Document ID: EPA-HQ-OPP-2010-0626-0026
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-09-25T04:00Z

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.