                            DATA EVALUATION RECORD
                              Tribenuron Methyl
                                PC Code: 128887
                                 TXR#: 0056213
                                MRID#: 48737601

              Study Type: Subchronic Neurotoxicity Study in Rats;
                                OPPTS 870.6200

                                 Prepared for

                            Health Effects Division
                         Office of Pesticide Programs
                     U.S. Environmental Protection Agency
                               One Potomac Yard
                             2777 S. Crystal Drive
                              Arlington, VA 22202

                                  Prepared by

                           Tetrahedron Incorporated
                           1414 Key Highway, Suite B
                              Baltimore, MD 21230

Principal Reviewer: ______________________________________	Date: 		4/23/2012
	Ahmed Elnabawi, Ph.D.

Secondary Reviewer: _____________________________________	Date: 		4/24/2012
	Katherine Squibb, Ph.D.

Quality Assurance: _________________________________________	Date: 		4/26/2012
	Nasrin Begum, Ph.D.

Contract Number:	EP-W-10013
Work Assignment No.:	WA-0-01

Task Number:	1-1-87
EPA Reviewer//WAM:	Christina Swartz and Alan Levy// Kit Farwell and Lori Brunsman

                                  Disclaimer

This review may have been altered by the EPA subsequent to the contractors' signature above.
EPA Reviewer: Jaime D'Agostino	Signature:
Risk Assessment Branch 2, Health Effects Division (7509P)	Date:
Work Assignment Manager: Lori Brunsman      	Signature:
Science Info. Mgmt. Branch, Health Effects Division (7509P)	Date:
	Template version 09/11
TXR#: 0056213

                            DATA EVALUATION RECORD

STUDY TYPE:	Subchronic Neurotoxicity, (oral, feeding)  -  (rat); OPPTS 870.6200b [§82-7],

PC CODE: 128887	DP BARCODE: D397466; D398740; D398929

TEST MATERIAL (PURITY): Tribenuron Methyl (DPX-L5300) (98.2% a.i.).

SYNONYMS: Methyl 2-[4-methoxy-6-methyl-1,3,5-triazin-2-yl(methyl)carbamoyl]benzoate; Methyl 2-[[[[(4-methoxy-6-methyl-l,3,5-triazin-2-yl)methylamino] carbon]amino]sulfonyl] benzoate; DPX-L5300-281.

CITATION:	Carpenter, C. (2012). Tribenuron Methyl (DPX-L5300) Technical: Subchronic Oral Neurotoxicity Study in Rats. E.I. du Pont de Nemours and Company, DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware, U.S.A. Laboratory project numbers: DuPont-33371, January 27, 2012. MRID 48737601. Unpublished.

SPONSOR:	E.I. du Pont de Nemours and Company, Wilmington, Delaware 19898, U.S.A.

EXECUTIVE SUMMARY:

In a subchronic neurotoxicity study (MRID 48737601), Tribenuron Methyl (DPX-L5300) (98.2 % a.i., batch # MAY10MA047) was administered in the diet to Crl:CD(SD) rats (12/sex/dose) at concentration levels of 0, 50, 200, or 700 ppm (equivalent to 0/0, 2.8/3.2, 11.3/12.8, and 40.1/46.6 mg/kg/day in males and females, respectively) for approximately 90 days Neurobehavioral assessment (functional observational battery and motor activity testing) was performed on all animals prior to test substance administration (baseline), and during Weeks 4, 8, and 13. At study termination (Days 95 and 96), 6 animals/sex in the control and high dose groups were euthanized and perfused in situ for neuropathological examination. The brain and peripheral nervous system tissues collected from the perfused animals in the control and 700 ppm groups were subjected to histopathological evaluation.

There were no treatment-related effects on mortality or clinical signs at any dietary concentration levels in males and females.

Treatment-related effects on body weights and body weight gains were evident at the dietary concentration level of 700 ppm in males and females, but not at 50 ppm or 200 ppm. Body weights were significantly reduced by ↓6-12% (Day 7 through 91) in males and ↓6-13% (Day 14 through 91) in females. Mean body weight gains were significantly decreased by ↓20-34% on  Day 0-7, Day 14-21, Day 21-28, Day 0-28, Day 42-49, and Day 28-56in the 700 ppm males. In the 700 ppm females, mean body weight gains were significantly decreased by ↓23-37% on test Day 0-7, Day 0-28, Day 28-56, and Day 56-91. Overall (Day 0-91) body weight gains were significantly decreased by 20% and 29% in males and females, respectively, in the 700 ppm groups. Treatment-related decreases on food consumption and food efficiency were also evident in the 700 ppm males and females. Lower (p<=0.05) overall (Day 0-91) mean food consumption was noted at 700 ppm in males (↓7%) and females (↓6%). In addition, overall (Day 0-91) mean food efficiency at 700 ppm was significantly decreased by ↓14% and ↓24% in males and females, respectively.

No treatment-related effects on FOB (home cage, open field, removal from the home cage and handling) parameters, rearing, hindlimb grip strength, body temperature or motor activity (duration of movements and number of movements) were observed at any dose level in either sex. However, decreased (p<=0.05) forelimb grip strength was noted in the 700 ppm males (↓19%) during Week 13 compared to control, but not in the females. In addition, hindlimb splay was significantly decreased by ↓23-24% at 50, 200, and 700 ppm in males during Week 13, but there was no effect on females. The decreases in forelimb grip strength and hindlimb splay observed in males were not considered treatment related, however, since the mean values were similar to or within the historical control mean data, and the mean of the control values exceeded the historical control mean and range. In addition, there were no effects on forelimb grip strength in any other male exposure groups (50 ppm or 200 ppm) or in any of the exposed females.

No treatment-related alterations were observed in gross histopathology observations or microscopic neurohistopathology in the 700 ppm male and female groups.

It is concluded that there were no neurotoxic effects observed at any dietary concentration level, based on the lack of altered behavior in the FOB parameters, no significant changes observed on motor activity (duration of movements and number of movements), and no effects on the macroscopic and microscopic pathology of nervous system tissues. However, systemic toxicity was apparent in the 700 ppm males and females. This was characterized by decreased body weight and body weight gains, and significant reductions in food consumption, and food efficiency.

The LOAEL is 700 ppm for males and females (equivalent to 40.1/46.6 mg/kg/day, respectively), based on decreased body weight and body weight gains, reduced food consumption, and food efficiency, with a NOAEL of 200 ppm for males and females (equivalent to 11.3/12.8 mg/kg/day, respectively). There were no treatment-related neurotoxic signs observed in the study.

This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.6200b; OECD 424) for a subchronic neurotoxicity study in rats.

COMPLIANCE: Signed and dated GLP, Quality Assurance, Flagging, and Data Confidentiality (no claim of confidentiality under FIFRA, but waiver does not apply to other regulatory agencies and information is labeled trade secret) were provided.

I.	MATERIALS AND METHODS:

A.	MATERIALS:

1.	Test material:
Tribenuron Methyl (DPX-L5300) Technical

Description:
Solid

Lot/Batch #:
MAY10MA047

Purity:
98.2% a.i.

Compound Stability:
The test substance was stable in the diet for up to 15-days refrigerated.

CAS # of TGAI:
101200-48-0

Structure:

2.	Vehicle: Diet.

3.	Test animals:

Species:
Rat

Strain:
Crl:CD(SD)

Age/weight at study initiation:
50 days of age. Males: 199.8-255.5 g; Females: 160.3-193.4 g.

Source:
Charles River Laboratories International, Inc., Kingston, NY.

Housing:
Housed in pairs in solid bottom caging with bedding mixed with enrichment (Shepherd's[TM] Cob + PLUS[TM]).

Diet:
PMI[(R)] Nutrition International, LLC Certified Rodent LabDiet[(R)]5002, ad libitum, except during neurobehavioral testing.

Water:
Tap water, ad libitum, except during neurobehavioral testing.

Environmental conditions:
Temperature:
Humidity:
Air changes:
Photoperiod:
18-26°C
30-70%
Not stated
12 hrs dark / 12 hrs light

Acclimation period:
12 days

B.	STUDY DESIGN:

1.	In life dates: Start: July 8, 2011; 							End: October 12, 2011.

2.	Animal assignment and dose rational: Animals were randomly assigned to the test groups noted in Table 1 using a weight stratification-based computer program. The body weights of all animals were within +-20% of the mean weight for each sex. Following assignment to groups, rats were subdivided into 4 replicates, each of which contained an equal representation of each group and sex. Test substance was administered orally in the diet to rats at dietary concentration levels of 0, 50, 200 and 700 ppm for 90 days (96 or 97 days).

   Dose levels were chosen based on the results of two studies: (1) a subchronic toxicity study in rats, conducted with the test substance at concentration levels of 100, 1,750 and 5,000 ppm (MRID 00148638) and (2) a 2-generation reproduction study in rats, conducted with test substance at dietary concentration levels of 0, 25, 250 and 1,000 ppm (MRID 40245515).

