1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 HED DOC. NO. 014596 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES DATE: June 20, 2001 MEMORANDUM SUBJECT: DIURON: Report of the Hazard Identification Assessment Review Committee FROM: Yung G. Yang, Ph. D. Toxicology 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: Diana Locke, Ph. D. Risk Assessor, RRB2 Health Effects Division ( 7509C)

PC CODE: 035505 On May 29, 2001, the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) convened to review the toxicology data base of diuron for hazard identification and to select doses and endpoints for acute dietary, chronic dietary ( RfD) as well as occupational and residential exposure assessments and to address the sensitivity of infants and children from exposure to diuron as required by the Food Quality Protection Act ( FQPA) of 1996. The HIARC's conclusions are presented in this report. 2 Committee Members in Attendance Members in attendance: Ayaad Assaad, Jonathan Chen, Pamela Hurley, Jess Rowland ( Chair), David Nixon, Brenda Tarplee, and Yung Yang.

Members in absentia: William Burnam, Elizabeth Doyle, and Elizabeth Mendez.

Also, in attendance: Paula Deschamp, Diana Locke, Alberto Protzel, John Punzi, Renee Sandvig, and Ibrahim Abdel Saheb ( EFED)

Data evaluation / presentation: Yung G. Yang Toxicology Branch. Diuron 3 INTRODUCTION Diuron is a substituted urea herbicide for the control of a wide variety of annual and perennial broadleaves and grassy weeds on both crop and noncrop sites. Its main use is as a pre emergent, soil applied herbicide, but it can also be used to control emerged weeds. Diuron is available as a technical material, at 95 98% active ingredient or as a manufacturing use product containing 80% diuron for formulation of diuron end use formulations or as manufacturing use products. As a sole active ingredient, diuron is available in wettable powder, granular, flowables, pelleted/ tableted, liquid suspensions, and soluble concentrate formulations. The exposure duration is expected to be short term for residential uses and short and intermediate term for occupational uses.

Empirical formula: C9H10Cl 2N2O Molecular weight: 233.1 CAS Registry No.: 330 54 1 PC Code: 035505 NH N CH 3 CH3 O Cl Cl The toxicology data base of diuron has been evaluated by the Health Effects Division RfD Review Committee on September 26, 1996 and the Carcinogenicity Peer Review Committee on December 12, 1996. A Section 18 exemption for the use of diuron 80W in catfish ponds in Mississippi has been issued on May 13, 1999 after brief reviews by the HIARC on March 18, 1999 and FQPA Safety Factor Committee on March 22, 1999. Since then, the toxicology data base of diuron has been rereviewed and updated by the Toxicology Branch for a Reregistration Eligibility Decision ( RED).

On May 29, 2001 the HIARC reviewed the toxicology data base of diuron for hazard identification and to select doses and endpoints for acute dietary, chronic dietary ( RfD) as well as occupational and residential exposure assessments in support of a RED and to address the sensitivity of infants and children from exposure to diuron as required by the Food Quality Protection Act ( FQPA) of 1996. The HIARC's conclusions are as follows. Diuron 4 Acute RfD = N/ A 1. HAZARD IDENTIFICATION 1.1 Acute Reference Dose ( RfD)

Study Selected: None MRID No.: N/ A Executive Summary: N/ A Dose and Endpoint for Establishing RfD: N/ A Uncertainty Factor ( UF): N/ A Comments about Study/ Endpoint/ Uncertainty Factor: No appropriate effects attributed to a single exposure ( dose) was identified including in the rat or rabbit developmental toxicity study. It should be noted that at the 5/ 13/ 99 HIARC meeting for Section 18 Exemption, a NOAEL of 16 mg/ kg/ day from a rat developmental study with an uncertainty factor of 100 was selected for the acute reference dose based on decreased maternal body weight ( beginning at gestation day 9) and food consumption ( during gestation day 6 10) at 80 mg/ kg/ day ( LOAEL). This dose/ endpoint was selected to provide a conservative risk assessment for that action. However, at this meeting ( 5/ 29/ 01) the HIARC determined that it is unlikely that one dose will cause body weight decrease. In addition, there was no developmental or neurotoxic concern for diuron; therefore, no hazard was identified and quantitative risk assessment is not required.

1.2 Chronic Reference Dose ( RfD)

Study Selected: Chronic toxicity/ carcinogenicity study rats Guideline #: 870.4300 MRID No.: 40886501, 43871901,43804501,44302003 Executive Summary: In a chronic toxicity/ oncogenicity study ( MRID 40886501; supplementary data provided in MRIDs 43871901, 43804501, and 44302003), diuron ( 98.7% a. i.; batch no. 232114080) was administered to groups of 60 male and 60 female Wistar rats at dietary concentrations of 0, 25, 250, or 2500 ppm ( 0, 1.0, 10, or 111 mg/ kg/ day, respectively, for males Diuron 5 and 0, 1.7, 17, or 202 mg/ kg/ day for females, respectively) for up to 24 months. At 12 months, 10 animals/ sex/ group were sacrificed for interim evaluation.

Treatment with diuron did not affect the survival of rats. The only reported treatment related clinical sign was reddish discolored or bloody urine in high dose males. A significant decrease in body weight was seen in both sexes of high dose rats ( 12 15% for males; 6 14% for females, p< 0.01) throughout the study. Body weight gains were similarly depressed, the total gains for high dose males and females were 82 and 79% of controls, respectively. The slight decreases in body weights and weight gains of mid dose males ( 4 6%; p< 0.05 or 0.01) were not biologically significant. Food consumption was unaffected but overall food efficiency was lowered for high dose males and females ( 86% and 76% of controls, respectively).

Diuron affected hematopoietic system resulting in hemolytic anemia and compensatory hematopoiesis, which were manifested as significantly decreased ( p< 0.05 or 0.01) erythrocyte counts, hemoglobin levels, and hematocrit and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte counts ( with no effect on differential counts) in midand or high dose males and females, and in low dose females ( # 25% change for most parameters; 3 fold increase for reticulocytes). Hemolysis also led to increased ( 39 50%) plasma bilirubin in high dose males and females. Consistent with erythrocyte damage, postmortem gross examination showed a dose related increase ( 18 220%) in spleen weight ( absolute and relative to body) for all test groups at 12 and/ or 24 months, and an increased incidence of spleen dark discoloration and/ or swelling in mid and high dose males and females after 12 and/ or 24 months. Morphometric analysis of spleen sections to determine the percentage area of hemosiderin revealed an increase at $ 250 ppm in both sexes at 12 months and in all groups at 24 months ( p< 0.05 or 0.01), with the females being affected more severely. The chronic overburden of spleen function led to an increased incidence of spleen fibrosis in 2500 ppm males and females ( p< 0.01). Bone marrow activation occurred in both sexes at all test doses at 24 months ( p< 0.05 or 0.01 for all but low dose females). This was evident morphometrically as an increase in hematopoietic ( red) bone marrow for mid and high dose rats at 12 and/ or 24 months ( possibly in low dose males at 12 months) with a concomitant decrease in fat marrow at 12 months ( not evaluated at 24 months).

Gross pathology showed that the incidence of urinary bladder wall thickening was elevated at 24 months for low and high dose males and high dose females ( p< 0.05 or 0.01). Microscopic evaluation showed that epithelial focal hyperplasia of the urinary tract and renal pelvis increased in severity in both sexes at 12 and/ or 24 months, and increased in incidence ( p< 0.01) in high dose males at 12 months and in mid and high dose females at 12 and/ or 24 months. Some gross and/ or microscopic changes were also seen in the liver ( increased weight, swelling, discoloration, vacuolar cell degeneration, round cell infiltration, hyperemia) although Diuron 6 Chronic RfD = 1.0 ( LOAEL) mg/ kg/ day = 0.003 mg/ kg/ day 300 ( UF) these effects were not clearly primary effects of treatment.

Based on evidence of hemolytic anemia and compensatory hematopoiesis ( decreased erythrocyte count, increased reticulocyte counts, increased spleen weight and bone marrow activation), the LOAEL is 25 ppm for both sexes of rats ( 1.0 and 1.7 mg/ kg/ day for males and females, respectively). A NOAEL was not established.

This chronic toxicity / carcinogenicity study in rats is classified as Acceptable/ Guideline.

Dose and Endpoint for Establishing RfD: 1.0 mg/ kg/ day ( LOAEL) based on evidence of hemolytic anemia and compensatory hematopoiesis ( decreased erythrocyte count, increased reticulocyte counts, increased spleen weight and bone marrow activation). A NOAEL was not established.

Uncertainty Factor( s): 300 Comments about Study/ Endpoint/ Uncertainty Factor: An uncertainty factor ( UF) of 100 is applied to account for both interspecies extrapolation and intra species variability. An additional UF of 3 is applied for the use of a LOAEL.

