[Federal Register Volume 84, Number 163 (Thursday, August 22, 2019)]
[Notices]
[Pages 43798-43799]
[FR Doc No: 2019-18125]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. IC19-23-000]

Commission Information Collection Activities (FERC-725P1);
Comment Request

AGENCY: Federal Energy Regulatory Commission, Department of Energy.

ACTION: Comment request.

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SUMMARY: In compliance with the requirements of the Paperwork Reduction
Act of 1995, the Federal Energy Regulatory Commission (Commission or
FERC) is submitting its information collection FERC-725P1 (Mandatory
Reliability Standards: PRC-005-6 Reliability Standard) to the Office of
Management and Budget (OMB) for review of the information collection
requirements. Any interested person may file comments directly with OMB
and should address a copy of those comments to the Commission as
explained below. The Commission previously published a Notice in the
Federal Register on May 31, 2019, requesting public comments. The
Commission received no comments and is making this notation in its
submittal to OMB.

DATES: Comments on the collection of information are due by September
23, 2019.

ADDRESSES: Comments filed with OMB, identified by the OMB Control No.
1902-0280, should be sent via email to the Office of Information and
Regulatory Affairs<EMAIL_ADDRESS>Attention: Federal Energy
Regulatory Commission Desk Officer.
    A copy of the comments should also be sent to the Commission, in
Docket No. IC19-23-000, by either of the following methods:
     eFiling at Commission's Website: http://www.ferc.gov/docs-filing/efiling.asp.
     Mail/Hand Delivery/Courier: Federal Energy Regulatory
Commission, Secretary of the Commission, 888 First Street NE,
Washington, DC 20426.
    Instructions: All submissions must be formatted and filed in
accordance with submission guidelines at: http://www.ferc.gov/help/submission-guide.asp. For user assistance contact FERC Online Support
by email at<EMAIL_ADDRESS>or by phone at:<PHONE_NUMBER>
(toll-free), or<PHONE_NUMBER> for TTY.
    Docket: Users interested in receiving automatic notification of
activity in this docket or in viewing/downloading comments and
issuances in this docket may do so at http://www.ferc.gov/docs-filing/docs-filing.asp.

FOR FURTHER INFORMATION CONTACT: Ellen Brown may be reached by email at
<EMAIL_ADDRESS>by telephone at<PHONE_NUMBER>, and by fax at
(202) 273-0873.

SUPPLEMENTARY INFORMATION:
    Title: FERC-725P1 (Mandatory Reliability Standards: PRC-005-6
Reliability Standard).
    OMB Control No.: 1902-0280.
    Abstract: The Commission requires the information collected by the
FERC-725P1 to implement the statutory provisions of section 215 of the
Federal Power Act (FPA). On August 8, 2005, Congress enacted into law
the Electricity Modernization Act of 2005, which is Title XII, Subtitle
A, of the Energy Policy Act of 2005 (EPAct 2005). EPAct 2005 added a
new section 215 to the FPA, which required a Commission-certified
Electric Reliability Organization (ERO) to develop mandatory and
enforceable Reliability Standards, which are subject to Commission
review and approval. Once approved, the Reliability Standards may be
enforced by the ERO subject to Commission oversight, or the Commission
can independently enforce Reliability Standards.
    On February 3, 2006, the Commission issued Order No. 672,
implementing section 215 of the FPA. Pursuant to Order No. 672, the
Commission certified one organization, North American Electric
Reliability Corporation (NERC), as the ERO. The Reliability Standards
developed by the ERO and approved by the Commission apply to users,
owners and operators of the Bulk-Power System as set forth in each
Reliability Standard.
    On November 13, 2015, the North American Electric Reliability
Corporation (NERC) filed a petition for Commission approval of proposed
Reliability Standard PRC-005-6 (Protection System, Automatic Reclosing,
and Sudden Pressure Relaying Maintenance). NERC also requested approval
of the proposed implementation plan for PRC-005-6, and the retirement
of previous versions of Reliability Standard PRC-005.
    NERC explained in its petition that Reliability Standard PRC-005-6
represents an improvement upon the most recently-approved version of
the standard, PRC-005-4. FERC approved the proposed Reliability
Standard PRC-005-6 on December 18, 2015.
    Type of Respondent: Planning Coordinators (PCs) and Generator
Owners (GOs).
    Estimate of Annual Burden: \1\ The Commission estimates the annual
public reporting burden for the information collection as:
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    \1\ ``Burden'' is the total time, effort, or financial resources
expended by persons to generate, maintain, retain, or disclose or
provide information to or for a Federal agency. For further
explanation of what is included in the information collection
burden, refer to Title 5 Code of Federal Regulations 1320.3.
    \2\ Entities affected by the PRC-005-6 Reliability Standard are
registered to serve any of the following roles:
     PC = Planning Coordinators;
     GO = Generator Owners.
    Some entities are registered to serve both roles.
    \3\ The estimated hourly cost (salary plus benefits) provided in
this section is based on the salary figures (http://www.bls.gov/oes/current/naics2_22.htm) and benefits (http://www.bls.gov/news.release/ecec.nr0.htm) for May 2017 posted by the Bureau of
Labor Statistics for the Utilities sector. The hourly estimates for
salary plus benefits are $66.90/hour based on the Electrical
Engineering career (Occupation Code: 17-2071).
    \4\ Total Annual Cost is rounded-up from $133,264.80 to
$133,265.
    \5\ 20 (PC role only) + 927 (GO role only) + 49 (joint role as
PC and GO) = 996 unique entities.
    \6\ This number is rounded from $133,264.80.

                           FERC-725P1: Mandatory Reliability Standards: PRC-005-6 \2\
----------------------------------------------------------------------------------------------------------------
                                                                                Total annual
                                  Number of     Annual number   Total number    Average burden     burden hours
                                 respondents    of responses    of responses    hours and cost      and total
                                               per respondent                  per response \3\  annual cost \4\
                                          (1)             (2)     (1) * (2) =  (4).............  (3) * (4) = (5)
                                                                          (3)
rrrrrrrrrrrrrrrrrrrrrrrrrrrrrr
PRC-005-6 Reliability                 \5\ 996               1             996  2 hrs.; $133.80.  1,992 hrs.;
 Standard.                                                                                $133,265 \6\
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    Comments: Comments are invited on: (1) Whether the collection of
information is necessary for the proper performance of the functions of
the Commission, including whether the information will have practical
utility; (2) the accuracy of the agency's estimate of the burden and
cost of the collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility and clarity of the information collection; and (4) ways to
minimize the burden of the collection of information on those who are
to respond, including the use of automated collection techniques or
other forms of information technology.

    Dated: August 16, 2019.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2019-18125 Filed 8-21-19; 8:45 am]
BILLING CODE 6717-01-P


OMB Control Number 2070-0060; EPA ICR Number 0277.15

ICR ATTACHMENT K

Display Related to OMB Control #2070-0060

Listings of Related Regulations in 40 CFR 9.1

	As of May 10, 1993, the OMB approval numbers for EPA regulations in
Chapter I of Title 40 of the Code of Federal Regulations (CFR) appear in
a listing in 40 CFR 9.1 (58 FR 27472).  This listing fulfills the
display requirements in section 3507(f) of the Paperwork Reduction Act
(PRA) for EPA regulations.  The listing at 40 CFR 9.1 displays this OMB
Control number for the following regulations:

Program Title 	40 CFR citation

Pesticide Registration and Classification Procedures	152.46

                                                           	152.50

                                                           	152.80

                                                           	152.85

                                                           	152.98

                                                           	152.122

                                                           	152.135

                                                           	152.164

                                                           	152.404

                                                           	152.406

                                                           	152.412

                                                           	152.414

Labeling Requirements for Pesticides and Devices	156.10

                                                           	156.206

                                                           	156.208

                                                           	156.210

                                                           	156.212

Data Requirements for Registration	158.32

                                                           	158.34

                                                           	158.45

                                                           	158.75

                                                           	158.110

                                                           	158.200

                                                           	158.310

                                                           	158.320

                                                           	158.325

                                                           	158.330

                                                           	158.335

Program Title 	40 CFR citation

Data Requirements for Registration (cont’d)	158.340

                                                           	158.345

                                                           	158.350

                                                           	158.355

                                                           	158.400

                                                           	158.500

                                                           	158.630

                                                           	158.660

                                                           	158.1050

                                                           	158.1100

                                                           	158.1300

                                                           	158.1410

                                                           	158.2000

                                                           	158.2100

Good Laboratory Practice Standards	Part 160

Data Requirements for Registration of Antimicrobial Pesticides	161.30

                                                           	161.32

                                                           	161.34

                                                           	161.45

                                                           	161.75

                                                           	161.101

                                                           	161.150

                                                           	161.160

                                                           	161.162

                                                           	161.165

                                                           	161.167

                                                           	161.170

                                                           	161.175

                                                           	161.180

                                                           	161.190

                                                           	161.240

                                                           	161.290

                                                           	161.340

                                                           	161.390

                                                           	161.440

                                                           	161.490

                                                           	161.540

                                                           	161.590

                                                           	161.640

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From: Don DiCristofaro<EMAIL_ADDRESS>To: Melanie King/RTP/USEPA/US@EPA
Cc: Rick Counihan<EMAIL_ADDRESS>Date: 12/12/2012 10:55 PM
Subject: Follow up re EDF Late Filed Comment