   In the subchronic toxicity study, reduced body weights and reduced food consumption/efficiency were observed at a dietary concentration level of 1,750 ppm in males and females. In addition, changes in clinical chemistry parameters and in organ weights were noted in the 1,750 ppm group males and females. Therefore, the no-observed-adverse-effect level (NOAEL) for the subchronic toxicity study was 100 ppm.

   In the 2-generation rat reproduction study, the NOAEL for parental systemic toxicity during the 70-day pre-mating phase was 25 ppm, based on reduced mean body weights and body weight gains in males and females at 250 ppm and above. Based on these combined results, the concentration levels selected for the current study were 50, 200 and 700 ppm (Table 1). The highest dose was expected to result in reduction in body weight and/or nutritional parameters. The 50 ppm and 200 ppm concentrations were expected to demonstrate an absence of or decreased severity of these parameters and to define the NOAEL.

TABLE 1. Study Design
                            Experimental parameter
                         Concentration in Diet (ppm)

                                       0
                                      50
                                      200
                                      700
Achieved dose (mg/kg/day; M/F)
                                      0/0
                                    2.8/3.2
                                   11.3/12.8
                                   40.1/46.6
Total number of animals/sex/group
                                      12
                                      12
                                      12
                                      12
Behavioral testing (FOB, Motor activity)
                                    12/sex
                                    12/sex
                                    12/sex
                                    12/sex
Neuropathology (microscopic evaluation)
                                     6/sex
                                     0/sex
                                     0/sex
                                     6/sex
Concentrations of test substance were adjusted for purity.
Data were extracted from page 12 and 14 of the study report.

3.	Test Substance preparation and analysis: All diet formulations were prepared weekly by mixing appropriate amounts of test substance with the diet (PMI[(R)] Nutrition International, LLC Certified Rodent LabDiet[(R)]5002) and stored refrigerated until filling the feeders. Homogeneity and concentration analyses of test substance were verified in samples (top, middle and bottom) of all dietary concentrations at the start of the study. Stability of test substance in the diet was verified at concentrations of 50, 200 and 700 ppm for approximately 22 days at room temperature storage prior to the start of the study. Based on the results additional samples were analyzed that had been stored up to one week at room temperature, refrigerated for 15 days,  and refrigerated for 15 days followed by one week at room temperature.

   Results

   Homogeneity analysis (% RSD): <=1%.

   Stability analysis: The test substance was stable in the diet at all concentration levels for up to 15-days of refrigeration. However, the test substance was stable only at 200 and 700 ppm levels for 15-days of refrigeration followed by 1-week of room temperature storage. The test substance was stable at the 200 and 700 ppm levels but not stable at 50 ppm when stored at room temperature for 22 days prior to feeding.
   Concentration analysis (range as % nominal): 96.6-104%.

   These analytical data indicated that the mixing procedure was adequate and that the variance between nominal and actual dosage to the animals was acceptable.

4.	Statistics: The data were presented as mean +- standard deviation (SD). Each test substance exposed group was compared to the control group for the parameters listed below. The data were analyzed using the following statistical methods and significance was defined at p<0.05 for all tests.

                                  Parameters
                              Statistical Methods
- Body weight
- Body weight gain
- Food consumption
- Food efficiency

Levene's test for homogeneity and Shaprio-Wilk test for normality. If preliminary test was not significant, one-way analysis of variance followed by Dunnett's test was used to compare treated groups with control groups. If preliminary test was significant, transforms of the data were used. The rank order of transform was log, square-root, and rank-order.
- Rearing
- Grip strength
- Foot splay
- Body temperature
- Motor activity
Levene's test for homogeneity and Shaprio-Wilk test for normality. If preliminary test was not significant, repeated measures analysis of variance was followed by linear contrasts. If preliminary test was significant, a normalizing, variance stabilizing transformation followed by repeated measures analysis of variance or sequential application of the Jonckheere-Terpstra trend test was used.
Incidence of FOB, descriptive parameters
Cochran-Armitage test for trend; if the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test with a Bonferroni-Holm correction was used.
Data were obtained from page 22 of the study report.

These statistical analyses were considered to be appropriate.

C.	METHODS / OBSERVATIONS:

1.	Mortality and Clinical Observations: Animals were observed twice daily for mortality and morbidity throughout the study. General clinical observations were recorded once daily between 6 a.m. and 12 p.m. throughout the study.

2.	 Body Weight: Animals were weighed on the days of FOB assessment and weekly during the exposure period. Body weights were not recorded on the day of sacrifice.

3.	Food Consumption: Food consumption was recorded weekly throughout the study and reported as g/animal/day. The mean daily food efficiency and mean daily intake of test substance were calculated from the food consumption and body weight data.

4.	Cholinesterase determination: Cholinesterase activity was not evaluated.

5.	Neurobehavioral Assessment:

   a.	Functional Observational Battery (FOB): All animals were subjected to a FOB during acclimation (baseline) and during Weeks 4, 8 and 13. Animals were counterbalanced by sex and treatment and tested in replicates over multiple days to minimize the influence of uncontrolled factors. The FOB was conducted by an observer who was "blind" to the treatment status of the animal, and the same observer performed all of the evaluations. Animals were acclimated for at least 10 minutes prior to evaluation. The FOB evaluations were conducted in a sound-attenuated room equipped with a white-noise-generation system to minimize variations in environmental test conditions. Animals were weighed on the day of the FOB assessment. The time in the open-field was at least 2 minutes. Fore- and hindlimb grip strength were measured with a Chatillon Digital Force gauge. Rectal body temperature was measured with a YSI Precision 4000 thermometer and temperature probe.

      The following CHECKED (X) parameters were examined.

                            HOME CAGE OBSERVATIONS

REMOVAL FROM THE HOME CAGE AND HANDLING

                            OPEN FIELD OBSERVATIONS
                                       X
Posture
                                       X
Ease of removal
                                       X
Righting reflex
                                       X
Gait/coordination
                                       X
Ease of handling
                                       X
Gait/coordination
                                       X
Convulsions
                                       X
Vocalization
                                       X
Muscle spasms/fasciculation
                                       X
Tremors
                                       X
Muscle tone
                                       X
Convulsions
                                       X
Palpebral closure
                                       X
Piloerection
                                       X
Tremors

                                       X
Fur/skin appearance
                                       X
Ease of respiration

                                       X
Mucous membranes
                                       X
Rate of respiration

                                       X
Palpebral closure
                                       X
Posture

NEUROMUSCULAR OBSERVATIONS
                                       X
Exophthalmus
                                       X
Palpebral closure
                                       X
Landing foot splay
                                       X
Lacrimation
                                       X
Arousal
                                       X
Forelimb grip strength
                                       X
Salivation
                                       X
Vocalization
                                       X
Hindlimb grip strength
                                       X
Dehydration
                                       X
Diarrhea

Hindlimb extensor strength
                                       X
Emaciation
                                       X
Polyuria

PHYSIOLOGICAL OBSERVATIONS
                                       X
Number of rearing movements

                                       X
Approach and touch

X
Body temperature
                                       X
Tail pinch

X
Body weight
                                       X
Sharp auditory stimulus
Parameters based on OPPTS Guideline 870.6200.
Data were obtained from pages 20-21 of the study report.

   b.	Locomotor Activity: Locomotor activity was evaluated after the last animal completed the FOB pre-exposure and during Weeks 4, 8, and 13. Animals were counterbalanced by sex and treatment and tested in replicates over multiple days to minimize the influence of uncontrolled factors. An automated Coulbourn[(R)] Instruments activity monitor was used with infrared beams for motor activity data collection. The infrared monitoring device enabled measurements of two dependent variables: duration of movement and number of movements. A continuous movement, regardless of its duration, was counted as one movement by the activity measurement system. The technical characteristics of the measurement system are such that duration of movement was analogous to "counts" in other types of devices that employ interruption of light beams. Duration of movement and number of movements were evaluated in 9 consecutive intervals of 10 minutes each as well as for the total 90-minute session.

6.	Sacrifice and Pathology: Animals selected for neuropathological evaluation (6 rats/sex in the control and high dose groups) were deeply anaesthetized by i.p. injection of a mixture of ketamine/xylazine and perfused in situ. The perfusion and necropsy procedures were conducted according to Haskell Standard Operating Procedure-Neurotoxicity Necropsy Procedures. Animals were subjected to gross necropsy. The remaining animals were sacrificed by isoflurane anesthesia and CO2 asphyxiation and were disposed of without any pathological examinations.

   The tissues from the control and high-dose animals (700 ppm) were processed for microscopic evaluation. The brain, spinal cord sections,  eyes, optic nerve, and gastrocnemius muscle were embedded in paraffin, sectioned at 5um, and stained with hematoxylin-eosin (H&E). The dorsal root ganglia (including dorsal and ventral root fibers) from the cervical and lumbar swellings, gasserian ganglia, and peripheral nerves were embedded in glycolmethacrylate (GMA), sectioned at 3 um, and stained with hematoxylin-eosin (H&E). Stained histological sections were examined by light microscopy.