1.3 Occupational/ Residential Exposure 1.3.1 Short Term ( 1 7 days) Incidental Oral Exposure Study Selected: Developmental toxicity study rabbits § 870.3700 MRID No.: 40228802 Executive Summary: In a developmental toxicity study ( MRID 40228802), 24 25 artificially inseminated New Zealand white rabbits per group were administered 0, 2, 10, or 50 mg/ kg/ day of Diuron ( 99% a. i.; Lot No. not given) by gavage on gestation days ( GD) 7 19, inclusive. On GD 29, all surviving does were sacrificed and examined Diuron 7 grossly.

One control animal died on GD 0 due to an anaphylactic shock reaction during insemination and one high dose doe aborted and was killed on GD 26. These deaths were considered unrelated to treatment. All remaining animals survived to scheduled termination. No treatment related clinical signs of toxicity were observed in any animal. Maternal liver weights were comparable between the treated and control groups and gross necropsy was unremarkable.

Maternal body weights, body weight gains, and food consumption for the low and mid dose groups were similar to the control levels throughout the study. Absolute body weights of the high dose does were significantly ( p # 0.01) less than the controls on GD 20. Mean body weight gains by the high dose group were significantly ( p # 0.05 or 0.01) reduced as compared with the controls during the intervals of GD 10 13, 13 16, and 7 20 ( weight loss). Weight gain by the high dose group was significantly ( p # 0.05 or 0.01) greater than the controls during the post dosing interval. Food consumption by the high dose group was significantly ( p # 0.01) less than the controls during the GD 13 16, 16 20 and 7 20 intervals.

The maternal toxicity LOAEL is established at 50 mg/ kg/ day based on decreased body weights and food consumption during the dosing interval. The maternal toxicity NOAEL is established at 10 mg/ kg/ day.

At cesarean section, the pregnancy rates, numbers of corpora lutea, implantation sites, resorptions, and live fetuses, and fetal body weights were similar between the treated and control groups. No dose or treatment related external, visceral, or skeletal malformations/ variations were observed in any fetus.

The developmental toxicity NOAEL is $ 50 mg/ kg/ day and the developmental toxicity LOAEL is not identified.

This study is classified as Acceptable and satisfy the guideline requirements for a developmental toxicity study [ OPPTS 870.3700 ( 83 3b)] in rabbits.

Dose and Endpoint for Risk Assessment: 10 mg/ kg/ day ( NOAEL) based on maternal toxicity ( decreased body weights and food consumption during the dosing interval) at 50 mg/ kg/ day ( LOAEL).

Comments about Study/ Endpoint: This study was previously classified as Diuron 8 unacceptable/ upgradable based on deficiencies in analytical data of sample analysis. However, the HIARC determined that this study is acceptable because the low nominal level of sample concentration was observed at the low dose only and the NOAEL was established at the mid dose with the LOAEL at the high dose. Therefore, the deficiencies in the analytical data did not affect the results of the study. The systemic toxicity ( expressed as maternal toxicity) is relevant for the populations ( infants and children) and duration ( 1 7 days) of concern.

1.3.2 Intermediate Term ( 7 Days to Several Months) Incidental Oral Exposure Study Selected: Chronic toxicity/ carcinogenicity study rats § MRID No.: 40886501, 43871901, 43804501, 44302003 Executive Summary: See Chronic RfD.

Dose and Endpoint for Risk Assessment: A NOAEL of 1.0 mg/ kg/ day based on hematological effects observed at 10 mg/ kg/ day ( LOAEL) at the 6th month observations.

Comments about Study/ Endpoint: The HIARC established a NOAEL of 1.0 mg/ kg/ day for this time period based on hematological effects observed at 10 mg/ kg/ day at the 6th month observation. It is noted that this NOAEL/ LOAEL is different from the 24th month observation where the NOAEL is not established ( LOAEL= 1.0 mg/ kg/ day). The endpoint observed at the 6th month observation period is appropriate for this exposure scenario and is relevant for the population of concern.

1.3.3 Dermal Absorption No dermal absorption study is available.

Dermal Absorption Factor: An upper bound estimation of dermal absorption factor of 4% is extrapolated using the maternal LOAEL of 50 mg/ kg/ day from the developmental study in the rabbit and the NOAEL of 1200 mg/ kg/ day ( HDT) from the 21 day dermal toxicity study in the rabbit: the ratio is 50/ 1200 or 4%.

1.3.4 Short Term Dermal ( 1 7 days) Exposure Diuron 9 Study Selected: None MRID No.: N/ A Executive Summary: N/ A Dose and Endpoint for Risk Assessment: N/ A Comments about Study/ Endpoint:. No systemic toxicity following repeated dermal dosing at 1200 mg/ kg/ day was seen in the rabbit dermal toxicity study. Also, there is no developmental concern. No hazard was identified and no quantitative assessment is required.

1.3.5 Intermediate Term Dermal ( 7 Days to Several Months) Exposure Study Selected: None MRID No.: N/ A Executive Summary: N/ A Dose/ Endpoint for Risk Assessment: N/ A Comments about Study/ Endpoint: No systemic toxicity following repeated dermal dosing at 1200 mg/ kg/ day was seen in the rabbit dermal toxicity study. Also, there is no developmental concern. No hazard was identified and no quantitative assessment is required.

1.3.6 Long Term Dermal ( Several Months to Life Time) Exposure Study Selected: Chronic toxicity/ carcinogenicity study rats MRID No.: 40886501, 43871901, 43804501, 44302003 Executive Summary: See chronic RfD.

Dose and Endpoint for Risk Assessment: 1.0 mg/ kg/ day ( LOAEL) based on evidence of hemolytic anemia and compensatory hematopoiesis ( decreased erythrocyte count, Diuron 10 increased reticulocyte counts, increased spleen weight and bone marrow activation). A NOAEL was not established.

Comments about Study/ Endpoint: An additional UF of 3 is applied to account for the lack of a NOAEL in this study. A MOE of 300 is required for this risk assessment with a dermal absorption factor of 4%.

1.3.7 Inhalation Exposure Except for an acute inhalation study, for which diuron was placed in Toxicity Category IV ( LC 50> 7.1 mg/ L), no other studies are available via this route. Therefore, the HIARC selected the NOAELs from oral studies for risk assessment. Since the doses identified for inhalation risk assessment are from oral studies, route to route extrapolation should be as follows:

The inhalation exposure component ( i. e., F g a. i./ day) using a 100% ( default) absorption rate and application rate should be converted to an equivalent oral dose ( mg/ kg/ day).

Then, the oral equivalent doses should be compared to the following NOAELs/ LOAEL to calculate the MOEs.

Short term NOAEL= 10 mg/ kg/ day ( developmental rabbit study) Intermediated term NOAEL= 1.0 mg/ kg/ day ( chronic rat study at 6 month) Long term LOAEL= 1.0 mg/ kg/ day ( chronic rat study)

1.3.8 Margins of Exposure for Occupational/ Residential Risk Assessments A MOE of 100 is adequate for short and intermediate term occupational inhalation exposure. However, a MOE of 300 is required for long term occupational dermal and inhalation exposure due to the use of LOAEL. The acceptable MOEs for residential exposure will be determined by the FQPA SF committee.

1.4 Recommendation for Aggregate Exposure Risk Assessments A toxicological endpoint was not identified for acute dietary risk assessment; therefore, the acute aggregate is not required.

A common toxicological endpoint ( decreased body weight and food consumption) was Diuron 11 selected for assessment of short term exposure by oral and inhalation routes. These routes can be aggregated for this scenario.

A common toxicological endpoint ( altered hematological parameters) was selected for intermediated term exposure by oral and inhalation routes. These routes can be aggregated for this scenario.

A common toxicological endpoint ( evidence of hemolytic anemia and compensatory hematopoiesis) was selected for long term exposure by oral, dermal, and inhalation routes. These routes can be aggregated for this scenario.

2 CLASSIFICATION OF CARCINOGENIC POTENTIAL 2.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No. 40886501, 43871901, 43804501, 44302003 Discussion of Tumor Data: This study showed conclusive evidence for the carcinogenicity of diuron in male and female rats. The incidence of urinary bladder carcinoma was increased at 2500 ppm in both sexes ( males: 33/ 49 vs. 1/ 50 for controls; females: 11/ 50 vs. 0/ 48 for controls; p< 0.01). The malignancies were usually characterized as transitional epithelial carcinomas. The slight increase ( NS) in the incidence of urinary bladder papilloma and the 3 neoplasms in the renal pelvis in high dose males ( one papilloma and two carcinomas) were also considered treatment related.

Adequacy of the Dose Levels Tested: Dosing was adequate based on numerous toxic effects ( hematological, microscopic, etc.) observed in the animals at all tested doses.