Melanie,
This is a follow up to the conversation Rick Counihan and I had with you last Friday
regarding your question about the bar chart on page 5 of the late filed comment made by
the Environmental Defense Fund to the RICE NESHAP docket on December 3, 2012
(EPA-HQ-OAR-2008-0708-1482). This bar chart was created by EnerNOC using PJM
supplied data for economic demand response (DR) that has entered the PJM market as a
result of FERC Order 745. The data shown is the DR from the PJM Economic Load
Response Program. Any generators participating in this program must be permitted by the
appropriate state/county for non-emergency engine use. This chart has nothing to do with
engines participating in emergency demand response (e.g., the Emergency Load Response
Program (ELRP) in PJM).
Currently EnerNOC only has two sites with generators participating in the PJM Economic
Load Response Program and all of the generators are natural-gas fired. Currently,
EnerNOC only targets natural gas gens because other fuels are too expensive to run
relative to current power prices (which are driven by low price of natural gas).
Approximately 80 to 85% of EnerNOC’s portfolio in this DR program is from curtailment
only (e.g., turning off equipment or turning down lights, AC, etc.).
Please let me know if you have any questions or require additional information.
Don
Don DiCristofaro, CCM – Air Quality Meteorologist Consultant
EnerNOC, Inc. | 101 Federal Street, Suite 1100 | Boston, MA 02110
m:<PHONE_NUMBER> | f:<PHONE_NUMBER>
<EMAIL_ADDRESS>www.EnerNOC.com
EnerNOC - get more from energy

This email and any information disclosed in connection herewith, whether written or oral, is the property of
EnerNOC, Inc. and is intended only for the person or entity to which it is addressed. This email may contain
information that is privileged, confidential or otherwise protected from disclosure. Distributing or copying any
information contained in this email to anyone other than the intended recipient is strictly prohibited.


UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION PESTICIDES AND TOXIC SUBSTANCES TXR NO. 0050364 MEMORANDUM DATE: December 10, 2001 SUBJECT: Pronamide (Propyzamide): Report of the Hazard Identification Assessment Review Committee (HIARC) Meeting for the Herbicide, Pronamide.

FROM: Michelle M. Centra, Pharmacologist Reregistration Branch III Health Effects Division (7509C)

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

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

PC Code: 101701 On November 6, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for PRONAMIDE 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 PRONAMIDE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. The conclusions drawn at this meeting are presented in this report. 2 Committee Members in Attendance Members present were: Jess Rowland, Elizabeth Doyle, William Burnam, Pamela Hurley, David Nixon, Paula Deschamp, Susan Makris, John Liccione, and Brenda Tarplee.

Member( s) in absentia: Ayaad Assaad, Jonathan Chen, and Elizabeth Mendez.

Data evaluation prepared by: Michelle M. Centra, Reregistration Branch III.

Also in attendance were: Jose Morales (HED), Barry O'Keefe (HED), Steve Knizner (HED), Virginia Fornillo (HED), Lucy Shanaman (EFED), Kevin Crofton (NHEERL/ ORD), Michael McDavit (SRRD), and Cecelia Watson (SRRD).

Data Evaluation / Report Presentation _______________________ Michelle M. Centra Pharmacologist 3 Cl Cl O C CH 3 N H CH CH 3 1. INTRODUCTION Pronamide [3,5 dichloro N( 1,1 dimethyl 2 propynyl) benzamide], trade name Kerb ® , is a selective, systemic, pre and post emergence herbicide which inhibits root and shoot growth from seedlings and is used to control a wide range of annual and perennial grasses as well as certain broadleaf weeds. Pronamide is produced and formulated for use as a 50 W wettable powder in water soluble pouches (Kerb ® , EPA Reg. No. 707 159) by Rohm and Hass Co., Springhouse, Pennsylvania and may be applied to various food/ feed using ground spray equipment, by soil incorporation, or by aircraft. It is registered for use in/ on several food and feed crops (alfalfa, apples, globe artichokes, birdsfoot trefoil, blackberries, blueberries, cherries, clover, crown vetch, endive, grapes, lettuce, nectarines, peaches, pears, plums, prunes, raspberries, and sainfoin). Pronamide is also registered for terrestrial non domestic, non food use on woody ornamentals (azalea, holly, juniper, pine, rhododendron, and yew), Christmas trees, nursery stocks (forsythia, holly, juniper, pine, rhododendron, and yew) and for domestic outdoor uses on lawns, turfs, and fallow land to control bermudagrass, centipedegrass, St. Augustinegrass, and zoysiagrass.

Technical pronamide [also known as propyzamide] is a white crystalline solid with a melting point of 155 156 0 C and a specific gravity of 0.48 g/ cc. Pronamide is soluble in water (15 ppm at 25 0 C); in dimethyl sulfoxide and dimethyl formamide at 33 ppm; in mesityl oxide, isophorone, methyl ethyl ketone, and cyclohexanone at 20 ppm; in methanol, isopropanol, and chlorobenzene at 12 15 ppm; in butyl cellosolve, xylene, acetonitrile, and kerosene at 10 ppm; and in nitrobenzene and ethylene dichloride at 5 ppm. The chemical structure of pronamide is shown below:

Empirical Formula: C12H11NOCl2 Molecular Weight: 256.13 CAS Registry Number: 23950 58 5 On November 6, 2001, the HIARC met to evaluate the available toxicology data base, re assess the existing chronic RfD, select the toxicological endpoints for occupational and residential exposure risk assessments, and assess the potential susceptibility of infants and children from exposure as required by the FQPA for the pronamide tolerance reassessment eligibility decision (TRED). 4 2 HAZARD IDENTIFICATION 2.1 Acute Reference Dose (RfD)

No appropriate endpoint was available to quantitate risk to the general population from a single dose administration of pronamide. The developmental effect, abortions, were not considered to occur after a single dose in this instance because they were observed in rabbits during the postdosing phase of the study (days 22 24). Therefore, no endpoint was chosen to quantitate risk to females 13 50 from a single dose administration of pronamide.

2.2 Chronic Reference Dose (RfD)

Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: In a chronic oral (dietary) toxicity/ carcinogenicity study (MRID# 41714001 and 41714002), Crl: CD( BR) VAF/ Plus Rats (Supplier: Charles River Laboratories, Inc., Kingston, NY) received either 0, 25, 100, or 400 ppm for the first 2 weeks then 0, 35, 140, or 560 ppm for the next 3 weeks and then 0, 40, 200, or 1000 ppm thereafter (equal to 0, 1.73, 8.46, and 42.59 mg/ kg/ day for males and 0, 2.13, 10.69, and 55.09 mg/ kg/ day for females, respectively) Kerb ®

Technical (Purity: 96.4%; Batch No. 2 5002) in the diet. Animals were observed twice daily for moribundity, mortality and toxic signs. Body weights and food consumption were recorded weekly for 14 weeks and then biweekly thereafter, food efficiency was calculated at 26 and 53 weeks. Ophthalmological examinations were conducted on all animals prior to study initiation and in the control and high dose animals at sacrifice at 6, 12, and 24 months. Blood was collected from 10 animals/ sex/ dose group in the satellite groups at 6 and 12 months and from 10 animals/ sex/ dose group at 24 months for hematological and clinical chemistry studies. Urine was collected form 10 animals/ sex/ dose group at 5 months and due to the small amount of urine collected, it was repeated at 6 months. At 11 months in the satellite group and 23 months in the main study, urine was collected from 10 animals/ sex/ dose group in the control and high dose groups and prior to sacrifice at 24 months, urine was collected from the low and mid dose groups. Animals were sacrificed as specified at 6, 12, and 24 months and received a complete gross examination, organs were weighed as required and required tissues were collected and fixed for histopathological examination.