   Brain weight and measurements were not evaluated in this study.

   The following CHECKED (X) tissues from the control and high-dose animals, as well as all gross lesions were evaluated.

                            CENTRAL NERVOUS SYSTEM

                           PERIPHERAL NERVOUS SYSTEM

                                     BRAIN

                                 SCIATIC NERVE
                                       X
Olfactory bulb

Mid-thigh Region
                                       X
Cerebral cortex
                                       X
Sciatic Nerve
                                       X
Hippocampus

                                       X
Basal ganglia

                                       X
Cerebellum

                                       X
Thalamus

                                       X
Pons

                                       X
Medulla oblongata

                                     OTHER
                                       X
Midbrain
                                       X
Tibial nerve
                                       X
Hypothalamus
                                       X
Sural nerve

                                  SPINAL CORD

Peroneal Nerve
                                       X
Cervical swelling
                                       X
Lumbar dorsal root ganglion
                                       X
Lumbar swelling
                                       X
Lumbar dorsal root fibers

Thoracic swelling
                                       X
Lumbar ventral root fibers

                                     OTHER
                                       X
Cervical dorsal root ganglion
                                       X
Gasserian Ganglion
                                       X
Cervical dorsal root fibers

Trigeminal nerves

Cervical ventral root fibers
                                       X
Optic nerve

                                       X
Eyes

                                       X
Gastrocnemius muscle

Data were obtained from page 21 of the study report.

7.	Positive Controls: It was stated in this report that three separate reports (MRID 44628703, MRID 47053501, and MRID 48710304, performed in 1997, 2002 and 2011, respectively) were previously performed by DuPont Haskell to generate positive control data and validate the procedures and the inter-observer reliability of the performing lab to conduct and assess neurobehavioral and neuropathology tests. The data also documents that the equipment and procedures are capable of detecting effects that may be seen in neurotoxicity studies. The positive control data is acceptable for use with the current study.

II.	RESULTS:

A.	OBSERVATIONS:

1.	General Clinical Observations: There were no significant treatment-related clinical findings in the 50, 200 or 700 ppm group males or females. Scabs and hair loss were observed in a small number of both control and treated animals.

2.	Mortality: There were no treatment-related mortalities. One animal assigned to the low concentration (50 ppm) group was found dead on test Day 44. The cause of death was not determined. There were no significant gross findings in this animal. All other animals survived to scheduled termination.

B.	BODY WEIGHT AND BODY WEIGHT GAIN: Summary results of mean body weights and body weight gains are presented in Table 2 (a and b) and Table 3, respectively. Treatment-related effects on body weights were evident at the high dose (700 ppm) in males (Day 7 through 91) and females (Day 14 through 91). At 700 ppm, lower (p<=0.05) body weights ranged from ↓6-12% in males and from ↓6-13% in females (Table 2a and b). No significant differences in body weights were noted in either sex at dietary concentration levels of 50 or 200 ppm compared to the controls. On Day 7, body weight was reduced by ↓5% in the 700 ppm females compared to the control, but was not statistically significant.

TABLE 2a. Mean (+-SD) Body Weights in Male Rats
                                 Exposure Time
                          Concentration on Diet (ppm)

                                       0
                                      50
                                      200
                                      700
Day 0
                                  232.2+-13.3
                                  235.6+-9.5
                                  232.2+-15.9
                                  232.2+-14.5
Day 7
                                  296.0+-16.9
                                  296.7+-13.1
                                  288.7+-19.2
                                 279.4+-17.3*
                                    (↓6%)
Day 14
                                  343.6+-21.0
                                  346.5+-20.2
                                  332.9+-23.8
                                 321.7+-20.5*
                                    (↓6%)
Day 21
                                  387.3+-26.2
                                  385.4+-26.1
                                  368.8+-29.1
                                 355.7+-24.1*
                                    (↓8%)
Day 28
                                  416.9+-31.1
                                  415.7+-30.5
                                  392.9+-33.3
                                 377.3+-27.7*
                                   (↓10%)
Day 35
                                  446.1+-34.1
                                  447.5+-35.9
                                  420.2+-37.0
                                 403.9+-29.3*
                                   (↓10%)
Day 42
                                  471.2+-38.5
                                  471.9+-39.3
                                  441.8+-40.5
                                 423.9+-32.0*
                                   (↓10%)
Day 49
                                  495.7+-40.6
                                  493.0+-45.7
                                  464.4+-44.4
                                 440.1+-31.4*
                                   (↓11%)
Day 56
                                  508.3+-43.3
                                  506.2+-46.8
                                  475.0+-43.8
                                 450.2+-33.6*
                                   (↓11%)
Day 63
                                  527.1+-46.5
                                  522.6+-51.2
                                  491.6+-44.8
                                 465.6+-35.0*
                                   (↓12%)
Day 70
                                  541.0+-46.7
                                  539.7+-53.0
                                  504.4+-47.2
                                 478.7+-36.0*
                                   (↓12%)
Day 77
                                  552.2+-44.6
                                  548.3+-54.9
                                  514.1+-47.3
                                 489.8+-37.9*
                                   (↓11%)
Day 84
                                  560.7+-50.9
                                  555.1+-51.1
                                  524.8+-46.2
                                 496.7+-38.9*
                                   (↓11%)
Day 91
                                  569.5+-48.2
                                  558.4+-51.2
                                  533.7+-47.8
                                 502.4+-39.2*
                                   (↓12%)
Values represent mean+-SD, n=12, except at 50 ppm n=11 from Day 49 to 91 because one male was found dead.
Percent difference from the control is included in parentheses and was calculated by the Investigators.
* Significantly different from the control group, p<=0.05. Statistically significant results are shown in bold.
Data were obtained from Table 3 on pages 33-35 of the study report.

TABLE 2b. Mean (+-SD) Body Weights in Female Rats
                                 Exposure Time
                          Concentration on Diet (ppm)

                                       0
                                      50
                                      200
                                      700
Day 0
                                  177.7+-8.6
                                  178.0+-9.9
                                  176.7+-10.2
                                  175.6+-8.6
Day 7
                                  204.8+-10.0
                                  204.5+-12.9
                                  202.6+-13.7
                                  194.6+-10.9
Day 14
                                  222.9+-12.2
                                  222.3+-14.6
                                  218.2+-14.0
                                 209.0+-10.1*
                                    (↓6%)
Day 21
                                  240.5+-15.3
                                  424.0+-20.0
                                  237.3+-13.1
                                 221.9+-13.3*
                                    (↓8%)
Day 28
                                  252.1+-14.4
                                  252.5+-20.3
                                  246.8+-18.9
                                 232.7+-15.6*
                                    (↓8%)
Day 35
                                  265.9+-15.0
                                  264.6+-21.0
                                  259.6+-20.2
                                 240.2+-15.8*
                                   (↓10%)
Day 42
                                  273.9+-17.8
                                  269.4+-21.6
                                  263.6+-19.5
                                 244.8+-14.4*
                                   (↓11%)
Day 49
                                  280.7+-17.8
                                  276.7+-24.2
                                  271.7+-18.8
                                 250.9+-16.1*
                                   (↓11%)
Day 56
                                  288.3+-19.6
                                  283.0+-22.7
                                  279.6+-21.4
                                 256.1+-18.0*
                                   (↓11%)
Day 63
                                  295.0+-16.5
                                  289.2+-24.1
                                  283.1+-24.0
                                 260.8+-18.6*
                                   (↓12%)
Day 70
                                  298.5+-17.9
                                  292.5+-23.4
                                  282.4+-25.0
                                 262.8+-20.3*
                                   (↓12%)
Day 77
                                  304.9+-19.1
                                  299.7+-25.4
                                  289.7+-23.6
                                 265.6+-21.6*
                                   (↓13%)
Day 84
                                  305.7+-19.1
                                  303.0+-23.7
                                  292.7+-24.0
                                 267.4+-24.3*
                                   (↓13%)
Day 91
                                  310.3+-20.2
                                  307.0+-24.1
                                  299.9+-25.5
                                 269.9+-23.3*
                                   (↓13%)
Values represent mean+-SD, n=12.
Percent difference from the control is included in parentheses and was calculated by the Investigators.
* Significantly different from the control group, p<=0.05. Statistically significant results are shown in bold.
Data were obtained from Table 4 on pages 36-38 of the study report.

   Treatment-related effects on body weight gains were also evident at the dietary concentration level of 700 ppm in males and females (Table 3). In males, lower (p<=0.05) mean body weight gains were observed during test Day 0-7 (↓26%), Day 14-21 (↓22%), Day 21-28 (↓27%), Day 0-28 (↓21%), Day 42-49 (↓34%), Day 28-56 (↓20%), and overall (Day 0-91; ↓20%). Additionally, in the 200 ppm males, mean body weight gains were reduced by ↓11%, ↓18% and ↓13% during test Day 0-7, Day 14-21, and Day 0-28 compared to the controls (Table 3). However, overall (0-91) mean body gain was decreased by ↓11% in the 200 ppm males, but was not statistically significant. In the 700 ppm females, lower (p<=0.05) mean body weight gains were observed during test Day 0-7 (↓30%), Day 0-28 (↓23%), Day 28-56 (↓35%), Day 56-91 (↓37%), and overall (Day 0-91; ↓29%) compared to the controls (Table 3). No significant differences in body weight gains were noted in the 50 and 200 ppm females or in the 50 ppm males compared to the controls.