2.2 Carcinogenicity Study in Mice MRID No. : 42159501, 43349301 Discussion of Tumor Data: Treatment of up to 102 weeks with 2500 ppm diuron resulted in a significant increase in the incidences of mammary adenocarcinomas ( control, 4%; 2500 ppm, 12%, p # 0.05) and ovarian luteomas ( control, 6%; 2500 ppm, 14%, p # 0.01) in female NMRI ( SPF HAN) mice under the conditions of this study. However, the incidence of mammary adenocarcinoma in high dose females was at or near the high range of incidences seen in historic controls. Diuron 12 Adequacy of the Dose Levels Tested: Dosing was adequate based on observations at the highest dose tested including decreased body weight of both sexes, increased spleen and liver weights in males and increased incidence of urinary bladder edema and epithelial hyperplasia, thickened mucosa and enlarged uterine horn in females.

2.3 Classification of Carcinogenic Potential The HED Carcinogenicity Peer Review Committee ( CPRC) met on December 18, 1996 and classified diuron as a " known/ likely" human carcinogen by all routes, based on urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse. The CPRC also recommended a low dose linear extrapolation model with Q1 * ( mg/ kg/ day) 1 of 1.91x10 2 be applied to the animal data for the quantification of human risk, based on the urinary bladder carcinomas in the rat. The HIARC acknowledged that this classification may be re evaluated by the CARC pending Registrant's submissions of mechanistic study for cancer.

3 MUTAGENICITY Five acceptable genetic toxicology studies with Diuron have been submitted to the Agency. Findings from these studies indicated the following:

GENE MUTATIONS 1) Salmonella typhimurium reverse gene mutation assay ( MRID No. 00146608/ 40228805): Independent trials were negative in S. typhimurium strains TA1535, TA97, TA98 and TA100 up to the highest does tested ( 10 µ g/ plate  S9; 250 µ g/ plate + S9); higher concentrations ( $ 50 µ g/ plate  S9; 500 µ g/ plate + S9) were cytotoxic. The assay is Acceptable and satisfies the guideline requirement for gene mutation in microbial test systems.

2) Chinese Hamster Ovary ( CHO)/ HGPRT cell forward gene mutation assay ( MRID No. 00146609): Independent tests were negative up to cytotoxic doses without S9 activation ( 1.250 mM, . 291 µ g/ mL) and with S9 activation ( 0.5 mM , . 117 µ g/ mL). The assay is Acceptable and satisfies the guideline requirement for gene mutation in cultured mammalian cells.

CHROMOSOME ABERRATIONS Diuron 13 3) In vivo bone marrow cytogenetic assay ( MRID No. 00146611): The test was weakly positive in male Sprague Dawley rats administered 0, 50, 500 or 5000 mg/ kg/ day by single oral gavage. Signs of overt toxicity ( mortality, body weight loss, ocular discharge, depression, labored respiration, diarrhea, and tremors) and cytotoxicity to the target organ ( significantly decreased mitotic index) were seen at 5000 mg/ kg in conjunction with a significant ( p< 0.05) increase in the percentage of abnormal cells when the data for both sexes were combined ( 0.11 versus 0.00 in controls). A significant positive linear trend ( p< 0.01) was also recorded for the percentage abnormal cells combined. A total of 4/ 10 animals in the high dose group were affected: single chromatid breaks were seen in two males and one female and a chromatid fragment was seen in one male. This study is classified as Acceptable and satisfies the guideline requirement for in vivo cytogenetic mutagenicity data.

4) In vivo bone marrow cytogenetic assay ( MRID No. 44350301): The test was negative in male Sprague Dawley rats administered 0, 50, 500 or 5000 mg/ kg/ day by single oral gavage. Signs of overt toxicity ( mortality, body weight loss, ocular discharge, depression, labored respiration, diarrhea, and tremors) were noted at 5000 mg/ kg. Cytotoxicity to the target organ as indicated by the significantly decreased ( p # 0.01) mitotic indices at 24 and 48 hours for high dose males; data combined for both sexes were also significantly decreased at 24 hours. A significant ( p< 0.05) increase in the percentage of abnormal cells and the average number of aberrations per cell was seen but only when the data were combined for the high and mid dose males and females at the 48 hour sampling time. Values were 0.6 and 0.9 % ( combined percentage abnormal cells) at 500 and 5000 mg/ kg, respectively and 0.008 and 0.009 ( combined number of aberrations/ cell) at 500 and 5000 mg/ kg, respectively. A significant positive linear trend was also recorded for the combined ( by sex) aberrations per cell and percentage abnormal cells. Nevertheless, the values fell well within the range of historical control [ percent abnormal cells/ group: 0 2.6% ( % ) and 0 2.0% ( & ) ; average number of aberrations/ cell: 0 0.023% ( % ) and 0 0.060 % ( & ) ]. This study is classified as Acceptable and satisfies the guideline requirement for in vivo cytogenetic mutagenicity data.

OTHER MUTAGENIC MECHANISMS 4) Unscheduled DNA synthesis ( UDS) in primary rat hepatocytes assay ( MRID No. 00146610): The test was negative up to cytotoxic doses ( $ 0.33 mM, equivalent to . 76 F g/ mL). The assay is Acceptable and satisfies the guideline requirement for a UDS assay.

Conclusions: Diuron was not mutagenic in bacteria or in cultured mammalian cells and no indication of DNA damage in primary rat hepatocytes was observed. There was weak evidence of an in vivo clastogenic response in Sprague Dawley rats in one study and statistically significant increases in cells with structural aberrations in a second study conducted with the same rat strain. The data from the latter study, however, were shown to fall within the historical control range. Diuron 14 4 FQPA CONSIDERATIONS 4.1 Adequacy of the Data Base The data base is adequate for FQPA assessment.

 Acute delayed neurotoxicity study in hen: Not required.  Acute and subchronic neurotoxicity studies: Not available.  Developmental toxicity studies in Rats: Study was Unacceptable.  Developmental toxicity studies in Rabbits: Acceptable study available.  Two Generation Reproduction Study in rats: Acceptable study available.  Developmental neurotoxicity study: Not available.

4.2 Neurotoxicity No acute or subchronic neurotoxicity study is available. There are no neurotoxic signs in any of the subchronic or chronic studies. Literature search did not reveal studies relevant for assessing the potential neurotoxicity.

4.3 Developmental Toxicity Developmental toxicity study in rabbits See short term incidental oral exposure.

Developmental toxicity study in rats In a developmental toxicity study ( MRID 40228801), 25 presumed pregnant Crl: COBS ® CD ® ( SD) BR rats per group were administered H 16035 ( 99%; Lot No. not given) by gavage in 0.5% aqueous hydroxypropyl methylcellulose at doses of 0, 16, 80, or 400 mg/ kg/ day on gestation days ( GD) 6 15, inclusive. On GD 20, dams were sacrificed, subjected to gross necropsy, and all fetuses were examined externally. Approximately one half of all fetuses were examined viscerally by the Staples technique; these fetuses were decapitated, and the heads fixed in Bouin's solution for subsequent free hand sectioning. The remaining one half of the fetuses were eviscerated and all carcasses were processed for Diuron 15 skeletal examination.

All dams survived to terminal sacrifice. One high dose animal appeared thin on GD 13 18 as a result of marked weight loss. No other treatment related clinical signs of toxicity were observed in any group. Body weights, body weight gains, and food consumption by the lowdose group were similar to the controls throughout the study. No treatment related lesions were observed in any dam at necropsy.

Absolute body weights of the mid and high dose groups were significantly ( p # 0.01) less than the controls during the dosing interval and ranged from 92 94% and 84 88%, respectively, of the control levels. Body weight gains by the mid and high dose dams were significantly ( p # 0.05 or 0.01) less than that of the controls during the dosing period with the exception of GD 12 16. The most pronounced effect on body weight gain occurred immediately after the initiation of dosing ( GD 6 9) when the mid and high dose groups had a net weight loss compared to a gain by the controls. The high dose group also had a weight loss for GD 9 12. Weight change during the entire dosing interval was 37% of the control level for the mid dose group and a weight loss of 12.2 g by the high dose group. Food consumption by the mid and high dose groups was significantly ( 73 and 47%, respectively, of controls; p # 0.01) less than the controls during the dosing interval. Weight gain and food consumption by the mid and high dose dams during the post dosing period was significantly ( p # 0.01) greater than the controls.

The maternal toxicity LOAEL is established at 80 mg/ kg/ day based on decreased body weights, body weight gains, and food consumption. The maternal toxicity NOAEL is 16 mg/ kg/ day.

No differences were observed between the treated and control groups for pregnancy rate, number of corpora lutea, number of implantation sites, number of fetuses/ litter, or fetal sex ratios. No dead fetuses or late resorptions were observed. Two high dose dams had total litter resorption and the number of early resorptions/ dam in the high dose group ( 3.2) was slightly greater than that of the controls ( 1.2). Mean fetal body weight in the high dose group was significantly ( p # 0.01; 91% of controls) less than that of the controls.