At 1000 ppm (55.09 mg/ kg/ day), mean body weights and body weight gains were decreased in female rats. Increased incidences of non neoplastic lesions were observed in the liver, thyroid, and ovaries of high dose (1000 ppm) rats. In the liver, centrilobular hypertrophy was observed in males and females at 12 months (65% in males; 95% in females) and 24 months (20% in males; 48% in females). Hypertrophy was accompanied by eosinophilic cell alteration at 24months (positive trend in both sexes; pair wise comparison in high dose/ controls for males and females). The histologic liver changes were accompanied by increases in relative (to body) weight in the high dose groups of both sexes. In the thyroid, follicular cell hypertrophy was observed (positive trend in males and in females) at 12 months but not at 24 months. The increased incidence observed at 1000 ppm was only significant (pair wise comparison in high dose/ controls) in females. At 24 months, follicular cell hyperplasia was observed in females (positive trend) but the increased incidence observed at 5 1000 ppm was not statistically significant. In the ovaries, sertoliform tubular hyperplasia (positive trend) was observed in females at 24 months and the increase in incidence observed at 1000 ppm was significant by pair wise comparison. No toxicologic effects were observed at 25 ppm or 200 ppm treated male and female rats.

The Systemic Toxicity NOAEL was 200 ppm (8.46 mg/ kg/ day for males; 10.69 mg/ kg/ day for females) and the Systemic Toxicity LOAEL was 1000 ppm (42.59 mg/ kg/ day for males; 55.09 mg/ kg/ day for females) based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries.

At 1000 ppm, in the 24 month phase, both male and female rats had increased rates of thyroid follicular cell adenomas, and male rats had an increased incidence of benign testicular interstitial cell tumors. Thyroid tumors were not observed until weeks 53 and 82 for males and females, respectively, and testicular tumors were not observed until week 67. The increase in thyroid tumor rate was statistically significant by pair wise comparison (p < 0.01) only in males, but there was a positive trend (p < 0.01) for both sexes. Both high dose male and female tumor rates (21% and 10%, respectively) exceeded the historical control range which was 0 14.8% (mean 5%) for males and 0 9.5% (mean 2%) for females (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 13 studies conducted between 1985 and 1990). There were no significant differences in thyroid follicular cell carcinoma rates between groups. There was increasing trends and/ or rates in combined thyroid follicular cell adenomas and carcinomas (trend p < 0.01 in males, p < 0.05 in females; pair wise comparison of high dose males/ controls, p < 0.05) which were a reflection of the treatment related changes in thyroid follicular cell adenoma rates. The increase in testicular interstitial cell benign tumor rate was statistically significant by pair wise comparison (p < 0.05) and there was a positive trend (p < 0.01). In high dose males, the tumor rate (27%) exceeded the historical range of 4.8 18.2% with a mean value of 5.6% (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 11 studies conducted between 1985 and 1990). In the 12 month phase, thyroid follicular cell and testicular interstitial cell neoplasia were not observed in any group.

Benign pituitary adenomas of the pars distalis were observed in every dose group during both the 12 and 24 month phases, but the tumor rates were statistically comparable among all groups. The respective tumor rates for the 0, 40, 200, and 1000 ppm dose groups were 1/ 19, 0/ 19, 0/ 20, and 3/ 20 in males and 0/ 20, 2/ 20, 1/ 19, and 3/ 20 in females in the 12 month phase and 31/ 60, 33/ 60, 35/ 60, and 34/ 60 in males and 49/ 60, 49/ 60, 49/ 60, and 54/ 60 in females in the 24 month phase.

Under the conditions of this study, the dosing was considered adequate for assessing carcinogenic potential of Pronamide, based on body weight gain depressions (p < 0.05) of $ 10% observed at 1000 ppm (weeks 0 26 in males; weeks 0 52 in females), increased relative liver weight in both sexes and the non neoplastic histological changes in the liver, thyroid and ovaries. The statistical evaluation of mortality indicates no significant incremental changes with increasing doses of pronamide in either male or female rats.

CLASSIFICATION: This study is classified as Acceptable Guideline and satisfies the guideline requirements (OPPTS 870.4300; § 85 3) for a chronic oral (dietary) toxicity/ carcinogenicity study in rodents. 6 Dose and Endpoint for Establishing RfD: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day.

Uncertainty Factor( s): Uncertainty factor of 100 was applied to account for intraspecies extrapolation (10x) and interspecies variability (10x).

Comments about Study/ Endpoint/ Uncertainty Factor( s): The current RfD (0.08 mg/ kg/ day) for pronamide is based on the NOAEL of 8.46 mg/ kg/ day established in the two year chronic toxicity/ carcinogenicity study in rats (MRID 41714001, 41714002) and an uncertainty factor of 100 (10x for intraspecies extrapolation and 10x for interspecies variation). The LOAEL of 42.59 mg/ kg/ day was based on increased relative liver weight and non neoplastic histologic changes in the liver, thyroid, and ovaries. Since the long term feeding/ carcinogenicity study in rats is appropriate for the route and duration of exposure and the dose/ endpoint established in this study is the most protective dose (NOAEL = 8.46 mg/ kg/ day) for the target effects of concern (organ toxicities in the liver, thyroid, and ovaries) in the available pronamide toxicity data base, it will remain as the study selected for the chronic RfD.

2.3 Occupational/ Residential Exposure 2.3.1 Short Term (1 30 Days) Incidental Oral Exposure Study Selected: Developmental Toxicity in Rabbits Guideline #: 870.3700 MRID No.: 00148065, 00148064 Executive Summary: In a prenatal developmental toxicity study (MRID# 00148065, 00148064), pregnant six month old New Zealand white rabbits received Pronamide as an aqueous suspension in 0.5% methyl cellulose by gavage from gestation days 7 through 19, inclusive, at dose levels of 0, 5, 20, or 80 mg/ kg/ day. Each animal was examined once daily for signs of toxicity and mortality. Body weights were recorded on gestation days 0, 4, 7, 11, 15, 20, 25, and 29. All surviving rabbits were weighed and sacrificed on gestation day 29, the numbers or corpora lutea, implantation sites, live and dead fetuses and embyronic deaths were recorded, in addition the maternal livers, gall bladders and kidneys (with ureters) were removed and process for microscopic examination. All live fetuses were weighed and examined for external abnormalities. The fetuses were then sacrificed, internally sexed and the viscera was examined for anomalies. The brain was examined by mid coronal incision and the heart by a modified Staples technique. The fetuses were then fixed and cleared and stained in Alizarin red S for skeletal examinations. Maternal toxicity was noted at the mid dose as soiled anal area, anorexia, and punctate vacuolation of hepatocytes. The high dose group was also associated with abortions, late resorptions, and 1 death as well as additional histopathology in the liver (hepatocellular necrosis eosinophilia, swelling of hepatocytes, pigmentation of Kupffer cells, etc). The Maternal Toxicity NOAEL is 5 mg/ kg/ day and Chronic RfD = 8.46 mg/ kg/ day (NOAEL) = 0.08 mg/ kg/ day 100 (UF) 7 the Maternal Toxicity LOAEL is 20 mg/ kg/ day based on clinical signs of toxicity and liver effects.

Developmental Toxicity was seen at the high dose as abortions. The Developmental Toxicity NOAEL is 20 mg/ kg/ day and the Developmental Toxicity LOAEL is 80 mg/ kg/ day based on abortions.

CLASSIFICATION: This study is classified as Acceptable Guideline and satisfies the guideline requirements for a prenatal developmental toxicity study in rabbits (OPPTS 870.3700; OPP §83 3b).

Dose and Endpoint for Risk Assessment: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits.

Comments about Study/ Endpoint: Although the developmental toxicity study in rabbits selected for short term incidental exposure is of the appropriate route (oral) and duration (13 days), the NOAEL (5 mg/ kg/ day) in this study is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the the doses of pronamide selected for testing in these studies. The HIARC concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day rather than 5 mg/ kg/ day would provide a sufficiently protective dose for risk assessment.

The NOAEL of 3 mg/ kg/ day established in the special thyroid study conducted in male rats was also considered. However this dose was not selected because the wide gap between the NOAEL (3 mg/ kg/ day) and the LOAEL (67 mg/ kg/ day) in this study resulted in the 3 mg/ kg/ day dose (NOAEL) being artificially low. In addition, the LOAEL of 67 mg/ kg/ day is comparable to the LOAEL (56 mg/ kg/ day) established in the chronic toxicity /carcinogenicity study conducted in rats.