   It is concluded that lower body weight gains observed in males and females in the high dose (700 ppm) groups were associated with the reduction in body weights observed over the entire study period and were treatment-related.

TABLE 3. Selected Mean (+-SD) Body Weight Gains in Male and Female Rats
                                 Exposure Time
                          Concentration on Diet (ppm)

                                       0
                                      50
                                      200
                                      700
                                     Males
Day 0-7
                                   63.8+-6.7
                                   61.1+-7.9
                                  56.5+-5.6*
                                   (↓11%)
                                  47.2+-5.5*
                                   (↓26%)
Day 14-21
                                   43.7+-7.5
                                   38.9+-7.3
                                  35.9+-6.9*
                                   (↓18%)
                                  34.0+-5.7*
                                   (↓22%)
Day 21-28
                                   29.6+-7.3
                                   30.3+-7.3
                                   24.1+-5.0
                                  21.6+-5.4*
                                   (↓27%)
Day 0-28
                                  184.7+-26.9
                                  180.0+-29.2
                                 160.7+-20.7*
                                   (↓13%)
                                 145.2+-16.9*
                                   (↓21%)
Day 42-49
                                   24.5+-5.6
                                   24.8+-8.7
                                   22.6+-5.1
                                  16.3+-2.5*
                                   (↓34%)
Day 28-56
                                  91.4+-15.0
                                  94.6+-23.0
                                  82.1+-12.9
                                  72.8+-8.4*
                                   (↓20%)
                              Overall (Day 0-91)
                                  337.3+-44.5
                                  324.6+-53.0
                                  301.5+-36.1
                                   (↓11%)
                                 270.2+-29.8*
                                   (↓20%)
                                    Females
Day 0-7
                                   27.1+-6.0
                                   26.5+-7.0
                                   25.9+-4.9
                                  19.0+-3.8*
                                   (↓30%)
Day 0-28
                                   74.4+-9.1
                                  74.6+-12.4
                                  70.2+-11.2
                                  57.1+-8.9*
                                   (↓23%)
Day 28-56
                                   36.2+-7.8
                                   30.5+-5.6
                                   32.8+-6.4
                                  23.4+-4.9*
                                   (↓35%)
Day 56-91
                                   22.1+-7.6
                                   24.0+-8.7
                                   20.3+-6.8
                                  13.9+-6.7*
                                   (↓37%)
                              Overall (Day 0-91)
                                  132.6+-17.0
                                  129.0+-17.1
                                  123.2+-18.6
                                  94.4+-16.0*
                                   (↓29%)
Values represent mean+-SD, n=12, except at 50 ppm n=11 from Day 49 to 91 because one male was found dead.
Percent difference from the control is included in parentheses and was calculated by the Investigators.
* Significantly different from the control group, p<=0.05. Statistically significant results are shown in bold.
Data were obtained from Tables 5 (pages 39-41) and 6 (pages 42-44) of the study report.

C.	FOOD CONSUMPTION:

   Results of mean food consumption (g/animal/day) in males and females are presented in Table 4. Treatment-related effects on food consumption were evident at the high dose (700 ppm) in males and females. Lower food consumption at 700 ppm was observed earlier in males (Day 0-7, ↓9%, p<=0.05) compared to females (Day 0-28, ↓9% , p<=0.05 ).

   In the 700 ppm group males, lower (p<=0.05) food consumption ranged between  a decrease of ↓6-9% on Days 0-7, 21-28, 56-63, 35-63, 63-70, 77-84, 56-91, and overall (0-91) (Table 4). No significant differences were noted on food consumption in the 50 and 200 ppm males when compared to the control group. In females, lower (p<=0.05) mean food consumption was observed on test Days 0-28 (↓5%), 28-35 (↓6%), 35-42 (↓10%), 42-49 (↓8%), 49-56 (↓7%), 28-56 (↓8%), 56-63 (↓6%), 70-77 (↓8%), and overall (0-91; ↓6%) (Table 4). In addition, lower (p<=0.05) mean food consumption in females was observed in the low dose (50 ppm) on test Day 56-63 (↓5%) and in the mid dose (200 ppm) on Day 21-28 (↓6%) and Day 56-63 (↓7%). However, overall (0-91) mean food consumption was not statistically different from the control groups at the low (50 ppm) or mid dose (200 ppm).

   It is concluded that the effect on body weight and body weight gains reflected the effects observed on food consumption in the 700 ppm groups, but the small decreases observed in food consumption at the low and mid doses were not associated with a significant decrease in body weight.

TABLE 4. Selected Mean (+-SD) Food Consumption (g/animal/day) in Male and Female Rats
                                 Exposure Time
                          Concentration on Diet (ppm)

                                       0
                                      50
                                      200
                                      700
                                     Males
Day 0-7
                                   23.7+-1.5
                                   23.8+-1.9
                                   22.8+-0.8
                                  21.6+-1.0*
                                    (↓9%)
Day 21-28
                                   25.1+-2.0
                                   25.0+-2.5
                                   23.6+-1.0
                                  22.9+-2.0*
                                    (↓9%)
Day 56-63
                                   25.5+-1.6
                                   24.8+-2.1
                                   24.2+-0.9
                                  23.6+-1.2*
                                    (↓7%)
Day 35-63
                                   25.8+-1.9
                                   25.4+-2.2
                                   24.4+-0.8
                                  23.9+-1.4*
                                    (↓7%)
Day 63-70
                                   25.5+-1.2
                                   25.0+-2.3
                                   24.0+-0.5
                                  23.6+-1.4*
                                    (↓7%)
Day 77-84
                                   24.7+-1.9
                                   23.6+-1.8
                                   23.7+-0.5
                                  23.0+-1.4*
                                    (↓7%)
Day 56-91
                                   24.9+-1.3
                                   24.1+-1.9
                                   23.8+-0.6
                                  23.3+-1.4*
                                    (↓6%)
                              Overall (Day 0-91)
                                   25.1+-1.6
                                   24.7+-2.1
                                   23.9+-0.6
                                  23.4+-1.4*
                                    (↓7%)
                                    Females
Day 21-28
                                   17.0+-0.5
                                   17.0+-1.6
                                  16.0+-1.0*
                                    (↓6%)
                                   16.2+-0.9
Day 0-28
                                   16.7+-0.6
                                   16.6+-0.9
                                   16.2+-0.6
                                  15.9+-1.0*
                                    (↓5%)
Day 28-35
                                   17.8+-0.7
                                   17.2+-0.8
                                   17.2+-1.0
                                  16.7+-0.8*
                                    (↓6%)
Day 35-42
                                   18.4+-1.3
                                   17.9+-1.2
                                   17.2+-0.7
                                  16.5+-1.5*
                                   (↓10%)
Day 42-49
                                   17.8+-1.0
                                   16.6+-1.2
                                   17.1+-1.0
                                  16.3+-1.5*
                                    (↓8%)
Day 49-56
                                   17.1+-0.9
                                   16.3+-0.9
                                   16.8+-1.1
                                  16.0+-1.3*
                                    (↓7%)
Day 28-56
                                   17.7+-0.8
                                   17.0+-0.6
                                   17.1+-0.9
                                  16.3+-1.2*
                                    (↓8%)
Day 56-63
                                   16.9+-0.3
                                  16.2+-0.7*
                                    (↓5%)
                                  15.7+-1.1*
                                    (↓7%)
                                  15.9+-1.5*
                                    (↓6%)
Day 70-77
                                   17.1+-0.6
                                   16.4+-1.2
                                   16.5+-1.0
                                  15.7+-1.6*
                                    (↓8%)
                              Overall (Day 0-91)
                                   16.9+-0.4
                                   16.6+-0.6
                                   16.4+-0.8
                                  15.9+-1.2*
                                    (↓6%)
Values represent mean+-SD, n=12, except at 50 ppm n=11 from Day 49 to 91 because one male was found dead.
Percent difference from the control is included in parentheses and was calculated by the Investigators.
* Significantly different from the control group, p<=0.05. Statistically significant results are shown in bold.
Data were obtained from pages Tables 7 (pages 45-47) and 8 (pages 48-50) of the study report.