In the 0, 16, 80, and 400 mg/ kg/ day groups, the total number of fetuses( litters) examined for external and skeletal malformations/ variations was 288( 22), 305( 23), 297( 22), and 279( 20), respectively, and for visceral malformations/ variations was 138( 22), 149( 23), 144( 22), and 134( 20), respectively. No treatment related external or visceral malformations/ variations were observed in any group. Diuron 16 Delayed ossification of the vertebrae and sternebrae was observed in fetuses of the high dose group. In the 0, 16, 80, and 400 mg/ kg/ day groups the incidence rates for litters containing fetuses with bifid thoracic vertebral centra was 1/ 22, 1/ 23, 2/ 22, and 7/ 20 ( p # 0.05), respectively. Incomplete ossification of the sternebrae was observed in fetuses from 3/ 22, 3/ 23, 1/ 22, and 9/ 20 ( p # 0.05), litters respectively. Unossified thoracic vertebral centra was observed in fetuses from 3/ 20 ( p # 0.05) high dose litters but not in fetuses from the other treated or control groups.

The developmental toxicity LOAEL is established at 400 mg/ kg/ day based on whole litter resorption, reduced fetal body weights, and delayed ossification of the vertebrae and sternebrae. The developmental toxicity NOAEL is 80 mg/ kg/ day.

This study is classified as Unacceptable and does not satisfy the requirements for a developmental toxicity study [ 870.3700 ( § 83 3a)] in rats. Test article concentrations in the mid and high dose solutions were highly variable and well outside of acceptable ranges. Based upon available analytical data, it appears that target doses may not have been representative of the actual doses to the animals. In addition, the lot number and corresponding analyses were not provided. It is unlikely that this study may be upgraded.

However, the HIARC determined that this study is adequate for the assessment of susceptibility in rats. This decision was made based on the fact that maternal toxicity was seen at a lower dose ( 80 mg/ kg/ day) compared to developmental toxicity ( 400 mg/ kg/ day). At 400 mg/ kg/ say, developmental effects ( increased incidence of early resorption and decreased fetal body weight) were seen in the presence of maternal toxicity ( significantly decreased body weight gain and food consumption). The HIARC also determined that a repeat of this study is not required since the effects of the range finding study showed maternal toxicity ( decreased body weight gain and food consumption) at 100, 200, and 400 mg/ kg/ day and developmental toxicity ( increased incidence of early resorption and decreased fetal body weight) at 400 mg/ kg/ day. Also, the rabbit was shown to be the more susceptible species for developmental toxicity study. A repeat rat study would not provide additional data for risk assessment/ risk characterization.

4.4 Reproductive Toxicity In a two generation reproduction study Diuron ( 97.1% a. i., Lot No. 8805540) was administered to groups of 30 male and 30 female Crl: CD ® BR rats in the diet at concentrations of 0, 10, 250, or 1750 ppm ( MRID 41957301). One litter was produced by each generation. Test substance intake for the treated F0 groups was 0.58, 14.8, and 101 mg/ kg/ day, respectively, for males and 0.71, 18.5, and 131 mg/ kg/ day, respectively, for females. Test substance intake for the treated F1 groups was 0.77, 18.9, and 139 mg/ kg/ day, respectively, Diuron 17 for males and 0.8, 22.1, and 157 mg/ kg/ day, respectively, for females. F0 and F1 parental animals were administered test or control diet for 73 or 105 days, respectively, prior to mating and throughout mating, gestation, and lactation, and until necropsy.

Deaths or premature sacrifices of several F0 and F1 parental animals were considered incidental to treatment. No treatment related clinical signs of toxicity were observed in the adult animals of either generation. Gross necropsy was unremarkable and testes weights were not affected by treatment.

For the low and mid dose groups of both generations, occasional significant differences from the control group for body weights, body weight gains, food consumption, and food efficiencies were considered incidental to treatment.

Body weights of the high dose F0 males and females were significantly ( p # 0.05) decreased by an average of 7% beginning on day 7. Body weight gains by the high dose F0 males were significantly ( p # 0.05) less than the control group on days 0 14, 21 28, 42 49, 77 84, and 91 98. Premating, post mating, and overall ( entire study) body weight gains by the F0 males were significantly ( p # 0.05) decreased by 16%, 28%, and 18%, respectively, compared with the controls. Body weight gains by the high dose F0 females were significantly ( p # 0.05) less than the control group on days 0 14 and 21 28 with overall premating body weight gains significantly ( p # 0.05) decreased by 28% compared with the controls. Significant ( p # 0.05) reductions in food consumption were observed in the high dose F0 males and females on days 0 14, 21 28, 35 49 ( females), 42 56 ( males), and 0 70. Food efficiencies for the F0 males and females were significantly ( p # 0.05) reduced at similar intervals to food consumption with overall premating food efficiency reduced by 8.3% and 22.7%, respectively.

Body weights of the high dose F1 males and females were significantly ( p # 0.05) decreased by an average of 16% beginning on day 0 of premating. Body weight gains by the high dose F1 males were significantly ( p # 0.05) less than the control group on days 0 28, 42 49, 63 70, 91 98, and 147 154. Premating, post mating, and overall ( entire study) body weight gains by the F1 males were significantly ( p # 0.05) decreased by 15%, 41%, and 17%, respectively, compared with the controls. Body weight gains by the high dose F1 females were significantly ( p # 0.05) less than the control group on days 0 14 with overall premating body weight gains significantly ( p # 0.05) decreased by 14% compared with the controls. Significant ( p # 0.05) reductions in food consumption were observed in the high dose F0 males and females throughout premating with the exception of days 77 84 for males. Food efficiencies were significantly ( p # 0.05) reduced for the high dose F1 males on days 91 98 and for the high dose F1 females on days 0 7, 21 28, and 0 70. Diuron 18 The systemic toxicity LOAEL is 1750 ppm ( approximately 132 mg/ kg/ day) based on reduced body weight, body weight gain, food consumption, and food efficiency during both generations. The systemic toxicity NOAEL is 250 ppm ( approximately 18.6 mg/ kg/ day).

For the F0 and F1 females, reduced body weights and food consumption during gestation were considered a continuation of premating effects.

No treatment related effects were noted in either generation on fertility indices, gestation length, pup survival, pup clinical observations, and pup anomalies. Pup body weights for sexes combined or separate were significantly ( p # 0.05) reduced in high dose litters as compared with the controls throughout lactation for the F1 pups and beginning on lactation day 7 for the F2 pups.

The offspring toxicity LOAEL is 1750 ppm ( approximately 132 mg/ kg/ day) based on decreased body weights of the F1 and F2 pups during lactation. The offspring toxicity NOAEL is 250 ppm ( 18.6 mg/ kg/ day).

The reproductive toxicity NOAEL is 1750 ppm ( HDT).

This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a reproductive toxicity study [ OPPTS 870.3800 ( § 83 4)] in rats.

4.5 Additional Information from Literature Sources Literature searches have been conducted and no additional neurotoxicity, developmental or reproductive toxicity was found.

4.6 Determination of Susceptibility Base on the developmental and reproductive toxicity studies, there was no evidence ( qualitative or quantitative) for increased susceptibility following in utero and/ or pre/ post natal exposure.

4.7 Recommendation for a Developmental Neurotoxicity Study There are no evidence that suggest requiring a developmental neurotoxicity study. The Diuron 19 developmental toxicity studies in rats and rabbits as well as the reproductive toxicity study in rats did not show any adverse effects below maternal or parental doses.

5 HAZARD CHARACTERIZATION Diuron is a substituted urea herbicide for the control of a wide variety of annual and perennial broadleaved and grassy weeds on both crop and noncrop sites. The mechanism of action is the inhibition of photosynthesis. Diuron has a low acute toxicity ( Tox. Cat. 3 or 4) by oral, dermal, or inhalation route exposure. Diuron is not an eye or skin irritant and not a skin sensitizer. A rat metabolism study indicated that diuron is rapidly absorbed and metabolized within 24 hours post dose at low dose and within 48 hours post dose at high dose. The urine is the major route of excretion in both sexes. A small amount of diuron is detected in the feces. The highest tissue residue levels were found in the liver and kidneys 4 days post 14C diuron dose. Metabolism of diuron involved N oxidation, ring hydroxylation, demethylation, dechlorination, and conjugation to sulfate and glucuronic acid.

The primary diuron target organs are hematopoietic system and bladder ( and renal pelvis). Erythrocyte damage resulted in hemolytic anemia and compensatory hematopoiesis, which are manifested as significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit, and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte count. Consistent observations of erythocytic regeneration are seen in chronic toxicity studies in rats, mice and dogs. Gross pathology findings in chronic rat and mouse studies showed increased incidences of urinary bladder edema and wall thickening at high doses. Microscopic evaluation showed dose related increases in the severity of epithelial focal hyperplasia of the urinary bladder and renal pelvis in both sexes.