2.3.2 Intermediate Term (1 6 Months) Incidental Oral Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day.

Comments about Study/ Endpoint: The NOAEL of 12.3 mg/ kg/ day established in the 90 day subchronic toxicity study in rats was considered for risk assessment. However, the severity of the toxicities (increased absolute and relative liver weights and hepatocellular hypertrophy) observed in this study were determined to be minimal. Since this NOAEL (12.3 mg/ kg/ day) is numerically close to the NOAEL of 8.46 mg/ kg/ day established in the 8 long term toxicity study conducted in rats and the organ toxicities (liver, thyroid, and ovaries) observed in the 24 month study occurred as early as 6 months and continued to study termination, the HIARC determined that the chronic feeding/ carcinogenicity study in rats is an appropriate study for the (1 6 months) intermediate term exposure duration. Therefore, the selection of a NOAEL of 8.46 mg/ kg/ day for the intermediate term incidental oral exposure scenario is adequately protective of the population of concern (infants and children).

2.3.3 Dermal Absorption Percentage (%) Dermal Absorption: 100% dermal absorption (default value).

Comments about Dermal Absorption: A dermal absorption study submitted to the Agency was classified as unacceptable because 1) the actual dose applied to the skin was not determined and 2) there were discrepancies in recovery for the 50W formulation doses (78% and 122% of nominal doses). In addition, there were no dermal toxicity studies submitted which could be used for comparison to oral toxicity studies. A 100% dermal absorption default value was determined for risk assessment purposes due to the limitations of the available pronamide toxicity data base (absence of dermal toxicity studies as well as an unacceptable dermal absorption study).

2.3.4 Short Term (1  30 Days) Dermal Exposure Study Selected: Developmental Toxicity in Rabbits Guideline#: 870.3700 MRID No.: 00148065, 00148064 Executive Summary: See Short Term (1 30 days) Incidental Oral Exposure, Section 2.3.1 Dose and Endpoint for Risk Assessment: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits.

Comments about Study/ Endpoint: See Short Term (1 30 days) Incidental Oral Exposure, Section 2.3.1. Since there were no dermal toxicity studies submitted, it is appropriate to select an endpoint from an oral study of the appropriate duration of exposure. A dermal absorption factor of 100% should be applied for this risk assessment.

2.3.5 Intermediate Term (1 6 Months) Dermal Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 9 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day.

Comments about Study/ Endpoint: See Intermediate Term (1 6 months) Incidental Oral Exposure, Section 2.3.2. Since no dermal toxicity studies were submitted, it is appropriate to select an oral endpoint from a study of the appropriate duration of exposure. A dermal absorption factor of 100% should be applied for this risk assessment.

2.3.6 Long Term (> 6 Months) Dermal Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day.

Comments about Study/ Endpoint: Since no dermal toxicity studies were submitted, the selected endpoint is from an oral study of the appropriate duration of exposure. A dermal absorption factor of 100% should be applied for this risk assessment.

2.3.7 Short Term (1  30 Days) Inhalation Exposure Study Selected: Developmental Toxicity in Rabbits Guideline #: 870.3700 MRID No.: 00148065, 00148064 Executive Summary: See Short Term (1 30 days) Incidental Oral Exposure, Section 2.3.1 Dose and Endpoint for Risk Assessment: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits.

Comments about Study/ Endpoint: See Short Term (1 30 days) Incidental Oral Exposure, Section 2.3.1. With the exception of an acute oral inhalation toxicity study conducted with the 50W Kerb formulation, no other inhalation toxicity studies were submitted. Therefore, an oral end point was selected from a study of the appropriate duration of exposure. An inhalation absorption factor of 100% should be applied for this risk assessment. 10 2.3.8 Intermediate Term (1 6 Months) Inhalation Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day.

Comments about Study/ Endpoint: See Intermediate term (1 6 months) Incidental Oral Exposure, Section 2.3.2. With the exception of an acute oral inhalation toxicity study conducted with the 50W Kerb formulation, no other inhalation toxicity studies were submitted. Therefore, an oral end point was selected from a oral study of the appropriate duration of exposure. An inhalation absorption factor of 100% should be applied for this risk assessment.

2.3.9 Long Term (> 6 Months) Inhalation Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day.

Comments about Study/ Endpoint: With the exception of an acute oral inhalation toxicity study conducted with the 50W Kerb formulation, no other inhalation toxicity studies were submitted. Therefore, an oral end point was selected from a oral study of the appropriate duration of exposure. An inhalation absorption factor of 100% should be applied for this risk assessment.

2.3.10 Margins of Exposure for Occupational/ Residential Risk Assessments A MOE of 100 is required for short, intermediate, and long term occupational risk assessments for both dermal and inhalation routes of exposure. This includes 10x for interspecies extrapolation and 10x for intraspecies variation.

The acceptable MOEs for residential exposure will be determined by the FQPA SF committee. 11 2.4 Recommendation for Aggregate Exposure Risk Assessments For short term exposure, incidental oral, dermal, and inhalation routes can be aggregated because of the use of oral equivalents and a common endpoint (clinical signs of toxicity and liver effects). For intermediate term and long term exposure, incidental oral, dermal and inhalation routes can be aggregated because of oral equivalents and a common endpoint (increased relative liver weight and non neoplastic histologic changes in the liver, thyroid, and ovaries).

3 CLASSIFICATION OF CARCINOGENIC POTENTIAL 3.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 00417140, 00417141 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Discussion of Tumor Data: Statistical analysis of tumor rates was based on the Cochran Armitage Trend Test and Fisher's Exact Test for pair wise comparison of controls and each treated group since there was no significant statistical evidence of differential mortality with increasing doses of Pronamide.

At 1000 ppm, in the 24 month phase, both male and female rats had increased rates of thyroid follicular cell adenomas, and male rats had an increased incidence of benign testicular interstitial cell tumors. Thyroid tumors were not observed until weeks 53 and 82 for males and females, respectively, and testicular tumors were not observed until week 67. The increase in thyroid tumor rate was statistically significant by pair wise comparison (p < 0.01) only in males, but there was a positive trend (p < 0.01) for both sexes. Both high dose male and female tumor rates (21% and 10%, respectively) exceeded the historical control range which was 0 14.8% (mean 5%) for males and 0 9.5% (mean 2%) for females (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 13 studies conducted between 1985 and 1990). There were no significant differences in thyroid follicular cell carcinoma rates between groups. There were increasing trends and/ or rates in combined thyroid follicular cell adenomas and carcinomas (trend p < 0.01 in males, p < 0.05 in females; pair wise comparison of high dose males/ controls, p < 0.05) which were a reflection of the treatment related changes in thyroid follicular cell adenoma rates. The increase in testicular interstitial cell benign tumor rate was statistically significant by pair wise comparison (p < 0.05) and there was a positive trend (p < 0.01). In high dose males, the tumor rate (27%) exceeded the historical range of 4.8 18.2% with a mean value of 5.6% (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 11 studies conducted between 1985 and 1990). In the 12 month phase, thyroid follicular cell and testicular interstitial cell neoplasia were not observed in any group.

Benign pituitary adenomas of the pars distalis were observed in every dose group during both the 12 and 24 month phases, but the tumor rates were statistically comparable among all groups. The respective tumor rates for the 0, 40, 200, and 1000 ppm dose groups were 1/ 19, 0/ 19, 0/ 20, and 3/ 20 in males and 0/ 20, 2/ 20, 1/ 19, and 3/ 20 in females in the 12 month phase and 31/ 60, 33/ 60, 35/ 60, and 34/ 60 in males and 49/ 60, 49/ 60, 49/ 60, and 54/ 60 in females in the 24 month phase. 12 Adequacy of the Dose Levels Tested: The dosing was considered to be adequate for assessing carcinogenic potential of Pronamide, based on body weight gain depressions (p < 0.05) of $ 10% observed at 1000 ppm (weeks 0 26 in males; weeks 0 52 in females). Feed consumption was also depressed (p < 0.05) at 1000 ppm in males during weeks 1 13 (7%), 1 26 (7%), and 1 52 (5%). Survival rate was comparable between groups. The statistical evaluation of mortality indicates no significant incremental changes with increasing doses of Pronamide in either male or female rats.

3.2 Carcinogenicity Studies in Mice Carcinogenicity Study in Male and Female Mice, 1974 MRID No.: 00107968, 00066794 Executive Summary: In a carcinogenicity study (MRID# 00107968), pronamide (97 % a. i.) was administered to male and female B6C3F1 mice (125/ sex/ dose) in the diet at dose levels of 0 (control) 1000, or 2000 ppm for 18 months. This corresponds approximately to 0, 150, and 300 mg/ kg/ day. Mice (25/ sex/ dose) were sacrificed at the end of a 30 week treatment period (interim sacrifice); the remaining mice were sacrificed at the end of the 18 month treatment period. The study design also included, for comparison, mice treated with known hepatocarcinogens, including 4 6 mg/ kg/ day diethylnitrosamine (DEN) and 2 acetamidofluorene (AAF).

