations; International Securities Exchange,
LLC; Notice of Filing and Immediate Effectiveness of Proposed Rule
Change To Amend the Schedule of Fees To Reflect Regulatory Fees Related
To the Central Registration Depository

March 12, 2013.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(the ``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given
that on March 11, 2013, the International Securities Exchange, LLC (the
``Exchange'' or the ``ISE'') filed with the Securities and Exchange
Commission (``Commission'') the proposed rule change as described in
Items I and II below, which items have been prepared by the Exchange.
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.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend it Schedule of Fees with respect to
regulatory fees related to the Central Registration Depository (``Web
CRD''), which are collected by the Financial Industry Regulatory
Authority (``FINRA''). The text of the proposed rule change is
available on the Exchange's Web site www.ise.com, at the principal
office of the Exchange, and at the Commission's Public Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange 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. The self-regulatory organization has prepared summaries,
set forth in Sections A, B and C below, of the most significant aspects
of such statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    The Exchange proposes to amend its Schedule of Fees with respect to
regulatory fees related to Web CRD, which are collected by FINRA
(``FINRA Web CRD Fees'').\3\ The proposed fees, which the Exchange is
adopting for the first time on its Schedule of Fees, are collected and
retained by FINRA via Web CRD for the registration of employees of ISE
members that are not FINRA members (``Non-FINRA members''). The
Exchange is merely listing these fees on its Schedule of Fees. The
Exchange does not collect or retain these fees.
---------------------------------------------------------------------------

    \3\ FINRA operates Web CRD, the central licensing and
registration system for the U.S. securities industry. FINRA uses Web
CRD to maintain the qualification, employment and disciplinary
histories of registered associated persons of broker-dealers.
---------------------------------------------------------------------------

    The FINRA Web CRD Fees listed on ISE's Schedule of Fees consists of
General Registration Fees of $100 (for each initial Form U4 filed for
the registration of a representative or principal), $110 (for the
additional processing of each initial or amended Form U4, Form U5 or
Form BD that includes the initial reporting, amendment or certification
of one of more disclosure events or proceedings), and $45 (annual
system processing fee assessed only during renewals). The FINRA Web CRD
Fees listed on the ISE Schedule of Fees also consists of Fingerprint
Processing Fees for the initial, second and third submissions. There is
a separate fee for electronic submissions and paper submissions. The
initial electronic and paper submission fees are $29.50 and $44.50,
respectively. The second electronic and paper submission fees are
$15.00 and $30.00, respectively. The third electronic and paper
submission fees are $29.50 and $44.50, respectively. Finally, there is
a $30 processing fee for fingerprint results submitted by self-
regulatory organizations other than FINRA.
    The FINRA Web CRD Fees are user-based and there is no distinction
in the cost incurred by FINRA if the user is a FINRA member or a Non-
FINRA member. Accordingly, the proposed fees mirror those currently
assessed by FINRA.\4\
---------------------------------------------------------------------------

    \4\ See Securities Exchange Act Release No. 67247 (June 25,
2012), 77 FR 38866 (June 29, 2012) (SR-FINRA-2012-030) (``FINRA Fee
Filing'').
---------------------------------------------------------------------------

2. Statutory Basis
    The Exchange believes that its proposal to amend its Schedule of
Fees is consistent with Section 6(b) \5\ of the Act, in general, and
furthers the objectives of Sections 6(b)(4) \6\ and 6(b)(5) \7\ of the
Act, in particular, because it provides for the equitable allocation of
reasonable dues, fees and other charges among its members, issuers and
other persons using its facilities and does not unfairly discriminate
between customers, issuers, brokers or dealers.
---------------------------------------------------------------------------

    \5\ 15 U.S.C. 78f(b).
    \6\ 15 U.S.C. 78f(b)(4).
    \7\ 15 U.S.C. 78f(b)(5).
---------------------------------------------------------------------------

    The Exchange believes that the proposed rule change is reasonable
because the proposed fees are identical to those adopted by FINRA for
use of Web CRD for disclosure and the registration of FINRA members and
their associated persons. In the FINRA Fee Filing, FINRA noted that it
believed that its fees are reasonable based on the increased costs
associated with operating and maintaining Web CRD, and listed a number
of enhancements made to Web CRD in support of its fee change. These
costs are borne by FINRA when a Non-FINRA member uses Web CRD. FINRA
further noted its belief that the fees are reasonable because they help
to ensure the integrity of the information in Web CRD, which is very
important because the Commission, FINRA, other self-regulatory
organizations and state securities regulators use Web CRD to make
licensing and registration decisions, among other things.
    The Exchange notes that the proposed rule change is reasonable
because the amount of the fees are those provided by FINRA, and the
Exchange does not collect or retain these fees. The proposed rule
change is also equitable and not unfairly discriminatory because the
Exchange will not be collecting or retaining these fees, therefore will
not be in a position to apply them in an inequitable or unfairly
discriminatory manner.

B. Self-Regulatory Organization's Statement on Burden on Competition

    This proposed rule change does not impose any burden on competition
that is not necessary or appropriate in furtherance of the purposes of
the Act. The Exchange notes that the proposed rule change will result
in the same regulatory fees being charged to all members required to
report information to Web CRD and for services performed by FINRA,
regardless of whether or not such members are FINRA members.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants or Others

    The Exchange has not solicited, and does not intend to solicit,
comments on this proposed rule change. The Exchange has not received
any unsolicited written comments from members or other interested
parties.

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

    Because the foregoing proposed rule change does not: (i)
Significantly affect the protection of investors or the public
interest; (ii) impose any significant burden on competition; and (iii)
become operative for 30 days from the date on which it was filed, or
such shorter time as the Commission may designate, it has become
effective pursuant to Section 19(b)(3)(A) \8\ of the Act and Rule 19b-
4(f)(6) \9\ thereunder.
---------------------------------------------------------------------------

    \8\ 15 U.S.C. 78s(b)(3)(A).
    \9\ 17 CFR 240.19b-4(f)(6).
---------------------------------------------------------------------------

    The Exchange has requested the Commission to waive the 30-day
operative delay to allow the proposed rule change to become operative
upon filing.\10\ The Commission believes it is consistent with the
public interest to waive the 30-day operative delay. The proposed rule
change lists FINRA's fees on the Exchange's Schedule of Fees--the
Exchange will not collect or retain these fees. As such, the Commission
believes that the proposal presents no novel regulatory issues and will
make the fees more transparent to ISE members. Waiver of the operative
delay will allow the Exchange to list on its Schedule of Fees the fees
that FINRA charges for use of WebCRD without undue delay. Therefore,
the Commission grants such waiver and designates the proposal operative
upon filing.\11\
---------------------------------------------------------------------------

    \10\ As required under Rule 19b-4(f)(6)(iii), the Exchange
provided the Commission with written notice of its intent to file
the proposed rule change along with a brief description and the text
of the proposed rule change, at least five business days prior to
the date of filing of the proposed rule change, or such shorter time
as designated by the Commission.
    \11\ For purposes only of waiving the 30-day operative delay,
the Commission has considered the proposed rule's impact on
efficiency, competition, and capital formation. See 15 U.S.C.
78c(f).
---------------------------------------------------------------------------

    At any time within 60 days of the filing of the proposed rule
change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is necessary or
appropriate in the public interest, for the protection of investors, or
otherwise in furtherance of the purposes of the Act. If the

Commission takes such action, the Commission shall institute
proceedings to determine whether the proposed rule change should be
approved or 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 No. SR-ISE-2013-21 on the subject line.

Paper Comments

     Send paper comments in triplicate to Elizabeth M. Murphy,
Secretary, Securities and Exchange Commission, 100 F Street NE.,
Washington, DC 20549-1090.

All submissions should refer to File No. SR-ISE-2013-21. 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 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 such filing also will be available for inspection
and copying at the principal office of the Exchange. 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 No. SR-ISE-2013-21 and should be
submitted on or before April 8, 2013.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\12\
---------------------------------------------------------------------------

    \12\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

Kevin M. O'Neill,
Deputy Secretary.
[FR Doc. 2013-06157 Filed 3-15-13; 8:45 am]
BILLING CODE 8011-01-P