Although the developmental toxicity studies in rats is classified unacceptable, the data base on diuron are adequate for pre and post natal toxicity evaluation and did not reveal developmental or reproductive toxicity. The NOAELs for maternal/ parental toxicity were either less than or equal to the NOAELs for fetal or reproductive toxicity The HED Carcinogenicity Peer Review Committee ( CPRC) characterized diuron as a " known/ likely" human carcinogen by all routes, based on urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse. The CPRC also recommended a low dose linear extrapolation model with Q1 * ( mg/ kg/ day) 1 of 1.91x10 2 be applied to the animal data for the quantification of human risk, based on the urinary bladder carcinomas in the rat. Diuron 20 6 DATA GAPS The HIARC determined that a 28 day inhalation study is required to address the concern for inhalation exposure potential based on the use pattern. The Registrant can follow the 90 day inhalation study protocol but cease exposure at 28 days. The HIARC also determined that a repeated chronic dog study is not required because a new study would not provide additional data since the observed effects are similar in the rat and the rat is the more sensitive species for this chemical. Diuron 21 7 ACUTE TOXICITY Acute Toxicity of Diuron Guideline No. Study Type MRIDs # Results Toxicity Category 81 1 Acute Oral 00146144 LD50 = 4721 mg/ kg ( M) > 5000 mg/ kg ( F) III 81 2 Acute Dermal 00146146 LD50 > 2000 mg/ kg III 81 3 Acute Inhalation 40228803 LC50 > 7.1 mg/ L IV 81 4 Primary Eye Irritation 00146147 At 48 hrs, all irritation had cleared. III 81 5 Primary Skin Irritation 00146148 All irritation had cleared by 72 hrs. IV 81 6 Dermal Sensitization 00146149 Nonsensitizer N/ A 81 8 Acute Neurotoxicity N/ A Not available N/ A Diuron 22 8. SUMMARY OF TOXICOLOGY ENDPOINT SELECTION The doses and toxicological endpoints selected for various exposure scenarios are summarized below.

EXPOSURE SCENARIO DOSE ( mg/ kg/ day) ENDPOINT STUDY Acute Dietary There is no appropriate endpoint attributed to a single dose was identified. Therefore, an acute RfD was not established.

Chronic Dietary LOAEL = 1.0 UF = 300 Evidence of hemolytic anemia and compensatory hematopoiesis. Chronic toxicity/ carcinogenicity study in rats Chronic RfD = 0.003 mg/ kg/ day Cancer Known/ likely human carcinogen Q1* = 1.91 x 10 2 Urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse Carcinogenicity study in rats and mice Incidental Oral, short Term NOAEL= 10 Decreased body weight and food consumption Developmental toxicity study in rabbits Incidental Oral, Intermediate Term NOAEL = 1.0 Altered hematological parameters observed at 6 months. Chronic toxicity/ carcinogenicity study in rats Dermal, Short Intermediate Term No systemic toxicity following repeated dermal dosing at 1200 mg/ kg/ day was seen in the dermal toxicity study. Also, there is no developmental concern. No hazard was identified and no quantitative assessment is required.

Dermal, Long Terma LOAEL = 1.0 Evidence of hemolytic anemia and compensatory hematopoiesis. Chronic toxicity/ carcinogenicity study in rats Inhalation, Short Termb NOAEL = 10 Decreased body weight and food consumption Developmental toxicity study in rabbits Inhalation, Intermediate Termb NOAEL = 1.0 Altered hematological parameters observed at 6 months. Chronic toxicity/ carcinogenicity study in rats Inhalation, Long Termb LOAEL = 1.0 Evidence of hemolytic anemia and compensatory hematopoiesis. Chronic toxicity/ carcinogenicity study in rats a An oral endpoint was used for dermal exposure: dermal absorption factor of 4% of oral exposure shall be used. b An oral endpoint was used for inhalation exposure: inhalation exposure assumed equivalent to oral exposure.


[Federal Register Volume 85, Number 170 (Tuesday, September 1, 2020)]
[Notices]
[Page 54475]
[FR Doc No: 2020-19187]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

[Docket No 2020-0260]

Agency Information Collection Activities: Requests for Comments;
Clearance of a Renewed Approval of Information Collection: Verification
of Authenticity of Foreign License, Rating, and Medical Certification

AGENCY: Federal Aviation Administration (FAA), Transportation (DOT).

ACTION: Notice and request for comments.

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

SUMMARY: In accordance with the Paperwork Reduction Act of 1995, FAA
invites public comments about our intention to request the Office of
Management and Budget (OMB) approval to renew an information
collection. The Federal Register Notice with a 60-day comment period
soliciting comments on the following collection of information was
published on 04/15/2020. The information is used to identify foreign
airmen in order to allow the agency to verify their foreign license
when used to qualify for a US certificate. Respondents are holders of
foreign licenses wishing to obtain US Certificates.

DATES: Written comments should be submitted by October 1, 2020.

ADDRESSES: Interested persons are invited to submit written comments on
the proposed information collection to the Office of Information and
Regulatory Affairs, Office of Management and Budget. Comments should be
addressed to the attention of the Desk Officer, Department of
Transportation/FAA, and sent via electronic mail to
<EMAIL_ADDRESS>or faxed to<PHONE_NUMBER>, or mailed to
the Office of Information and Regulatory Affairs, Office of Management
and Budget, Docket Library, Room 10102, 725 17th Street NW, Washington,
DC 20503.

FOR FURTHER INFORMATION CONTACT: Margaret A Hawkins by email at:
<EMAIL_ADDRESS>phone:<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:
    Public Comments Invited: You are asked to comment on any aspect of
this information collection, including (a) Whether the proposed
collection of information is necessary for FAA's performance; (b) the
accuracy of the estimated burden; (c) ways for FAA to enhance the
quality, utility and clarity of the information collection; and (d)
ways that the burden could be minimized without reducing the quality of
the collected information. The agency will summarize and/or include
your comments in the request for OMB's clearance of this information
collection.
    OMB Control Number: 2120-0724.
    Title: Verification of Foreign License, Rating and Medical
Certification.
    Form Numbers: Form 8060-71.
    Type of Review: Renewal of an information collection.
    Background: The Federal Register Notice with a 60-day comment
period soliciting comments on the following collection of information
was published on 04/15/2020 (85 FR 21061). The information collected is
used to properly identify airmen to allow the agency to verify their
foreign license being used to qualify for a U.S. certificate. The
respondents are holders of foreign license wishing to obtain a U.S.
certificate. A person who is applying for a U.S. pilot certificate or
rating on the basis of a foreign pilot license must apply for
verification of that license at least 90 days before arriving at the
designated FAA FSDO where the applicant intends to receive the U.S.
pilot certificate.
    Respondents: Approximately 8,700 foreign applicants for U.S.
certificates annually.
    Frequency: On occasion.
    Estimated Average Burden per Response: 10 Minutes.
    Estimated Total Annual Burden: 1450 Hours.

Margaret A Hawkins,
Compliance Specialist, Forms Manager, Airmen Certification Branch, AFB-
720.
[FR Doc. 2020-19187 Filed 8-31-20; 8:45 am]
BILLING CODE 4910-13-P


[Federal Register Volume 80, Number 158 (Monday, August 17, 2015)]
[Notices]
[Pages 49297-49298]
[FR Doc No: 2015-20146]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

Government/Industry Aeronautical Charting Forum Meeting

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of public meeting.

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SUMMARY: This notice announces the bi-annual meeting of the Federal
Aviation Administration (FAA) Aeronautical Charting Forum (ACF) to
discuss informational content and design of aeronautical charts and
related products, as well as instrument flight procedures development
policy and design criteria.

DATES: The ACF is separated into two distinct groups. The Instrument
Procedures Group (IPG) will meet October 27, 2015 from 8:30 a.m. to
5:00 p.m. The Charting Group will meet October 28 and 29, 2015 from
8:30 a.m. to 5:00 p.m.

ADDRESSES: The meeting will be held at the United States Geological
Survey (USGS) Headquarters at 12201 Sunrise Valley Drive, Reston, VA
20192.

FOR FURTHER INFORMATION CONTACT: For information relating to the
Instrument Procedures Group, contact Thomas E. Schneider, FAA, Flight
Procedures Standards Branch, AFS-420, 6500 South MacArthur Blvd., P.O.
Box 25082, Oklahoma City, OK 73125; telephone:<PHONE_NUMBER>.
    For information relating to the Charting Group, contact Valerie S.