There were no apparent treatment related effects on survival. At the end of the 18 month study, survival rates were comparable between groups with no gender differences (rates greater than 90%). Significant decreases in mean body weights were observed in females treated with 2000 ppm (the high dose) during the study. Mean body weight gains were reduced in the low dose (1000 ppm) females (50 78 weeks), the high dose females (0 30 weeks; 50 78 weeks) and the high dose males ( 50 78 weeks). At interim sacrifice, absolute and relative liver weights were significantly increased in the low dose and high dose females, and in the high dose males. At terminal sacrifice, relative liver weights were significantly increased in the low and high dose males and females.

A dose related increase in the incidence of hepatocellular carcinomas (respective rates at 0, 1000, and 2000 ppm were 7/ 100, 18/ 99, and 24/ 99) was observed in male mice sacrificed at 18 months. The hepatocellular carcinomas were characterized as non metastisizing. Pronamide did not significantly induce hepatocellular carcinomas in female mice compared to controls (respective rates at 0, 1000, and 2000 ppm were 0/ 100, 1/ 100, and 2/ 100) at 18 months. Some of the high dose males exhibited cholestasis in hepatocytes and/ or Kupffer's cells.

The LOAEL is 1000 ppm (150 mg/ kg/ day) based on decreased body weight gain in treated females and increased relative (to body weight) liver weights in both sexes. A NOAEL was not established.

Under the conditions of this study, there was evidence of a treatment related increase in tumor incidence in the livers of male mice when compared to controls. Dosing is considered adequate to assess the carcinogenic potential of pronamide based on body weight gain depressions in treated females and increases in relative (to body) weight of the liver at $ 1000 ppm in both sexes.

Although this study would not normally meet the guideline requirement for a carcinogenicity study (83 2b) in this species (i. e., study deficiencies included lack of dietary analyses and food consumption to ensure homogeneity, stability, and concentration of test material in the diet, and to 13 assess potential palatability problems with the diet), confidence in the reported tumor data is enhanced by the findings of a subsequent 1982 special carcinogenicity study in male mice (MRID# 001114114) that confirm the tumor findings. Moreover, if reviewed in conjunction with the 1982 special carcinogenicity study in male mice, the present study is adequate to assess the carcinogenic potential of pronamide in mice, and can be used for regulatory and risk assessment purposes.

Discussion of Tumor Data: A dose related increase in the incidence of hepatocellular carcinomas was observed in male mice sacrificed at termination (18 months). The increases in tumor rates observed at 1000 and 2000 ppm were both statistically significant by pair wise comparison with controls (p < 0.01). Pronamide did not induce hepatocellular carcinomas in female mice (rates at termination were 0/ 100 in controls; 1/ 100 at 1000 ppm; 2/ 100 at 2000 ppm). Survival rates of all groups were comparable ( $ 90%).

Adequacy of the Dose Levels Tested: The dosing was considered to be adequate for assessing the carcinogenic potential of Pronamide, based on body weight gain depressions in high dose females (16.5% decrease, weeks 2 78, p < 0.05), and increasers in relative body weight of the liver at $ 1000 ppm in both sexes [23% at 1000 ppm and 41% at 2000 ppm, p < 0.05 (males); 14% at 1000 ppm and 36% at 2000 ppm, p < 0.05 (females)].

Carcinogenicity Study in Male Mice, 1982 MRID No.: 00114114, 00151822 Executive Summary: In a special carcinogenicity study (MRID# 0011411), pronamide (93.8 99% a. i.) was administered to male B6C3F1 mice (63/ group) in the diet at dose levels of 0 (control group1 and control group 2), 20, 100, 500, or 2500 ppm for 24 months. This corresponds to 0, 3, 15, 75, and 375 mg/ kg/ day. The two matched control groups received untreated diet. Additional groups were assigned to interim sacrifices at 6 months (42 mice at 0 ppm; 42 mice at 2500 ppm) and at 15 and 18 months (42/ group including control groups 1 and 2, and 20, 100, 500, and 2500 ppm groups). Survival rats were greater than 93% for all groups. Both the 500 ppm and 2500 ppm males exhibited gross findings of increased incidences of liver nodules/ masses and enlarged livers at the 24 month interval. Non neoplastic hepatic effects observed in males treated with the high dose (2500 ppm) for 24 months, included increased incidences of liver enlargement, liver nodules/ masses, hypertrophy, parenchymal necrosis, and cholestasis. Administration of pronamide also resulted in decreased body weights.

The results of the special study confirmed that long term exposure of male mice to pronamide was associated with an increased incidence of hepatocellular carcinomas (respective rates at 0, 0, 20, 100, 500, or 2500 ppm at the 24 month sacrifice were 5/ 63, 5/ 63, 9/ 63, 12/ 63, 18/ 63, and 14/ 61). Additionally, hepatocellular adenomas were observed (respective rates at 0, 0, 20, 100, 500, or 2500 ppm at the 24 month sacrifice were 4/ 63, 6/ 63, 6/ 63, 7/ 63, 8/ 63, and 28/ 61). The incidence of adenoma and carcinoma was significantly increased in the 500 ppm and 2500 ppm males when compared to controls. There was an apparent progression from benign to malignant tumors. This special study confirmed the carcinogenic effect of pronamide in male mice.

The LOAEL is 500 ppm (75 mg/ kg/ day) based on gross findings (increased incidences of hepatic nodules/ masses and hepatic enlargement) observed after 24 months of treatment. The NOAEL is 100 ppm (15 mg/ kg/ day). 14 Under the conditions of this study, there was evidence of a treatment related increase in tumor incidence in the liver of male mice when compared to controls. Dosing is considered adequate to assess the carcinogenic potential of pronamide based on liver effects (non neoplastic lesions and increased weight).

This special carcinogenicity study in the male mice is classified as Acceptable Nonguideline. The data confirmed the results of a previously conducted carcinogenicity study in mice (1974, MRID# 00107968). When reviewed in conjunction with the 1974 carcinogenicity study, these two studies fulfill the guideline requirement for a carcinogenicity study [870.4200 (§ 83 2b)] in mice and can be used for regulatory and risk assessment purposes.

Discussion of Tumor Data: This study confirmed the results of the MCV 1974 study; long term (24 months) exposure of male mice to Pronamide was associated with an increased incidence of hepatocellular carcinomas. A positive trend (p < 0.05) in incidences of hepatocellular carcinomas was observed in mice sacrificed at 24 months, and the increased tumor rates observed at $ 100 ppm were statistically significant (p < 0.05 at 100 ppm; p < 0.01 at 500 and 2500 ppm). Hepatocellular adenomas were not observed in pair wise differences at 2500 ppm (p < 0.01) in mice sacrificed at 24 months in this study. There also appeared to be a progression from benign to malignant tumors. Survival rates were excellent for all groups ( $ 93%).

Adequacy of the Dose Levels Tested: The dosing was considered to be adequate for assessing the carcinogenic potential of Pronamide, based on decreased body weight (30%, months 6 24) and increased liver weight (30 40% absolute weight increase; 100% relative body weight increase) in the high dose group.

3.3 Classification of Carcinogenic Potential In accordance with the Agency's Proposed Guideline for Carcinogen Risk Assessment (April, 1996), the HED Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a Group B2 chemical, probable human carcinogen with inadequate evidence in humans (Memorandum: N. B. Thoa and E. Rinde, May 26, 1993). This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1*) is used for human risk characterization. The most potent unit risk Q1*, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 2 (mg/ kg/ day) 1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor] (Memorandum: L. Brunsman, October 26, 2001, TXR# 0050181).

4 MUTAGENICITY With the exception of one gene mutation toxicology study, the remaining five mutagenicity studies were reviewed and found to be acceptable for regulatory purposes (The acceptable studies statisfy the 1991 mutagencity guideline requirements). The results from these studies indicate that pronamide was not mutagenic in Salmonella typhimurium, Escherichia coli or in cultured Chinese hamster lung cells and did not produce a genotoxic response in Bacillus subtiltis or in cultured primary rat hepatocytes. There was also no evidence of clastogenicity in cultured Chinese hamster ovary cells and pronamide administration did not result in the induction of micronucleated polychromatic erythrocytes in bone marrow of mice. Overall, the data suggest that pronamide is negative for mutagenicity in vitro and in vivo. 15 Gene Mutation in Salmonella typhimurium/ mammalian microsome mutagenicity assay; OPPTS 870.5100 [§ 84 2]. In a microbial reverse gene mutation assay (MRID No. 40090601) Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 were exposed to four doses of propyzamide as RH 315 (purity not specified) ranging from 1 500 : g/ plate in both the presence and the absence of S9 activation. The S9 fractions were derived from Aroclor 1254 induced C57BL/ 6 x C3H/ Anf male and female mouse livers and the test material was delivered to the test system in an unspecified solvent. Cytotoxicity was reported at levels >500 µg/ plate with or without the two S9 fractions (male and female S9 fractions were processed separately) but no data were presented. Strains TA1535, TA1538, TA98 and TA100 responded in the expected manner to the solvent and the appropriate positive controls. However, the spontaneous revertant colony counts of strain TA1537 +/ S9 were outside of the expected range and this strain failed to respond to the positive control, activated by either the S9 fraction derived from male or female mouse livers. There was no evidence that RH 315 induced a mutagenic effect in any strain at any dose without or without the S9 homogenates. However, the study is not valid because neither the test material purity nor the solvent were reported, the claim of cytotoxicity was not supported, the number of replicates at each experimental concentration was not listed and strain TA1537 performed poorly. This study is classified as Unacceptable and does not satisfy the guideline requirements for a bacterial gene mutation assay (84 2).