D.	FOOD EFFICIENCY

   A summary of mean daily food efficiency (average weight gain/average food consumption) in males and females is presented in Table 5. Treatment-related effects on food efficiency were noted in the high dose (700 ppm) in males and females, but not at 50 ppm or 200 ppm males and females. Overall (0-91) mean food efficiency was significantly (p<=0.05) reduced by ↓14% in males and ↓24% in females at a dietary concentration level of 700 ppm. On Day 0-7 after treatment, mean food efficiency was significantly decreased by ↓19% in males and ↓25% in females at 700 ppm. Lower (p<=0.05) food efficiency was also observed on several test days in the 700 ppm males: Days 14-21 (↓17%), Days 21-28 (↓20%), Days 0-28 (↓15%), Days 42-49 (↓28%), and Days 28-56 (↓14%). Additionally, in the 700 ppm females, lower (p<=0.05) food efficiency was also observed on Days 0-28 (↓20%), 28-56 (↓30%), and 56-91(↓34%). No treatment-related effects on food efficiency were noted at 50 or 200 ppm in males or females. The reduction in overall food efficiency was consistent with the reduced food consumption observed in males and females.

TABLE 5. Selected Mean (+-SD) Daily Food Efficiency (g/g) in Male and Female Rats
                                 Exposure Time
                          Concentration on Diet (ppm)

                                       0
                                      50
                                      200
                                      700
                                     Males
Day 0-7
                                 0.385+-0.032
                                  0.366+-0.32
                                 0.354+-0.033
                                 0.311+-0.033*
                                   (↓19%)
Day 14-21
                                 0.247+-0.030
                                 0.223+-0.037
                                 0.211+-0.039*
                                   (↓15%)
                                 0.206+-0.027*
                                   (↓17%)
Day 21-28
                                 0.168+-0.034
                                 0.173+-0.037
                                 0.146+-0.028
                                 0.135+-0.029*
                                   (↓20%)
Day 0-28
                                 0.268+-0.027
                                 0.261+-0.032
                                 0.244+-0.030
                                 0.228+-0.020*
                                   (↓15%)
Day 42-49
                                 0.134+-0.027
                                 0.137+-0.043
                                 0.133+-0.031
                                 0.097+-0.015*
                                   (↓28%)
Day 28-56
                                 0.126+-0.014
                                 0.131+-0.028
                                 0.120+-0.018
                                 0.108+-0.012*
                                   (↓14%)
                                   Day 0-91
                                 0.147+-0.013
                                 0.144+-0.018
                                 0.139+-0.016
                                 0.127+-0.011*
                                   (↓14%)
                                    Females
Day 0-7
                                 0.235+-0.048
                                 0.231+-0.063
                                 0.228+-0.040
                                 0.175+-0.033*
                                   (↓25%)
Day 0-28
                                 0.159+-0.018
                                 0.160+-0.024
                                 0.154+-0.023
                                 0.128+-0.018*
                                   (↓20%)
Day 28-56
                                 0.073+-0.014
                                 0.064+-0.011
                                 0.068+-0.012
                                 0.051+-0.009*
                                   (↓30%)
Day 56-91
                                 0.038+-0.013
                                 0.042+-0.014
                                 0.036+-0.011
                                 0.025+-0.012*
                                   (↓34%)
                                   Day 0-91
                                 0.086+-0.010
                                 0.085+-0.010
                                 0.083+-0.011
                                 0.065+-0.010*
                                   (↓24%)
Food efficiency was reported as average weight gain/average food consumption
Values represent mean+-SD, n=12, except at 50 ppm, n=11 from Day 49 to 91because one male was found dead.
Percent difference from the control is included in parentheses and was calculated by the Investigators.
* Significantly different from the control group, p<=0.05. Significant results are shown in bold.
Data were obtained from pages Tables 9 (pages 51-53) and 10 (pages 54-56) of the study report.

E.	TEST SUBSTANCE INTAKE: The mean daily intake (mg/kg/day) of Tribenuron Methyl over the entire study period is presented in Table 6.

TABLE 6. Intake of Tribenuron Methyl in Males and Females
                                  Test Group
                             Concentration in Diet
                                     (ppm)
                               Mean daily intake
                                (mg/kg bw/day)

                                     Male
                                    Female
                                       1
                                      50
                                   2.8+-0.2
                                   3.2+-0.2
                                       2
                                      200
                                   11.3+-1.0
                                   12.8+-0.7
                                       3
                                      700
                                   40.1+-2.5
                                   46.6+-3.1
            Data were obtained from Tables 11 (pages 57-58) and 12 (pages 59-60) of the study report.

F.	NEUROBEHAVIORAL RESULTS:

1.	FOB findings: No treatment-related effects on FOB (home cage, open field, removal from the home cage and handling) parameters were noted at any dietary concentration level for either sex. However, a significantly (p<=0.05) higher incidence of low arousal was observed in the 50 ppm males (6/12 treated vs. 0/12 control) during Week 13, but not at 200 or 700 ppm. In addition, low arousal was seen in male control animals at baseline, week 4 and week 8 (ranging from 2/12-4/12). Thus, the lack of a dose response and the observation in control animals indicates this effect was not treatment-related.

          TABLE 7. Selected FOB Observations in Male and Female Rats
                                  Observation
                               Dose level (ppm)

                                      0
                                      50
                                      200
                                      700
                                     Males
Arousal (low)
Baseline
Week 4
Week 8
Week 13

2/12
2/12
4/12
0/12

1/12
1/12
3/12
6/12*

0/12
3/12
2/12
3/12

0/12
1/12
0/12*
1/12
                                    Females
Arousal (low)
Baseline
Week 4
Week 8
Week 13

0/12
0/12
0/12
0/12

0/12
0/12
0/12
0/12

0/12
0/12
0/12
0/12

0/12
0/12
0/12
0/12
Data were extracted from Table 15(page 67) and 16 (page 74).
Values represent incidence
* Significantly different from the control group, p<=0.05.
2.	Locomotor activity: No treatment-related effects were observed on motor activity (duration of movements and number of movements) in either sex at any dietary concentration level of the test substance. In addition, there were no statistically significant differences between the control and the test substance-exposed groups at any time point.

TABLE 8. Motor Activity in Male and Female Rats
                                 Exposure Time
                          Concentration on Diet (ppm)

                                       0
                                      50
                                      200
                                      700
                                    Males
                          Duration of Movements (sec)
Baseline
                                   1094+-256
                                   1129+-368
                                   1266+-417
                                   1180+-256
Week 4
                                   1821+-535
                                   1939+-505
                                   1810+-464
                                   1936+-521
Week 8
                                   1583+-521
                                   1629+-558
                                   1946+-483
                                   1616+-471
Week13
                                   1599+-334
                                   1722+-637
                                   1588+-608
                                   1790+-384
                                    Females
                          Duration of Movements (sec)
Baseline
                                   1526+-607
                                   1653+-552
                                   1674+-549
                                   1732+-647
Week 4
                                   2003+-601
                                   1828+-685
                                   1910+-507
                                   1991+-599
Week 8
                                   1724+-610
                                   1750+-573
                                   1644+-465
                                   1837+-548
Week13
                                   1937+-583
                                   2005+-489
                                   1838+-596
                                   1862+-430
                                     Males
                              Number of Movements
Baseline
                                   471+-125
                                   520+-243
                                   595+-219
                                    518+-94
Week 4
                                   809+-199
                                   899+-211
                                   848+-273
                                   881+-255
Week 8
                                   733+-207
                                   811+-290
                                   931+-270
                                   778+-224
Week13
                                   776+-175
                                   960+-326
                                   878+-355
                                   926+-241
                                    Females
                              Number of Movements
Baseline
                                   702+-276
                                   766+-192
                                   811+-267
                                   840+-294
Week 4
                                   970+-280
                                   885+-288
                                   894+-236
                                   991+-258
Week 8
                                   868+-262
                                   911+-302
                                   837+-254
                                   946+-260
Week13
                                   1076+-266
                                   1052+-216
                                   954+-245
                                   1052+-238
Values represent mean+-SD, n=12, except at 50 ppm n= 11 from Day 49 to 91because one male was found dead.
No results from treatment groups are significantly different from the control group.
Data were obtained from Tables 17-20 on pages 76-79 of the study report.

3.	Rearing: Mean number of rearing movements was unaffected by the test diet consumption at 50, 200, or 700 ppm in males and females. There were no statistically significant differences between the control and the test substance-exposed groups (by sex) at the study Week 4, 8, and 13 evaluations.

4.	Forelimb and Hindlimb Grip Strength: Forelimb grip strength was significantly decreased by 19% in the 700 ppm males during Week 13, but not in females (Table 9). This effect was not treatment related since the mean forelimb grip value (1.19+-0.34 kg) was within the historical control range (0.93 -  1.40 kg) and the concurrent control (1.47 kg) exceeded the historical control range (Table 9). There were no treatment-related or statistically significant effects on hindlimb grip strength in either sex at any dose level.