Watson, FAA, Aeronautical Information Services, Governance & Standards,
AJV-553, 1305 East-West Highway, SSMC4, Station 3409, Silver Spring, MD
20910; telephone:<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION: Pursuant to Sec.  10(a)(2) of the Federal
Advisory Committee Act (Pub. L. 92-463; 5 U.S.C. App. II), notice is
hereby given of a meeting of the FAA Aeronautical Charting Forum to be
held from October 27 through October 29, 2015, from 8:30 a.m. to 5:00
p.m. at USGS Headquarters at 12201 Sunrise Valley Drive, Reston, VA
20192, in the Auditorium (Room 1C111).
    The Instrument Procedures Group agenda will include briefings and
discussions on recommendations regarding pilot procedures for
instrument flight, as well as criteria, design, and developmental
policy for instrument approach and departure procedures.
    The Charting Group agenda will include briefings and discussions on
recommendations regarding aeronautical charting specifications, flight
information products, and new aeronautical charting and air traffic
control initiatives. Attendance is open to the interested public, but
will be limited to the space available.
    Please note the following special security requirements for access
to the USGS Headquarters. All visitors must enter at the Visitors
Entrance and pass through security screening process. All packages,
briefcases, handbags, etc. will be scanned. Visitors must sign in and
present a picture I.D., such as a State's driver's license. The guard
will then issue a visitor's badge which must be worn at all times.
    All foreign national participants are required to have a passport.
Additionally, not later than October 15, 2015, foreign national
attendees must provide their name, country of citizenship, company/
organization representing, passport number, passport expiration date,
issuing country of passport, and country of the company/organization.
Send the information to: Lance Christian via Email to:
<EMAIL_ADDRESS>Foreign nationals who do not provide the
required information will not be allowed entrance--NO EXCEPTIONS.
    Attendees bringing laptop computers for use at during the
conference are required to register their laptop when registering to
enter the USGS facility. Attendees are to write the word ``laptop'' and
the serial number on the sign-in beneath their printed name.
    The public must make arrangements by October 8, 2015, to present
oral statements at the meeting. The public may present written
statements and/or new agenda items to the forum by providing a copy to
the person listed in the FOR FURTHER INFORMATION CONTACT section not
later than October 8, 2015. Public statements will only be considered
if time permits.

    Issued in Washington, DC, on August 6, 2015.
Valerie S. Watson,
Co-Chair, Aeronautical Charting Forum.
[FR Doc. 2015-20146 Filed 8-14-15; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register Volume 79, Number 109 (Friday, June 6, 2014)]
[Notices]
[Pages 32729-32730]
[FR Doc No: 2014-13231]

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ENVIRONMENTAL PROTECTION AGENCY

[ER-FRL-9015-3]

Environmental Impact Statements; Notice of Availability

    Responsible Agency: Office of Federal Activities, General
Information<PHONE_NUMBER> or http://www.epa.gov/compliance/nepa/.

Weekly receipt of Environmental Impact Statements
Filed 05/27/2014 Through 05/30/2014
Pursuant to 40 CFR 1506.9.

Notice

    Section 309(a) of the Clean Air Act requires that EPA make public
its comments on EISs issued by other Federal agencies. EPA's comment
letters on EISs are available at: http://www.epa.gov/compliance/nepa/eisdata.html.

EIS No. 20140162, Final EIS, FAA, TX, SpaceX Texas Launch Site, Review
Period Ends: 07/07/2014, Contact: Stacey Zee<PHONE_NUMBER>.
EIS No. 20140163, Draft EIS (Tiering), NASA, FL, Tier 2--Mars 2020
Mission, Comment Period Ends: 07/

21/2014, Contact: George Tahu<PHONE_NUMBER>.
EIS No. 20140164, Final Supplement, FHWA, NCDOT, NC, Monroe Connector/
Bypass, Contact: George Hoops<PHONE_NUMBER>, Under MAP-21 section 1319,
FHWA has issued a single FSEIS and ROD. Therefore, the 30-day wait/
review period under NEPA does not apply to this action.
EIS No. 20140165, Draft EIS, USACE, WA, Skagit River Flood Risk
Management General Investigation, Comment Period Ends: 07/21/2014,
Contact: Hannah Hadley<PHONE_NUMBER>.
EIS No. 20140166, Draft EIS, USACE, WA, BP Cherry Point Dock, Comment
Period Ends: 08/06/2014, Contact: Olivia Romano<PHONE_NUMBER>.

Amended Notices

EIS No. 20130365, Draft EIS, NMFS, USFWS, BR, CA, Bay Delta
Conservation Plan, Comment Period Ends: 07/29/2014, Contact: Ryan Wulff
916-930-3733.

    Revision to the FR Notice Published 02/21/2014; Extending Comment
Period from 06/13/2014 to 07/29/2014; The U.S. Department of the
Interior's Bureau of Reclamation and Fish and Wildlife Service, the
U.S. Department of Commerce's National Marine Fisheries Service are
joint lead agencies for the above project.

    Dated: May 3, 2014.
Cliff Rader,
Director, NEPA Compliance Division, Office of Federal Activities.
[FR Doc. 2014-13231 Filed 6-5-14; 8:45 am]
BILLING CODE 6560-50-P


[Federal Register: May 28, 2008 (Volume 73, Number 103)]
[Notices]
[Page 30617-30618]
[DOCID:fr28my08-49]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-ORD-2008-0204; FRL-8572-4]

Board of Scientific Counselors, Land Research Program Mid-Cycle
Review Meetings--Spring 2008

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of meeting.

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SUMMARY: Pursuant to the Federal Advisory Committee Act, Public Law 92-
463, the Environmental Protection Agency, Office of Research and
Development (ORD), gives notice of one meeting of the Board of
Scientific Counselors (BOSC) Land Mid-Cycle Subcommittee.

DATES: The meeting (a teleconference call) will be held on Tuesday,
June 24, from 12 p.m. to 2 p.m. EDT. The meetings may adjourn early if
all business is finished. Requests for the draft agenda or for making
oral presentations at the meeting will be accepted up to 1 business day
before the meeting.

ADDRESSES: Participation in the conference call will be by
teleconference only--meeting rooms will not be used. Members of the
public may obtain the call-in number and access code for the call from
Heather Drumm, whose contact information is listed under the FOR
FURTHER INFORMATION CONTACT section of this notice. Submit your
comments, identified by Docket ID No. EPA-HQ-ORD-2008-0204, by one of
the following methods:
     http://www.regulations.gov: Follow the on-line
instructions for submitting comments.
     E-mail: Send comments by electronic mail (e-mail) to:
<EMAIL_ADDRESS>Attention Docket ID No. EPA-HQ-ORD-2008-0204.
     Fax: Fax comments to:<PHONE_NUMBER>, Attention Docket ID
No. EPA-HQ-ORD-2008-0204.
     Mail: Send comments by mail to: Board of Scientific
Counselors, Land Mid-Cycle Subcommittee Meeting--Spring 2008 Docket,
Mailcode: 28221T, 1200 Pennsylvania Ave., NW., Washington, DC 20460,
Attention Docket ID No. EPA-HQ-ORD-2008-0204.
     Hand Delivery or Courier. Deliver comments to: EPA Docket
Center (EPA/DC), Room B102, EPA West Building, 1301 Constitution
Avenue, NW., Washington, DC, Attention Docket ID No. EPA-HQ-ORD-2008-
0204. Note: this is not a mailing address. Such deliveries are only
accepted during the docket's normal hours of operation, and special
arrangements should be made for deliveries of boxed information.
    Instructions: Direct your comments to Docket ID No. EPA-HQ-ORD-
2008-0204. EPA's policy is that all comments received will be included
in the public docket without change and may be made available online at
http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through http://
www.regulations.gov or e-mail. The http://www.regulations.gov Web site
is an ``anonymous access'' system, which means EPA will not know your
identity or contact information unless you provide it in the body of
your comment. If you send an e-mail comment directly to EPA without
going through http://www.regulations.gov, your e-mail address will be
automatically captured and included as part of the comment that is
placed in the public docket and made available on the Internet. If you
submit an electronic comment, EPA recommends that you include your name
and other contact information in the body of your comment and with any
disk or CD-ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA
may not be able to consider your comment. Electronic files should avoid
the use of special characters, any form of encryption, and be free of
any defects or viruses. For additional information about EPA's public
docket, visit the EPA Docket Center homepage at http://www.epa.gov/
epahome/dockets.htm.
    Docket: All documents in the docket are listed in the http://
www.regulations.gov index. Although listed in the index, some
information is not publicly available, e.g., CBI or other information
whose disclosure is restricted by statute. Certain other material, such
as copyrighted material, will be publicly available only in hard copy.
Publicly available docket materials are available either electronically
in http://www.regulations.gov or in hard copy at the Board of
Scientific Counselors, Land Mid-Cycle Subcommittee Meeting--Spring 2008
Docket, EPA/DC, EPA

West, Room B102, 1301 Constitution Ave., NW., Washington, DC. The
Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through
Friday, excluding legal holidays. The telephone number for the Public
Reading Room is<PHONE_NUMBER>, and the telephone number for the ORD
Docket is<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: The Designated Federal Officer via
mail at: Heather Drumm, Mail Drop 8104-R, Office of Science Policy,
Office of Research and Development, Environmental Protection Agency,
1300 Pennsylvania Ave. NW., Washington, DC 20460; via phone/voice mail
at:<PHONE_NUMBER>; via fax at:<PHONE_NUMBER>; or via e-mail at:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

General Information

    Any member of the public interested in receiving a draft BOSC
agenda or making a presentation at the meeting may contact Heather
Drumm, the Designated Federal Officer, via any of the contact methods
listed in the FOR FURTHER INFORMATION CONTACT section above. In
general, each individual making an oral presentation will be limited to
a total of three minutes.
    Proposed agenda items for the meeting include, but are not limited
to finalizing the subcommittee's draft report and discussing the rating
component for the Land research program. The meeting is open to the
public.
    Information on Services for Individuals with Disabilities: For
information on access or services for individuals with disabilities,
please contact Heather Drumm at<PHONE_NUMBER> or
<EMAIL_ADDRESS>To request accommodation of a disability, please
contact Heather Drumm, preferably at least 10 days prior to the
meeting, to give EPA as much time as possible to process your request.