Gene Mutation in Salmonella typhimurium and Escherichia coli/ mammalian microsome mutagenicity assay/ Bacillus subtiltis DNA damage/ repair assay; OPPTS 870.5100/ 5500 [§ 84 2]. In a series of microbial assays (MRID No. 40090602), propyzamide as KERB® (93.7% a. i.) in dimethyl sulfoxide (DMSO) was tested for the ability to induce reverse gene mutations in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 and in Escherichia coli WP2 hcr at 10 to 5000 : g/ plate in both the presence and the absence of S9 activation. DNA damage/ repair was assessed in Bacillus subtilis H17 (rec + ) and M45 (rec  ) at 20 to 2000 : g/ disc with and without S9 activation. The S9 fractions were derived from Aroclor 1254 induced Sprague Dawley rat livers. No cytotoxicity was seen up to the limit dose (5000 µg/ plate) with or without S9 activation in either the S. typhimurium or the E. coli strains or up to a dose approaching the limit of solubility in the B. subtilis strains. All strains responded in the expected manner to the solvent and the appropriate positive controls. There was also no evidence that KERB® induced a genotoxic effect in any strain at any dose without or without the S9 homogenate. This study is classified as Acceptable and satisfies the guideline requirements for a bacterial gene mutation assay and a bacterial DNA damage/ repair assay (84 2).

Gene Mutation/ in vitro mammalian cell assay in Chinese hamster lung (CHL) cells; OPPTS 870.5300 [§ 84 2]. In independently performed in vitro mammalian cell gene mutation assays (MRID No. 40211106), cultures of Chinese hamster lung (CHL) fibroblasts were exposed for 3 hours to concentrations of of 2.5 to 40 : g/ mL propyzamide as KERB® Technical (96.3%) in the presence and absence of S9 activation. Treated cell cultures were allowed three expression times (48, 96 and 168 hours) with or without S9 activation. The S9 homogenate was derived from rat livers induced with phenobarbitone and $ naphthoflavone and the test material was delivered to the test system in dimethyl sulfoxide (DMSO). KERB® Technical was slightly cytotoxic at 40 : g/ mL+/ S9; higher levels were insoluble. Cells responded as expected to the solvent and positive controls. There was, however, no evidence that KERB® Technical was mutagenic at any dose under any assay condition. This study is classified as Acceptable and satisfies the guideline requirement for a gene mutation in cultured mammalian cell assay (§ 84 2).

Cytogenetics/ in vitro mammalian cell assay in Chinese hamster ovary (CHO) cells; OPPTS 870.5375 [§ 84 2]. In a mammalian cell cytogenetic assay (MRID No. 40211108), cultured Chinese hamster ovary (CHO) cells were exposed continuously to propyzamide as KERB technical (94.2%) at seven doses ranging from 16 25 400 : g/ mL in the absence of metabolic activation for 14 and 24 hours. Cells were also exposed to S9 activated doses of 25 400 : g/ mL for 2 hours and harvested following a 12 and 22 hour recovery period. The S9 homogenate was derived from Aroclor 1254 induced Sprague Dawley rat livers and the test material was delivered to the test system in dimethyl sulfoxide. Doses $ 250 : g/ mL were insoluble; cytotoxicity was not seen at any concentration. The positive controls induced the expected clastogenic responses with or without S9 activation. There was, however, no evidence that KERB technical induced a clastogenic response either in the presence or the absence of S9 activation. This study is classified as Acceptable and satisfies the guideline requirement for an in vitro mammalian cell cytogenetic assay (§ 84 2).

Cytogenetics/ in vivo mammalian bone marrow chromosomal aberration test in mice; OPPTS 870.5385 [§ 84 2]. In an in vivo cytogenetic assay (MRID No. 40211105), groups of 10 male B6C3F1 mice received single doses of 480, 1940 or 4940 mg/ kg propyzamide as KERB® technical (96.8%) once daily for 1 day or for 5 consecutive days and were sacrificed 6, 12 or 24 hours postdosing (acute exposure) or 6 hours postdosing (subacute exposure). The highest assayed dose was determined based on the estimated oral LD50 >5 g/ kg in male B6C3F1 mice. The test material was delivered to the animals in 0.5% methyl cellulose. At the appropriate sacrifice intervals (6, 24 and 48 hrs postdosing with 4940 mg/ kg acute exposure or 6 hrs after the 5 day administration of 1940 mg/ kg/ day), bone marrow cells were harvested and were examined for the incidence of structural chromosome aberrations. Unscheduled deaths occurred as follows: 7% in the acute high dose group, 10% in the subacute intermediate dose group and 60% in the subacute high dose group (Days 2 or 3). Other signs of compound toxicity observed in the surviving animals included signs of central nervous system depression [i. e., lethergy and ataxia  Day 1 (high and mid dose –acute regimen); lethergy, ataxia, reduced spontaneous motor activity, loss of righting reflex, catalepsy and abdominal breathing [Day 1 and/ or Day 2 (high and mid dose –subacute regimen)]. The positive control induced the expected significant increase in the frequency of cells with aberrant chromosomes. There was, however, no evidence that KERB® technical induced a clastogenic effect at the selected dose or sacrifice times. The study is classified as Acceptable and satisfies the requirements for FIFRA Test Guideline 84 2 for in vivo cytogenetic mutagenicity data.

Other Mutagenic Mechanisms/ in vitro unscheduled DNA synthesis in mammalian cells in culture; OPPTS 870.5550 [§ 84 2]. In an in vitro unscheduled DNA synthesis (UDS) assay (MRID No. 40211107), primary rat hepatocytes were exposed to propyzamide as KERB® technical (94.2%) at 9 doses ranging from 0.1 500 µg/ mL. Hepatocytes, harvested 19 hours after treatment with 1, 5, 10, 25 or 50 µg/ mL were scored for net nuclear grains/ nucleus. The test material was delivered to the test system in dimethyl sulfoxide. Cytotoxicity (< 50% cell survival) was seen at $ 100 µg/ mL and cells treated with these doses were not scored. The positive control induced the expected marked increases in UDS. There was, however, no evidence that KERB® technical induced a genotoxic response. This study is classified as Acceptable and satisfies the guideline requirement for a UDS assay (84 2).

5 FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base The following pronamide toxicity studies are available and adequate for evaluation of FQPA:

 Developmental Toxicity Study in Rabbits  Two Generation Reproduction Study There is a data gap for a developmental toxicity study in rats. A definitive NOAEL as well as a LOAEL were not established in this study; no toxicities were observed in the maternal animals and 17 their fetuses. Therefore, the rat developmental toxicity study is classified as unacceptable guideline (not upgradeable) and can not be used for endpoint selection.

5.2 Neurotoxicity Data Mammalian neurotoxicity studies for Pronamide have not been conducted. However, since this chemical is not an organophosphate and there is no evidence of neurotoxicity seen in any of the existing studies, neurotoxicity studies (e. g., an acute delayed neurotoxicity study in the hen, a neurotoxicity screening battery or a developmental neurotoxicity study) were not required.

5.3 Developmental Toxicity Developmental Rat In a prenatal developmental toxicity study (MRID# 40334501), pregnant Crl: CD ® BR rats (Charles River Breeding Laboratories, Montreal Quebec) received KERB ® Herbicide (94.2% a. i.; Lot 4859) as an aqueous suspension in 0.5% methyl cellulose by gavage from gestation days 6 through 15 inclusive at dose levels of 0, 5, 20, 80 or 160 mg/ kg/ day. Each animal was examined once daily for signs of toxicity and mortality. Body weights were recorded on gestation days 0, 6, 8, 10, 13, 16, and 20. All surviving rats were sacrificed on gestation day 20, the thoracic and abdominal cavities were examined for gross pathologic changes. The gravid uterus was weighed and the the numbers of corpora lutea, implantation sites, and resorptions were recorded. The number of fetuses were counted and their locations in the uterus were recorded. All fetuses were weighed and examined for external abnormalities. Half of the fetuses were then fixed and cleared and stained in Alizarin red S for skeletal examinations and the other half were examined for visceral anomalies.