TABLE 9. Mean (+-SD) Forelimb Grip Strength (kg) for Male Rats
                                 Exposure Time
                          Concentration in Diet (ppm)

                                       0
                                      50
                                      200
                                      700
Baseline (Pretest)
                                  0.72+-0.10
                                  0.69+-0.07
                                  0.68+-0.10
                                  0.69+-0.09
Week 4
                                  1.17+-0.24
                                  1.16+-0.23
                                  1.10+-0.13
                                  1.11+-0.13
Week 8
                                  1.07+-0.09
                                  1.08+-0.05
                                  1.05+-0.08
                                  1.03+-0.10
Week 13
                                  1.47+-0.27
                                  1.31+-0.26
                                  1.27+-0.25
                                  1.19+-0.34*
                                   (↓19%)
Historical control data for male forelimb grip at Week 13 [#]
            Mean = 1.19+-0.05 (0.93+-0.14  -  1.40+-0.14); n= 11-12
Values represent mean+-SD, n=11-12.
Percent difference from the control is included in parentheses and was calculated by the Reviewers.
* Significantly different from the control group, p<=0.05. Statistically significant results are shown in bold.
# Data were obtained from Appendix K on pages 292-293 of the study report.
Data were obtained from Table 13 on page 61 of the study report.

5.	Foot Splay: Foot splay was significantly reduced by ↓23-24% at 50, 200, and 700 ppm in males, but not in females. This effect was not treatment related since the mean hindlimb splay values were within the historical control range, no dose response relationship was evident, and the concurrent control group (10.1 cm) exceeded the historical control range (Table 10). No treatment-related effects on hindlimb splay occurred at any dietary concentration level in females.

TABLE 10. Mean (+-SD) Hindlimb Splay (cm) for Male Rats
                                 Exposure Time
                          Concentration in Diet (ppm)

                                       0
                                      50
                                      200
                                      700
Baseline (Pretest)
                                   6.4+-1.9
                                   5.2+-1.4
                                   6.3+-2.3
                                   6.6+-1.7
Week 4
                                   8.1+-2.4
                                   7.2+-2.5
                                   7.3+-2.6
                                   7.8+-2.7
Week 8
                                   8.7+-2.3
                                   8.1+-3.1
                                   6.8+-2.4
                                   7.0+-2.0
Week 13
                                   10.1+-1.6
                                   7.8+-3.1*
                                   (↓23%)
                                   7.7+-2.6*
                                   (↓24%)
                                   7.7+-2.4*
                                   (↓24%)
Historical control data for male hindlimb splay at Week 13 [#]
               Mean = 8.0+-0.4 (7.5+-2.1  -  8.5+-1.7); n= 11-12
Values represent mean+-SD, n=11-12.
Percent difference from the control is included in parentheses and was calculated by the Reviewers.
* Significantly different from the control group, p<=0.05. Statistically significant results are shown in bold.
# Data were obtained from Appendix K on pages 292-293 of the study report.
Data were obtained from Tables 13 on page 61 of the study report.

6.	Body Temperature: Body temperature was unaffected by the administration of test substance at 50, 200, or 700 ppm in males and females. There were no statistically significant differences between the control and test substance-treated groups

G.	SACRIFICE AND PATHOLOGY:

1.	Gross Pathology: No adverse, treatment-related effects were noted during gross pathology.

2.	Neuropathology: No adverse, treatment-related histological changes were noted in the 700 ppm group males or females.

III.	 DISCUSSION AND CONCLUSIONS:

A.	INVESTIGATORS' CONCLUSIONS:

   The investigators concluded that under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for systemic toxicity in males and females was 200 ppm (or 11.3 and 12.8 mg/kg/day for males and females, respectively) based on decreased body weight and nutritional parameters at 700 ppm (40.1 and 46.6 mg/kg/day for males and females, respectively). The NOAEL for neurotoxicity in males and females was greater than 700 ppm (the highest concentration tested) due to the absence of effects on neurobehavioral and neuropathological endpoints.

B.	REVIEWER COMMENTS:

   Tribenuron Methyl, at all dietary concentration levels tested, had no effect on mortality or clinical signs in either male or female rats.

   No treatment-related effects were observed on FOB (home cage, open field, removal from the home cage and handling) parameters, rearing, forelimb and hindlimb grip strength, hindlimb splay, body temperature or motor activity (duration of movements and number of movements) at any dietary concentration level in either sex.

   Decreased (p<=0.05) forelimb grip strength was noted in the 700 ppm males (↓19%) during Week 13 compared to control, but not in the females. In addition, hindlimb splay was significantly decreased by 23-24% at 50, 200, and 700 ppm in males during Week 13, but not in females. The decreases in forelimb grip strength and hindlimb splay observed in males were not considered treatment related, however, since their mean values were similar to or within the historical control mean data, and the mean of their control values exceeded the historical control mean and range. In addition, there were no effects on forelimb grip strength in any other male exposure groups (50 ppm or 200 ppm) or in any of the exposed females.

   Treatment-related effects on body weights, body weight gains, food consumption and/or food efficiency were evident at the high dose (700 ppm) in males and females, but not in the low dose (50 ppm) or mid dose (200 ppm). At 700 ppm, lower (p<=0.05) body weights ranged from ↓6-12% in males (Day 7 through 91) and from ↓6-13% in females (Day 14 through 91). No significant differences in body weights were noted in either sex at dietary concentration levels of 50 or 200 ppm compared to the controls. In 700 ppm males, lower (p<=0.05) mean body weight gains were observed on test Day 0-7 (↓26%), Day 14-21 (↓22%), Day 21-28 (↓27%), Day 0-28 (↓21%), Day 42-49 (↓34%), Day 28-56 (↓20%), and overall (Day 0-91; ↓20%). Significant decreases in body weight gains were observed in the 700 ppm females on Day 0-7 (↓30%), Day 0-28 (↓23%), Day 28-56 (↓35%), Day 56-91 (↓37%), and overall (Days 0-91; ↓29%). Lower (p<=0.05) overall (0-91) food consumption was noted in males (↓7%) and females (↓6%) at the dietary concentration level of 700 ppm. This reduction in food consumption was consistent with the significant decreases in overall (0-91) food efficiency observed in males (↓14%) and females (↓24%). It is concluded that impairment of body weight gains observed in the 700 ppm males and females were associated with the significant reduction in body weight observed over the entire study period, as well as reduced food consumption and food efficiency.

   No treatment-related alterations were observed in gross histopathology observations or microscopic neurohistopathology in the 700 ppm male and female groups.

   It is concluded that tribenuron methyl did not exhibit treatment-related neurotoxic effects on Crl:CD(SD) male and female rats at dietary concentration levels of 50, 200 and 700 ppm, based on the lack of altered behavior in the FOB parameters, no significant effects in motor activity (duration of movements and number of movements), and no effects on the macroscopic and microscopic pathology of nervous system tissues. However, systemic toxicity of Tribenuron Methyl was apparent in the 700 ppm males and females. This was characterized by decreased body weights and body weight gains, significant reductions in food consumption, and/or food efficiency.

   The LOAEL is 700 ppm
   for males and females (equivalent to 40.1/46.6 mg/kg/day, respectively), based on decreased body weight and body weight gains, reduced food consumption, and food efficiency, with a NOAEL of 200 ppm for males and females (equivalent to 11.3/12.8 mg/kg/day, respectively).  There was no evidence of neurotoxicity in the study.

   This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.6200b; OECD 424) for a subchronic neurotoxicity study in rats.

C.	STUDY DEFICIENCIES:

   Tribenuron methyl in the diet was not stable over the feeding periods used for the 50 ppm dose. This deficiency did not affect the conclusions of the study as no systemic toxicity was seen at the next highest dose (200 ppm) but was seen at the highest dose (700 ppm), both of which were stable over the course of the experiment.


[Federal Register Volume 80, Number 142 (Friday, July 24, 2015)]
[Proposed Rules]
[Pages 44017-44018]
[FR Doc No: 2015-18100]

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

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 52

[EPA-R05-OAR-2015-0407; FRL-9930-80-Region 5]

Air Plan Approval; MI, Belding; 2008 Lead Clean Data
Determination

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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

SUMMARY: On May 13, 2015, the Michigan Department of Environmental
Quality (MDEQ) submitted a request to the Environmental Protection
Agency (EPA) to make a determination under the Clean Air Act (CAA) that
the Belding nonattainment area has attained the 2008 lead (Pb) national
ambient air quality standard (NAAQS). In this action, EPA is proposing
to determine that the Belding nonattainment area (area) has attained
the 2008 Pb NAAQS. This clean data determination is based upon
complete, quality-assured and certified ambient air monitoring data for
the 2012-2014 design period showing that the area has monitored
attainment of the 2008 Pb NAAQS. Additionally, as a result of this
proposed determination, EPA is proposing to suspend the

requirements for the area to submit an attainment demonstration,
together with reasonably available control measures, a reasonable
further progress (RFP) plan, and contingency measures for failure to
meet the RFP plan and attainment deadlines for as long as the area
continues to attain the 2008 Pb NAAQS.

DATES: Comments must be received on or before August 24, 2015.