    Dated: May 15, 2008.
Jeff Morris,
Acting Director, Office of Science Policy.
 [FR Doc. E8-11874 Filed 5-27-08; 8:45 am]

BILLING CODE 6560-50-P


[Slide]
I will just briefly touch on hepatitis B.  That
will be discussed in more detail by Sue tomorrow.  With

sgg
MILLER REPORTING COMPANY, INC.
735 8th Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666
HBV, we have also uncovered examples where there is
intermittent pre-ramp-up viremia, in this case about two
months, a month and a half prior to antigenemia.  This is
surface antigen coming up in yellow.  That is followed by a
typical ramp-up phase with viral loads increasing
exponentially, a doubling time of about four days for HBV.
[Slide]
This is again a slide from Sue, which she will
focus on but basically illustrating that because the
doubling time is relatively slow there is a fairly long
period of about 20 days when you can detect viremia by
individual donation NAT before it reaches levels detected
by minipool NAT, shown by the line here.  Then, the
improved antigen assays have substantially reduced the pre-
antigenemic phase by virtue of detection of lower levels of
viremia.  This will be discussed in detail tomorrow in the
implications for why we are not doing HBV minipool NAT.
[Slide]
This slide just summarizes the data from the
panels that we have studied.  Again, HCV is unique in
having this plateau phase.  The doubling times for each
virus and the frequency of detecting this pre-ramp-up
viremia -- again, we see it in about a third of the HIV
cases; a good half or so of the HCV cases and, again, about

sgg
MILLER REPORTING COMPANY, INC.
735 8th Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666
half of the HBV cases seem to evidence this intermittent
fluctuating viremia during the eclipse phase.
[Slide]
This is just to illustrate that using the viral
load ramp-up dynamics we can then model out the impact of
reducing the sensitivity or enhancing the sensitivity from
minipool to individual or NAT versus antigen, and by
knowing the sensitivity of the assays we can derive an
estimate for the window period closure one achieves by
moving toward a more sensitive test.  It is that window
period closure which, when combined with incidence rates,
can estimate the yield of that transition.
So, as Jay indicated, there continues to be
interest in moving to individual donation NAT for minipool
and this is just an example of what the projected impact
would be of detecting ramp-up viremia, were one to do so,
given the model estimates of the window period closure that
would be achieved by moving from, for example, pools of 16-
24 down to individual samples.  So, what you can see here
is that for hep C and HIV, because the viral load ramps up
so quickly, less than a day, the window period closure by
enhancing the sensitivity of the assay is about 20-fold.
There is only about three to four days.  These viruses have
similar incidence rates of about 4/100,000.  So, that
really only translates into a projected two additional

sgg
MILLER REPORTING COMPANY, INC.
735 8th Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666
infections detected per ten million donations, which is
about the U.S. whole blood collection -- so, fairly modest
improvement with respect to HCV and HIV attributable to
going to individual donation.  For HBV, in contrast,
because the doubling time is slower, the enhanced window
closure would be more dramatic, about 12 days, and the
yield would be a little higher.
[Slide]
This just briefly summarizes the current
estimates of risk for each virus in the pre-NAT, the
minipool NAT and the single donation era.  Again, these
numbers, expressed both as number of cases detected per
million as well as rates in 1/1.3 million, for example, for
HIV, all assume that the pre-seroconversion eclipse phase
may be infectious.  Again, I think that is a question we
will focus on now, but what you can see is that we have
moved from risks in the range of one in a million for HIV
and one in about 100,000 to about 200,000 for HCV and HBV.
As we implement minipool NAT for HIV and HCV those risks
have dropped to one in two million or so, and going to
individual NAT will drop them a little bit lower, in the
range of one in three million.
[Slide]
Again, the question that has been posed, I think,
most critically by Mico Leli is whether we are really sure

sgg
MILLER REPORTING COMPANY, INC.
735 8th Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666
that that pre-ramp-up phase is infectious.  As we have
moved from serologic testing or antigen assays to various
pool size sensitivity nucleic acid tests, the question has
been raised as to whether infectivity, in fact, is present
at all of these levels of viremia, and also whether
infectivity may exist even in the pre-ramp-up phase, the
eclipse phase, and are these blips infectious.
[Slide]
Toward that end, there have been studies
undertaken, and some others are in progress, to try to
better understand this relationship between infectivity and
viral load during the pre-seroconversion period.  I am just
going to touch on these for lack of time. The first
approach is to simply take plasma stocks that have been
titered out in chimps to define chimp infectivity
concentrations.  By correlating the NAT detection of those
assays, either by doing quantitative viral load on the
starting stock or by testing, by the qualitative NAT
assays, serial dilutions of these pedigreed stocks, one can
estimate how many genome equivalents correspond to a chimp
infections dose.
In those studies, although they are limited, and
the precision of the titration of these panels is limited,
they suggest that for HBV and HCV as little as ten genome
equivalents in an inoculum, in the total volume of plasma

sgg
MILLER REPORTING COMPANY, INC.
735 8th Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666
introduced into the recipient, would be equivalent to one
chimp infectious dose 50.  So, this suggests that for
window phase HBV and HCV extremely infectious and
essentially all viral particles probably are capable of
transmitting, and very low concentrations are able to
transmit.
For HIV, the chimp model is relatively less
susceptible and there are issues around potential defective
virus.  So, those studies suggest that 1000 to 10,000
copies may be required to transmit in the chimp model.
Other studies have been undertaken -- this well-
known study by Harvey Alter, where you can infect an
animal, and this can be done with chimps and HIV or HCV or
with SIV models, for example.  The animal can be infected
and then sampled serially, plasma and cells, purified and
stored away.  Those samples can be characterized by NAT and
antigen and antibody tests.  Then one can transfuse those
serial samples, stored unit volumes of material from the
eclipse phase through the seroconversion phase, in
secondary test animals and correlate detection of viremia
with development of antibody.
This was a study by Chris Murthy, the first
author, published in Transfusion a few years ago, that
looked at this for HIV and demonstrated that there was no
ability to transmit until the animal became viremic as

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detectable by NAT.  So, through the eclipse phase there did
not seem to be infectivity.
One of the concerns though is that the chimp
isn't highly susceptible to primary HIV.  So, in order to
further address that, what is going on now are studies
where we are using these plasma donor panels and actually
infusing material from the plasma panels into chimps.
[Slide]
This is, again, a study with Harvey Alter and
Chris Murthy.  This is just to illustrate the design.  So,
we are really trying to understand the phenomenon of the
blips within the eclipse phase.  So, what we are doing is
transfusing 50 ml of plasma from each of five donors into
chimps, beginning with samples collected prior to any
detectable viremia, any blips or ramp-ups, and then going
to the valley between the blips and the ramp-up and
following that same animal after a period where we evaluate
the transition from the initial inocula, following up with
inocula from the valley between the blips and the ramp-up.
Then, if that does not transmit, moving to the ramp-up
itself to ask is this actually infectious in a chimpanzee.
If not, then we will work our way up the ramp-up phase.
So, these studies are currently under way.
[Slide]

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The other approach to understand infectivity is
to really try to milk, if you will, the human experience
that is going on all the time through transfusion.  One
approach is to follow, in essence, donor-directed look-back
strategies where a donor seroconverts to either NAT
positivity or antibody and the recipients are traced
through look-back.
Now, there have been a series of cases that have
been studied, and I will touch on several of these, that
reported recipient infection from pre-NAT or pre-
seroconversion units and then went back and have studied
these prior donations to ask did they have viremia that we
can detect retrospectively.  In a number of countries there
are stored units or there may be recovered plasma off the
donation.  So, this allows us to really directly ask the
question of the relationship between RNA levels and
detectable viremia in the human context.
Once you have data from a number of these cases,
you can then begin to model the duration of the infectious
window period based on the inter-donation interval between
the prior donation and the first positive, and compiling
the whole data set.  The model for this was first presented
by Lyle Peterson almost a decade ago.
[Slide]