No Maternal Toxicity was noted at the dose levels tested. The Maternal Toxicity NOAEL is equal to or greater than 160 mg/ kg/ day and the Maternal Toxicity LOAEL is greater than 160 mg/ kg/ day.

No Developmental Toxicity was noted at the dose levels tested. The Developmental Toxicity NOAEL is equal to or greater than 160 mg/ kg/ day and the Developmental Toxicity LOAEL is greater than 160 mg/ kg/ day.

CLASSIFICATION: This study is classified as Unacceptable Guideline (not upgradeable). It does not satisfy the guideline requirements for a prenatal developmental toxicity study in rats (OPPTS 870.3700; OPP §83 3a) because there were no maternal or fetal toxicities observed at any dose tested (a LOAEL was not established). In addition, the highest dose tested may not be the definitive NOAEL.

Developmental Rabbit See Short Term Incidental Oral Exposure (Section 2.3.1) for executive summary. 18 5.4 Reproductive Toxicity Reproduction Rat In a 2 generation reproduction study (MRID# 41540301), Pronamide (93.1% a. i.; Lot Number WHC1742 was administered to Crl: CD® BR Rats (Charles River Labs, Kingston, N. Y.) in the diet at dose levels of 0, 40, 200 or 1500 ppm (equal to 3.1, 16.0 and 120.7 mg/ kg/ day for females and 3.6, 18.0 and 130.1 mg/ kg/ day for males for the 40, 200 and 1500 ppm dose groups, respectively) through 2 generations (one mating period per generation). All animals were observed daily for clinical signs of toxicity and twice daily for mortality/ moribundity. Individual body weights and food consumption were recorded weekly during the premating period and females body weights were recorded on gestation days 0, 7, 14, and 21 and on lactation days 0, 7, 14, and 21. Reproductive parameters were recorded including number of females paired, mated, pregnant, duration of gestation, number of females with live litters, and sex ratio/ litter. The litter observations included number of pups born alive or dead, sex, gross abnormalities and the pus were examined twice daily for mortality/ moribundity and were weighed and examined for behavior and appearance on lactation days 0, 4, 7, 14, and 21. All animals found dead, sacrificed early and at termination were subject to a complete necropsy, this included all pups found dead before weaning, those not selected for breeding and all F2 weanling at study termination.

No treatment related mortalities and/ or clinical signs were observed in either parental (Pl and P2) generations. There were parental systemic effects at the high dose based on decreases in body weight and feed consumption in both sexes and increased incidences of histopathology of the liver (centrilobular hepatocytes hypertrophy; both sexes), adrenal gland (zona glomerulosa cellular hypertrophy; both sexes), thyroid gland (follicular cell hypertrophy; females), and anterior pituitary gland (cellular hypertrophy; males) in both P1 and P2 generations, and increased incidences of uterine gross pathology (black foci/ serosal surface) in P2 females. The Parental Systemic Toxicity NOAEL was 200 ppm (16.0 mg/ kg/ day for females and 18.0 mg/ kg/ day for males) and the Parental Systemic LOAEL was 1500 ppm (120.7 mg/ kg/ day for females and 130.1 mg/ kg/ day for males), based on decreases in body weight and feed consumption in both sexes and increased incidences of histopathology of the liver, adrenal gland, thyroid gland, and anterior pituitary gland in both P1 and P2 generations, and increased incidences of uterine gross pathology in P2 females.

There were no reproductive effects in either the P1 or P2 generations, including the females' mating, fertility, and gestation indexes, the number of pups born dead or alive/ litter and sex ratio per litter. The Reproductive Toxicity NOAEL is equal to or greater than 1500 ppm and the Reproductive Toxicity LOAEL is greater than 1500 ppm.

There were no effects on F1/ F2 litter parameters including the number of live pups/ litter on lactation days 0, 4, 7, 14, or 21 and the viability and lactation indexes. Combined (male + female) F1/ F2 pups body weight/ litter at birth and/ or during the lactation period were unaffected by the low or mid dose, but was significantly reduced by the high dose (F1 at birth and during the entire lactation period; F2 during lactation days 14 and 21). There were no treatment related filial abnormal necropsy findings. The Developmental/ Offspring Toxicity NOAEL was 200 ppm and the Developmental/ Offspring Toxicity LOAEL was 1500 ppm, based on decreases in combined male/ female pup weight/ litter. 19 Classification: This study is classified as Acceptable Guideline and satisfies the guideline requirements for a 2 generation reproductive toxicity study in rats (OPPTS 870.3800; OPP §83 4).

5.5 Additional Information from Literature Sources (if available)

There is no additional toxicity information from literature sources for the herbicide, pronamide.

5.6 Determination of Susceptibility There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the offspring of rats or rabbits following pre and/ or postnatal exposure to pronamide. In the prenatal developmental toxicity study in rabbits and the multigeneration reproduction study in rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than did toxicity to parental animals.

Evidence for susceptibility could not be ascertained in the developmental toxicity study conducted in rats because there were no maternal or fetal toxicities observed at any dose tested (a LOAEL was not established). In addition, the highest dose tested may not be the definitive NOAEL. The HIARC determined that this study is a data gap.

Although this study failed to demonstrate maternal and/ or developmental toxicities, it can be used in the weight of evidence evaluation for determining the FQPA safety factor since the highest dose tested in this rat developmental toxicity study exceeded the highest doses tested in both the rabbit developmental toxicity study (80 mg/ kg/ day) and the rat multigeneration reproduction study (120.7 mg/ kg/ day in males; 130.1 mg/ kg/ day in females).

5.7 Determination of the Need for Developmental Neurotoxicity Study 5.7.1 Evidence that suggest requiring a Developmental Neurotoxicity study:

 The results of several toxicity studies conducted in both the rat and dog demonstrated evidence of endocrine organ toxicity (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) following exposure to pronamide.

 Pronamide is listed as a potential endocrine disruptor on EPA's Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) list.

5.7.2 Evidence that do not support the need for a Developmental Neurotoxicity study – There was no evidence of increased susceptibility to rabbit fetuses in the developmental toxicity study or to rat offspring in the multigeneration reproduction study following pronamide exposure.

– There was no evidence of neurotoxicity in any of the available mammalian toxicity studies conducted with pronamide.

The HIARC recommended that a developmental neurotoxicity study in the rat not be required. A comparative study designed to assess thyroid function in adult animals and their offspring as well as potential central nervous system effects in the young will be required due to endocrine toxicities 20 observed in several organ systems (thyroid, testes, ovaries, adrenal glands, pituitary gland and thymus) of the rat and/ or dog. Since the data obtained from these toxicity studies (a special endocrine/ thyroid study in addition to the required guideline studies) are suggestive of a potential hormonal mechanism for thyroid toxicity and considering that it is thyroid hormone which is essential for growth, brain development and nervous system maturation, a comparative thyroid assay rather than a developmental neurotoxicity study, would provide a more complete characterization of endocrine disruption (precursor effects in the thyroid) associated with exposure to pronamide. The Registrant is advised to consult the Agency with regard to the submission of a thyroid assay protocol prior to the initiation of this special study.

6 HAZARD CHARACTERIZATION Pronamide technical has a low order of acute toxicity via the oral, dermal, and inhalation routes of exposure (Toxicity Category III or IV), produces mild irritation to the eyes and skin (Toxicity Category IV), and is not a dermal sensitizer.

Pronamide appears to be a liver toxicant. Adverse liver related effects (increases in liver weight and/ or liver related serum enzymes and/ or histopathology) were consistently observed in every animal species studied, including the rat (subchronic, chronic, and 2 generation reproduction studies), mouse (carcinogenicity studies), rabbit (developmental study), and dog (subchronic and chronic studies). Other target organs included the thyroid in rats (increase in weight and/ or histopathology observed in the chronic toxicity/ carcinogenicity and the 2 generation reproduction studies as well as a subchronic, special 13 week thyroid function study), the testes in rats (histopathology in the chronic toxicity/ carcinogenicity study) and the kidneys, adrenal glands thymus, heart, testes, and brain in dogs (increase in organ weights in the chronic toxicity study), and the pituitary in rats (histopathology observed in the subchronic and 2 generation reproduction studies). Many chemicals belonging to the class of organochlorine chemicals are known to produce disruption of the endocrine system. Pronamide belongs to this class of chemicals.