ADDRESSES: Submit your comments, identified by Docket ID No. EPA-R05-
OAR-2015-0407, by one of the following methods:
    1. www.regulations.gov: Follow the on-line instructions for
submitting comments.
    2. Email<EMAIL_ADDRESS>    3. Fax:<PHONE_NUMBER>.
    4. Mail: Douglas Aburano, Chief, Attainment Planning and
Maintenance Section, Air Programs Branch (AR-18J), U.S. Environmental
Protection Agency, 77 West Jackson Boulevard, Chicago, Illinois 60604.
    5. Hand Delivery: Douglas Aburano, Chief, Attainment Planning and
Maintenance Section, Air Programs Branch (AR-18J), U.S. Environmental
Protection Agency, 77 West Jackson Boulevard, Chicago, Illinois 60604.
Such deliveries are only accepted during the Regional Office normal
hours of operation, and special arrangements should be made for
deliveries of boxed information. The Regional Office official hours of
business are Monday through Friday, 8:30 a.m. to 4:30 p.m., excluding
Federal holidays.
    Please see the direct final rule which is located in the Rules
section of this Federal Register for detailed instructions on how to
submit comments.

FOR FURTHER INFORMATION CONTACT: Sarah Arra, Environmental Scientist,
Attainment Planning and Maintenance Section, Air Programs Branch (AR-
18J), Environmental Protection Agency, Region 5, 77 West Jackson
Boulevard, Chicago, Illinois 60604,<PHONE_NUMBER><EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: In the Final Rules section of this Federal
Register, EPA is making a clean data determination 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 action 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 public comments received will
be addressed in a subsequent final rule based on this proposed rule.
EPA will not institute a second comment period. Any parties interested
in commenting on this action should do so at this time. Please note
that if EPA receives adverse comment on an amendment, paragraph, or
section of this rule and if that provision may be severed from the
remainder of the rule, EPA may adopt as final those provisions of the
rule that are not the subject of an adverse comment. For additional
information, see the direct final rule which is located in the Rules
section of this Federal Register.

    Dated: July 14, 2015.
Susan Hedman,
Regional Administrator, Region 5.
[FR Doc. 2015-18100 Filed 7-23-15; 8:45 am]
 BILLING CODE 6560-50-P


DATE:	January 30, 2012

SUBJECT:	Draft Technical Support Document for the Secondary Aluminum
Production Source Category

FROM:	Mark Bahner, RTI International

TO:		Rochelle Boyd, U.S. Environmental Protection Agency (the EPA)

The purpose of this memorandum is to document the technical approach and
rationale used to develop certain proposed modifications to the National
Emission Standards for Hazardous Air Pollutants (NESHAP) for Secondary
Aluminum Production (40 CFR Part 63, Subpart RRR). The modifications are
to be proposed in January 2012.

Capture Efficiency Assumption for Uncontrolled Furnaces

Test data related to the capture efficiency for uncontrolled furnaces
were analyzed. Two tests were available. Both were conducted at
Southwire Corporation in Hawesville, KY. Testing was also conducted on
an in-line fluxer, but those results were not included in the analysis.
Testing was performed for PM, HCl and PCDD/PCDF from April 30 – May
02, 2007 at Furnace #5 in Mill 3, as reported on June 26, 2007. Testing
was performed for PM, HCl and PCDD/PCDF from July 17 – 19, 2007 at a
Group 1 furnace located in Rod Mill 1 and reported on September 5, 2007.
Testing was performed on a furnace stack and also on a temporary canopy
hood, which was installed for the test, to capture emissions not
directed through the furnace stack.

One aspect of this testing, regarding sampling time at the canopy hoods
versus the furnace stacks, potentially affects the results. In the
testing reported on June 26, 2007, sampling at the furnace stack was
performed from 7.7 to 8 hours per run, whereas sampling at the canopy
hood was performed for 3.0 to 3.33 hours per run. This is consistent
with the concept that emissions captured by the canopy hood would only
occur during furnace charging, whereas emissions through the furnace
stack would occur throughout the cycle (charging, melting, tapping)
which presumably lasted 7.7 to 8.0 hours. However, in the testing
reported on September 5, 2007, testing at the furnace stack was
performed for 3.2 hours per run, whereas testing at the canopy hood was
performed for 3.0 hours per run. This could mean that the complete
furnace cycle was only 0.2 hours longer than the charging period, or it
could be a mistake in the testing reported on September 5, 2007, such
that the testing at the furnace stack did not occur throughout the
entire furnace cycle. If the testing reported on September 5th was
indeed flawed in that the sampling at the furnace stack did not occur
throughout the furnace cycle, then the ratio of emissions in the canopy
hood stack to total emissions would be biased high.

The results of the two tests are summarized in Table 1. From Table 1, it
can be seen that the average capture by the furnace stack, for all
pollutants and for both tests, was 71 percent. The EPA has considered
various potential furnace stack capture effiencies and resultant stack
test estimation factors for uncontrolled furnaces. For example, if the
furnace capture efficiency is assumed to be 50 percent, the furnace test
results would need to be multiplied by a factor of 2. If the furnace
capture efficiency was assumed to be 66.67 percent (approximately 67
percent), the furnace test results would need to be multiplied by a
factor of 1.5. The test results in Table 1 support multiplying the
furnace test results by a factor of 1.5, because the average capture
efficiency for all tests was 71 percent, which is slightly higher than
67 percent.

Additional tables related to this analysis are included in Appendix A to
this memorandum. The tables can be summarized as follows:

Table A1: This table presents data from the June 26, 2007 report. The
data included pollutant emissions in pounds per hour and test sampling
time. These are converted into total mass measured, so that the total
emissions from the furnace stack can be compared to the total emissions
in the canopy hood stack.

Table A2: This table presents data from the June 26, 2007 report. The
data are exclusively in pounds and the table includes a calculation of
the percentage of polluetants emitted through the canopy hood stack
versus the total mass of pollutants emitted through both the canopy hood
stack and the furnace stack.

Table A3: This table presents data from the September 5, 2007 report.
The data included pollutant emissions in pounds per hour and test
sampling time. These are converted into total mass measured, so that the
total emissions from the furnace stack can be compared to the total
emissions in the canopy hood stack.

Table A4: This table presents data from the September 5, 2007 report.
The data are exclusively in pounds and the table includes a calculation
of the percentage of polluetants emitted through the canopy hood stack
versus the total mass of pollutants emitted through both the canopy hood
stack and the furnace stack.

Costs for Lowering the Dioxin/Furan (D/F) limit for Group 1 Furnaces

The EPA multipathway screen analysis results indicated exceedances of
worst-case screening levels, which do not necessarily indicate risks;
however, they cannot be ruled out based on the results.

To evaluate the potential to reduce D/F emissions, our analysis focused
on two options: 1) lower the D/F limit from 15 to 10 µg TEQ/Mg
(micrograms toxic equivalent per Megagram of feed) for group 1 furnaces
processing other than clean charge at all facilities, and 2) lower the
D/F limit for Group 1 furnaces processing other than clean charge to 10
µg TEQ/Mg , after applying a subcategorization that only required
facilities producing more than 200,000 tpy in group 1 furnaces to meet
the lower limit. These lower limits could potentially be met with
activated carbon injection systems.

With regard to the first option, based on testing reported in
information collection request responses1,  it was estimated that
approximately 11 facilities would need to reduce their D/F emissions,
and that the costs would be approximately $5.9 million in total capital
costs, with total annualized costs of approximately $2.7 million. This
option was estimated to achieve an approximately 1.66 grams TEQ
reduction of D/F, with an overall cost-effectiveness of approximately
$1.61 million per gram D/F TEQ.

For the second option, again based on testing and production data
reported in information collection responses, approximately 4 facilities
were estimated to  need to reduce their D/F emissions, and that the
costs would be approximately $129,000 in total capital costs, with total
annualized costs of approximately $464,000. This option is estimated to
achieve an aproximately 0.38 grams TEQ reduction of D/F with an overall
cost-effectiveness of approximately $1.22 million per gram D/F TEQ.

Our cost estimates were based on furnaces that were already controlled
by fabric filters simply adding an activated carbon injection system,
which is relatively low in capital cost, but is high in operating costs,
due to the cost of activated carbon. Our cost estimates for uncontrolled
furnaces were based on adding fabric filters and activated carbon
injection systems, which have high capital costs as well as operating
costs. All costs were based on a study done for the costs of adding
fabric filters and activated carbon injection done for a utility in New
Jersey2, with costs adjusted for the lower flow rate for secondary
aluminum furnaces (assumed to be 45,000 acfm, based on ICR responses).

Compliance with Emission Limits during Startup/Shutdown

The EPA is proposing standards for startup and shutdown for all
secondary aluminum process units. The subpart RRR standards would apply
at all times, including periods of startup and shutdown. Because the
scrap processed at secondary aluminum production facilities is the
source of emissions, emissions during startup and shutdown are expected
to be no higher and probably much lower than emissions during normal
operations since no scrap would be processed. Therefore, the agency sees
no reason why the existing standards should not apply at all times.