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Just a few examples.  This is the so-called
Singapore case, which was published in JAMA about a year
and a half ago.  In this case, a donor seroconverted to
antibody.  The prior donation was determined and confirmed
by molecular methods to have transmitted HIV to the
recipient.  We obtained that material, the plasma was
available, and evaluated that by both the Chiron Gen-Probe
and Roche assays, serially diluting the sample to model the
pool sizes that were used.
What one can see is that out of the pool sizes
that are currently employed in the U.S. of 1 to 16 and 1 to
24 both assays began to detect the viremia.  This unit was
estimated to have about 100 genome equivalents per
milliliter.  So, clear documentation of an HIV.  Although
in this example, this was actually prior to NAT screening.
This was sort of a retrospective study of an HIV antibody
seroconverter where the plasma was available.
[Slide]
A second case was reported from Germany, in
Lancet, where there was an HICV transmission by NAT
negative blood.  Again, a donor seroconverted to HCV
antibody.  The donation was eight weeks prior.  The
platelet transmitted interestingly -- platelets have about
50 ml of plasma, whereas the red cells do not -- only 5 ml
of plasma.  The plasma was available and was able to be

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tested.  In the publication it was tested by an enhanced
input PCR that was modeled or projected to have sensitivity
down in the range of 10-30 copies and it was negative.
Interestingly, we obtained that plasma and were able to run
the Gen Probe and NGI assays, and Gen Probe could detect
virus, qualitative high input analysis, in two of three
reps.  So, again, suggesting that an infectious unit for
HCV could have extremely low levels of viremia, right at
the limit of detection.
[Slide]
This case is probably new to most of you.  This
was a recent documented transmission in the U.S.  It
represents, to our knowledge, the first case of HIV
transmission prospectively identified by NAT screened
blood.  This was identified at the San Antonio blood
center.  In this case, similar to the Singapore case, the
donor seroconverted to antibody two months earlier.  The
donation that was transfused did infect the recipient.  As
I will show you in a moment the genetic studies confirmed
that this was a linked transmission.  In the same context,
we identified the plasma component and have now run the
serial dilutions by the two U.S. licensed NAT assays.
Essentially identical to the Singapore case, in both assays
--
here is the summary -- this sample consistently detected
undiluted and high rate of detection at 1 to 8 but at 1 to

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16, 1 to 24 the assays began to miss this unit -- estimated
copy number, again, about 100 genome equivalent.  Clearly,
transmissions can occur by minipool negative blood but in
the cases that have been studied aggressively we can detect
viremia in transmission cases.
[Slide]
This just shows the linkage, the donor and the
recipient, both in the envelop and gag regions -- virtually
identical.  So, this is an unequivocal transmission from
minipool screened blood.
[Slide]
A compilation of data on a larger scale though is
really needed to feed a model as Lyle Peterson developed.
This is probably best illustrated by what Kurt Roth has
done in Germany and Austria where, in the setting where
they are doing NAT screening they have rigorously followed
all prior donations from seroconverting recipients, by they
NAT or antibody seroconverters.  Then, when they follow
those recipients, they determine whether the recipients
were infected and they also have a repository so they can
test the stored donation samples.
Interestingly, in this analysis of a number of
seroconverters for all three viruses none of the recipients
were infected.  This is important to emphasize.  We tend to
focus on these cases where transmission did occur but there

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are lots of look-backs that are done where recipients
aren't infected.  Again, in order to get a comprehensive
understanding of the infectivity of this window, we really
need to generate data like this that feeds the model with
both the transmitting and non-transmitting case data.
[Slide]
Finally, the other approach to human evaluation
is when recipients are reported to be infected potentially
by transfusion, and then the donors get investigated, the
so-called recipient trace back.  Here one can retest
aliquots of the donation plasma from all those donors if
available or recall the donors, and if a transmission does
occur it is important to validate that because we all know
there is a higher level of background infections now than
transfusion related.
[Slide]
I am not going to go through this in detail, but
in a study just published in Transfusion, the Japanese
investigators did a very rigorous investigation of reported
transfusion cases.  They had 103 reported HBV, 92 reported
HCV cases and no reported HIV cases.  The bottom line here
was that of the 103 HBV, only 16 could be determined to
really be transfusion related, and most of those would have
been detected by either NAT or even contemporary surface
antigen assays.  Of the 92 HCV recipient infections

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detected, none of them proved to be real.  All of the
donors were negative by NAT and on follow-up.  So, just
again to emphasize that not every case of post-transfusion
hepatitis or HIV really is transfusion determined.
[Slide]
With Sue Stramer, just over the last week, we
sort of canvassed the world about the experience with NAT
and this is the whole blood sector yield.  I can make this
available to anyone who is interested.  I think there
really needs to be kind of a global collaboration to keep
up to date and compile the NAT yield experience.
So, what we see here again are the various
countries that have implemented NAT; the pool size
currently employed; the number of units screened in each
region; the number of NAT positives for hep C; and then the
yield.  An important observation here is that we seem to
see countries like the U.S., Japan and Australia that, with
HCV, have NAT yields very similar, in the range of 1 in
300,000.  Germany and Austria is about 1 in 600,000.  Then
there are a number of countries that seem to have a much
lower rate of NAT detection, in the range of less than one
in a million donations.  Some countries, like Holland, 2.4
million without a single yield case to date.  So, there is
quite a variance in yield, with really the U.S. kind of
driving the high end.

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[Slide]
Here, HIV rates again.  One in about two million
in several countries, but then a number of countries again
that have yet to have a single detection of an HIV NAT
yield case.
[Slide]
In trying to understand this variance in yield,
we recognize that the model predictions actually may give
us the answer, and the incidence rates model allows us to
predict yield.  Toward this end, this is an analysis that
Sue Stramer just reported at the AABB, where she looked in
the U.S. at the CDC area division of the United States, and
broke her donor pool up into a pattern consistent with CDC-
defined healthcare regions.
What this slide compares is the HCV incidence,
estimated by the anti-HCV frequency in repeat donors,
relative to the HCV NAT yield.  One sees the relationship
that is actually clarified on this regression map which
shows, again, the HCV NAT yield and the incidence rate or
anti-HCV prevalence in repeat donors.  One sees a nice
relationship sort of on a micro level within the U.S.
itself.  So, we are now trying to get incidence estimates
from these various countries, and we are going to extend
this analysis of NAT yield relative to incidence rates to
an international perspective.

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[Slide]
Just briefly, a quick mention of cost
effectiveness and kind of issues around the relative
benefits of the different NAT target agents.  Importantly -
-
and this is some work that is going to be coming out in
Annals of Internal Medicine shortly, if you look at these
various agents, we tend to group them all together and say
the yield is this or that, assuming that each one is
equally important.  But on a clinical consequence analysis,
HIV, as we all know, is really a terribly important and
pathogenic virus.  So, for every HIV transmission we
prevent we actually save the patient society seven quality
life years.
Importantly, relatively for HCV one only saves
0.6 quality life years per infection prevented.  One-tenth
is important from a clinical prevention perspective.  In
HBV one-fifth is as important as HCV.  Again, we know most
people resolve HBV spontaneously.  So, this really fits,
and it is important to take this into account when we talk
about adding other agent detection -- hepatitis A, parvo-
B19 -- because these are even less important clinically for
the patient.
This translates out into the dollars per quality
life years saved.  For example, with HIV we will only
detect about three additional infections by adding minipool

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NAT and a total of six by going to single donation NAT
relative to HCV, where we are detecting 60 or so per year
with minipool NAT and, yet, the quality saved is virtually
identical.  Again, that is because HIV is much more
important and prevents much more disease by implementing
NAT.
[Slide]
I am not going to go through this again.  This is
a paper that is in press, but the bottom line is, as we all
know, this is extremely expensive technology with fairly
modest yields.  So, the result is that we are dealing with
cost effectiveness in the range of two, three million
dollars per quality life year and we are not going to do
any better by going from minipool NAT with or without HBV;
a little bit of benefit if we can drop some other assays
like antigen and anti-core to offset the cost; and even
going to single donation NAT will still leave us with a
technology that is extremely expensive, in the range of two
million dollars per quality life year, and we are spending
just in the U.S. hundreds of millions of dollars to prevent
these modest numbers of infections.
[Slide]
I am sure you can't see this but I just want to
juxtapose that with reality.  Unfortunately, in much of the
world where the incidence of these agents is much greater

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and, therefore, the benefits of NAT would be dramatic.
This is some data developed with Anton Hanes, in South
Africa, where we did what is called the detuned assay on
all of the HIV positive donors detected in about a year and
a half period.  In South Africa, the prevalence of HIV
antibody in their donor pool is about 1.2 percent.  They
currently stratify their donor pool into relative
prevalence groups, defined by region of the country and
race ethnicity parameters, and the high prevalence groups
have about a 5 percent prevalence of HIV antibody, whereas
low prevalence groups are at 0.7 percent, almost the same
as in developed countries.
[Slide]
Now, when we did the detuned assay we could