There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the offspring of rats or rabbits following pre and/ or postnatal exposure to pronamide. In the prenatal developmental toxicity study in rabbits and the multigeneration reproduction study in rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than did toxicity to parental animals. Although the highest dose of pronamide tested in the rat developmental toxicity study exceeded the highest doses tested in both the rabbit developmental toxicity study and the rat multigeneration reproduction study without demonstrating toxicities, it failed to assess the potential increased susceptability to infants and children as required by the Food Quality Protection Act (FQPA) of 1996.

The Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a group B2  probable human carcinogen with inadequate evidence in humans. This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1*) is used for human risk characterization. The most potent unit risk Q1*, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 2 (mg/ kg/ day) 1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor].

Although endocrine effects have been observed in several toxicity studies, the data provided in two special studies conducted to explore pronamide's effect on hormonal balance in support of a threshold mechanism for the induction of thyroid and testicular neoplasms, are incomplete. Based on the CPRC's weight of the evidence evaluation of this data base, it was determined that even if a hormonal mechanism could be demonstrated for tumors in the rat, the mouse liver tumors can not be discounted (the Q1* is based on the 21 incidence of liver tumors in mice). Therefore, a mechanistic approach to risk assessment for the active ingredient pronamide is not plausible.

Results of mutagenicity studies with an acceptable classification (forward and reverse gene mutation, in vivo and in vitro cytogenetic/ structural chromosome aberration and unscheduled DNA synthesis assays) indicate that pronamide is not a mutagenic agent.

Mammalian neurotoxicity studies for Pronamide have not been conducted. However, since this chemical is not an organophosphate and there is no evidence of neurotoxicity seen in any of the existing studies, neurotoxicity studies (e. g., an acute delayed neurotoxicity study in the hen, a neurotoxicity screening battery or a developmental neurotoxicity study) were not required.

Pronamide is rapidly absorbed and completely and rapidly eliminated; the radioactivity administered was recovered (93 103%) in the urine (40 61%), feces (40 60%) and tissues and carcass (0.08 2.43%). No bioaccumulation was apparent and tissues with the highest radioactivity content were, in decreasing order, the fat, adrenals, bone marrow, thyroids, liver kidney, and plasma. The elimination of radioactivity from the plasma of low dose rats was biphasic [rapid phase = 12.6 hrs (males) and 12.7 hrs (females); slow phase = 36.6 hrs (males) and 45.3 (females)] and that of the high dose rats was monophasic [t½ = 24.1 hrs (males) and 24.8 hrs (females)]. Very little unchanged pronamide was recovered in the urine and no significant difference in urinary metabolite profile was observed between the doses or the sexes. The two major urinary metabolites were SS47 70 (3.0 5.9%) of the dose and metabolite 10 (12.7 18.9%). In the urine, 27 metabolites were found and none exceeded 3.3% of the dose, whereas, almost all of the unknowns were less than 1% of the dose.

There is no acceptable dermal absorption study in the pronamide data base. In addition, there were no dermal toxicity studies submitted which could be used for comparison to oral toxicity studies. Therefore, a 100% (default value) dermal absorption factor was determined for risk assessment purposes.

7 DATA GAPS Developmental Toxicity Study in Rats 21 Day Dermal Toxicity Study 28 Day Inhalation Toxicity Study Dermal Penetration Study A Comparative Thyroid Rat Assay in Adult Animals and Offspring 22 8 ACUTE TOXICITY Acute Toxicity of Pronamide (Propyzamide)

Guideline Number Study Type MRID# Results Toxicity Category 870.1100 (§ 81 1) Acute Oral  Rat, > 92.0% a. i. 00085505 LD50 (males and females) > 5000 mg/ kg IV 870.1100 (§ 81 1) Acute Oral (Limit test) Rat 95.7% a. i. 43583901 LD50 (males and females) > 5000 mg/ kg IV 870.1200 (§ 81 2) Acute Dermal (Limit Test)  Rabbit, 95.7% a. i. 43583902 LD50 (males and females) > 2000 mg/ kg III 870.1300 (§ 81 3) Acute Inhalation  Rat, 95.7% a. i. 44034201 LC50 > 2.1 mg/ L (4 hour exposure) III 870.2400 (§ 81 4) Primary Eye Irritation Rabbit 95.7% a. i. 43583904 Mild occular irritant IV 870.2500 (§ 81 5) Primary Dermal Irritation  Rabbit, 95.7% a. i. 43583903 Slight dermal irritant IV 870.2600 (§ 81 6) Dermal Sensitization Guinea pig, > 92.0% a. i. 00062605 Not a sensitizer N/ A 23 9 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 females (13 50) and general population including infants and children No appropriate endpoint was available to quantitate risk to the general population from a single dose administration of pronamide. The developmental effect, abortions, were not considered to occur after a single dose in this instance because they were observed in rabbits during the post dosing phase of the study (days 22 24). Therefore, no endpoint was chosen to quantitate risk to females 13 50 from a single dose administration of pronamide.

Chronic Dietary (all populations) NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study  Rat UF = 100 Chronic RfD = 0.08 mg/ kg/ day Cancer Q1* = 2.59 x 10  2 (mg/ kg/ day) 1 Group B2 chemical  "Probable human carcinogen" based on thyroid follicular cell adenomas (males and females) and benign interstitial cell tumors (males) in rats and hepatocellular carcinomas in male mice. Combined Chronic Toxicity/ Carcinogenicity Study  Rat Incidental Oral, Short Term NOAEL = 8.46* Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). Developmental Toxicity Study  Rabbit Incidental Oral, Intermediate Term NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study  Rat Dermal, Short Term a NOAEL = 8.46* Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). Developmental Toxicity Study  Rabbit Dermal, Intermediateand long Term a NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study  Rat Inhalation, Short Term a NOAEL = 8.46* Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation hepatocytes). Developmental Toxicity Study  Rabbit Inhalation, Intermediateand Long Term a NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study  Rat a Since an oral endpoint was selected, a dermal absorption factor of 100% (default value) and an inhalation absorption factor of 100% (default value) should be used in route to route extrapolation. * An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits.


[Federal Register Volume 82, Number 3 (Thursday, January 5, 2017)]
[Proposed Rules]
[Page 1296]
[FR Doc No: 2016-31754]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 52

[EPA-R04-OAR-2016-0468; FRL-9957-51-Region 4]

Air Plan Approval; Georgia: Procedures for Testing and Monitoring
Sources of Air Pollutants

AGENCY: Environmental Protection Agency.

ACTION: Proposed rule.

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SUMMARY: The Environmental Protection Agency (EPA) is proposing to
approve portions of State Implementation Plan (SIP) revisions submitted
by the State of Georgia, through the Georgia Department of Natural
Resources' Environmental Protection Division (GA EPD), on April 11,
2003, November 29, 2010, July 25, 2014, November 23, 2015, and November
29, 2016. The SIP submittals include changes to GA EPD's air quality
rules that modify definitions. The portions of the SIP revisions that
EPA is proposing to approve are consistent with the requirements of the
Clean Air Act (CAA or Act).

DATES: Written comments must be received on or before February 6, 2017.

ADDRESSES: Submit your comments, identified by Docket ID No. EPA-R04-
OAR-2016-0468 at http://www.regulations.gov. Follow the online
instructions for submitting comments. Once submitted, comments cannot
be edited or removed from Regulations.gov. 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 additional submission methods, the full EPA public comment
policy, information about CBI or multimedia submissions, and general
guidance on making effective comments, please visit http://www2.epa.gov/dockets/commenting-epa-dockets.

FOR FURTHER INFORMATION CONTACT: Sean Lakeman, Air Regulatory
Management Section, Air Planning and Implementation Branch, Air,
Pesticides and Toxics Management Division, U.S. Environmental
Protection Agency, Region 4, 61 Forsyth Street SW., Atlanta, Georgia
30303-8960. Mr. Lakeman can be reached by phone at<PHONE_NUMBER> or
via electronic mail at<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: In the Final Rules section of this Federal
Register, EPA is approving the State's implementation plan revision as
a direct final rule without prior proposal because the Agency views
this as a noncontroversial submittal and anticipates no adverse
comments. A detailed rationale for the approval is set forth in the
direct final rule. If no adverse comments are received in response to
this rule, no further activity is contemplated. If EPA receives adverse
comments, the direct final rule will be withdrawn and all public
comments received will be addressed in a subsequent final rule based on
this proposed rule. EPA will not institute a second comment period on
this document. Any parties interested in commenting on this document
should do so at this time.

    Dated: December 15, 2016.
Heather McTeer Toney,
Regional Administrator, Region 4.
[FR Doc. 2016-31754 Filed 1-4-17; 8:45 am]
 BILLING CODE 6560-50-P