For production processes in the secondary aluminum production source
category where the standards are expressed in units of pounds per ton of
feed or similar units (i.e. thermal chip dyers, scrap dryer/delacquering
kiln/decoating kilns, dross-only furnaces, in-line fluxers using
reactive flux and group 1 furnaces), the form of the standard would
raise implementation issues if facilities were simply required
facilities to demonstrate compliance in the exact same way as they do
during normal operations , because the equipment is not receiving feed
material during startup and shutdown periods. For example, the startup
procedure for a furnace consists of gradually heating the furnace to
normal operating temperature, without any addition of feed material.
Since the feed rate is zero, the emission rate per ton of feed would be
calculated to be infinite.

One possibility would be to have concentration-based limits. However,
these are probably not appropriate for the secondary aluminum industry,
because hooding draws in large amounts of ambient air in order to
increase hooding capture. Therefore, it is expected that emissions
during startup and shutdown will be measured and determined under the
applicable test method in pounds per hour (lb/hr).Under the proposed
rule, to demonstrate compliance during the startup and shutdown periods,
for the emissions standards that are in units of lbs per ton, the
emissions in units of pounds per hour would be divided by the feed rate
in tons per hour (ton/hr) from the most recent or current performance
test and compared to the emission limit for the affected source. For
example, the PM limit for a new or existing group 1 furnace is 0.4
lb/ton. If, during a startup or shutdown, the emission rate determined
under the applicable test method is 2 lb/hr, and the furnace charge rate
during the most recent performance test was 10 tons per hour, the
calculated emission rate for that test during a period of startup or
shutdown would be 0.2 lb/ton of feed (2 lb/hr of PM divided by 10 tons
per hour of feed). This would be in compliance with the PM standard of
0.4 lb/ton of feed.

Representativeness for Nine-Company HAP Metals and HAP Organics Testing

The EPA used a nine-company ICR to gather testing data that would
correlate emissions of THC surrogate to speciated organic HAPs and
emissions of PM surrogate to speciated metal HAPs. Testing was limited
to nine companies for efficiency and to avoid undue burden to the
industry. The nine companies were chosen primarily because they were
large companies operating many facilities, and because they were
companies that were known to operate major source facilities that had
thermal chip dryers or scrap dryer/delacquering/decoating kilns. Thermal
chip dryers and scrap dryer/delacquering decoating kilns are the only
types of equipment that have THC limits. These two pieces of equipment
were limiting in selecting companies for testing, in that few companies
in the secondary aluminum source category currently operate those pieces
of equipment. Therefore, the sampling for those pieces of equipment was
representative, because the sampling represented a large fraction of
those pieces of equipment operated by the industry. The sampling for HAP
metals in fabric filter dust represented a much smaller fraction of the
industry (less than 10 percent of all pieces of equipment). However,
there were a total of 55 samples analyzed for the full suite of HAP
metals (including arsenic, cadmium, total chromium and hexavalent
chromium, manganese, mercury, nickel, etc.). Because 55 samples were
taken from many facilities owned by nine companies, these results are
believed to be representative of metal concentrations in fabric filter
dust within the secondary aluminum industry and are suitable for use in
developing speciated metal HAP emissions from PM emissions.

References

Letter, Peter Tsirigotis (U.S. EPA) to Russell Mayfield (Mayfield
Salvage Company) et al., “Requirement to provide information according
to 42 U.S.C 7414,” February 7, 2011. This was the cover letter for the
all-company data collection ICR.

Memorandum, Serpil Guran (New Jersey Department of Environmental
Protection) to William O’Sullivan (New Jersey Department of
Environmental Protection). Subject: Analysis for Coal Burning Boilers
Mercury Emissions Levels and Control Options. May 8, 2003.

List of Tables

  TOC \h \z \t "Table Title,1"    HYPERLINK \l "_Toc315445237"  Table 1.
    Southwire Test Results Summary	  PAGEREF _Toc315445237 \h  6

  HYPERLINK \l "_Toc315445238"  Table 2.     Group 1 Furnace D/F
Reduction Options	  PAGEREF _Toc315445238 \h  7

  HYPERLINK \l "_Toc315445239"  Table 3.     Cost-effectiveness
Calculation for D/F Reduction Options	  PAGEREF _Toc315445239 \h  7

  HYPERLINK \l "_Toc315445240"  Table A1.  Southwire Testing Reported
June 26, 2007: Complete Test Results	  PAGEREF _Toc315445240 \h  9

  HYPERLINK \l "_Toc315445241"  Table A2.  Southwire Testing Reported on
June 26, 2007: Results in Pounds	  PAGEREF _Toc315445241 \h  10

  HYPERLINK \l "_Toc315445242"  Table A3.  Southwire Testing Reported
September 5, 2007: Complete Test Results	  PAGEREF _Toc315445242 \h  11

  HYPERLINK \l "_Toc315445243"  Table A4.  Southwire Testing Reported on
September 5, 2007: Results in Pounds	  PAGEREF _Toc315445243 \h  12

Table 1. Southwire Test Results Summary

Test Report Date	Pollutant	Three-run Average

Fraction in Furnace Stack	Three-run Average

Fraction in Canopy Hood Stack

June 26, 2007	PM	0.78	0.22

June 26, 2007	HCl	0.81	0.19

June 26, 2007	D/F	0.97	0.03

Sept. 5, 2007	PM	0.49	0.51

Sept. 5, 2007	HCl	0.77	0.23

Sept. 5, 2007	D/F	0.42	0.58

Average for all	All	0.71	0.29

Table 2. Group 1 Furnace D/F Reduction Options

Option	Furnace Status	Number of Furnaces	Capital Cost1 Each (2011 $)
Annual Operating Cost Each

(2011 $)	Combined Total Capital Cost (2011$)	Combined Total Annualized
Cost (2011$)

Limit of 10 µg/Mg TEQ for all	Controlled	11	32,478	115,983	5,910,258
2,680,713

Limit of 10 µg/Mg TEQ for all	Uncontrolled	9	617,000	156,100

Limit of 10 µg/Mg TEQ if production >200,000 tpy	Controlled	4	32,478
115,983	129,912	463,932

Limit of 10 µg/Mg TEQ if production >200,000 tpy	Uncontrolled	0	617,000
156,100

Table 3. Cost-effectiveness Calculation for D/F Reduction Options

Option	Combined Total Annualized Cost (2011$)	Annual D/F Emission
Reduction (grams TEQ)	D/F Removal Cost Effectiveness

($/gram TEQ)

Limit of 10 µg/Mg TEQ for all	2,680,713	1.66	1,610,000

Limit of 10 µg/Mg TEQ if production >200,000 tpy	463,932	0.38	1,220,000

Appendix A

Southwire Test Results

Table A1.  Southwire Testing Reported June 26, 2007: Complete Test
Results

* reported as 2378-TCDD equivalent

Table A2.  Southwire Testing Reported on June 26, 2007: Results in
Pounds

Table A3.  Southwire Testing Reported September 5, 2007: Complete Test
Results

Table A4.  Southwire Testing Reported on September 5, 2007: Results in
Pounds

  PAGE   \* MERGEFORMAT  4

  PAGE   \* MERGEFORMAT  7


John Silvasi/ RTP/ USEPA/ US 07/ 01/ 2005 02: 33 PM T o Art Fraas, Amy Flynn c c Denise Gerth/ RTP/ USEPA/ US@ EP A, Jan Tierney/ DC/ USEPA/ US@ EP A, Jim Ketcham Colwill/ DC/ USEPA/ US@ EP A, John Silvasi/ RTP/ USEPA/ US@ EP A, Kevin McLean/ DC/ USEPA/ US@ E PA, Robert Meyers/ DC/ USEPA/ US@ EP A, Sara Schneeberg/ DC/ USEPA/ US @ EPA, Tom Helms/ RTP/ USEPA/ US@ EP A, Lydia Wegman/ RTP/ USEPA/ US@ EPA, Allen Basala, Doug Grano, Rich Damberg/ RTP/ USEPA/ US@ EPA, Geoffrey Wilcox/ DC/ USEPA/ US@ EP A S u b j e c t * Revised RACT section of preamble 8 hr O3 NAAQS implementation rule phase 2 Hi, Art and Amy,

Attached are Doug Grano's revisions to address the discussions from last Tuesday and the prior Thursday on the RACT section of the phase 2 8 hr ozone implementation rule. These changes have NOT been reviewed by our management and counsel and therefore we may need to make changes as a result of that review, but we believe these address the kinds of revisions we had discussed.

John J. Silvasi Environmental Engineer Ozone Policy and Strategies Group ( C539 02) Office of Air Quality Planning and Standards U. S. Environmental Protection Agency Research Triangle Park, NC 27711 919 541 5666 ( v); 919 541 0824 ( fax) silvasi. john@ epa. govHere's a redline strikeout compared to the 2/ 6/ 05 version originally sent to OMB: Here's a " blueline" strikeout compared to the more recent 6/ 6/ 05 version that also describes the changes made: