Document ID: EPA-HQ-OPP-2010-0626-0025
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-09-25T04:00Z

DATA EVALUATION RECORD
                        Tribenuron Methyl (DPX-L5300) 
                                PC Code: 128887
                                 TXR#: 0056213
                                MRID#: 48732501
                                       
                Study Type: Acute Neurotoxicity Study in Rats;
                                OPPTS 870.6200a
                                       
                                 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:	Acute Neurotoxicity, (oral, gavage)  -  (rat); OPPTS 870.6200a [§81-8], OECD 424; MAFF12 Nousan 8147; EEC B.43 Directive 2004/73/EC

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-l,3,5-triazin-2-yl)methylamino]carbonyl] amino]sulfonyl]benzoate; Methyl 2-[4-methoxy-6-methyl-l,3,5-triazin-2-yl(methyl)carbamoylsulfamoyl]benzoate; DPX-L5300-281

CITATION:	Carpenter, C. (2012). Tribenuron Methyl (DPX-L5300) Technical: Acute 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-31859, January 13, 2012. MRID 48732501. Unpublished.
	
	Carpenter, C. (2011). Tribenuron Methyl (DPX-L5300) Technical: Acute 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-31859, December 15, 2011. MRID 48703401. Unpublished.

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

EXECUTIVE SUMMARY:

In an acute neurotoxicity study (MRID 48703401 and 48732501; revised report), groups of Crl:CD(SD) rats (12/sex/dose) were administered a single oral (gavage; 10 ml/kg) dose of Tribenuron Methyl (DPX-L5300) (98.2 %) in 0.5% methylcellulose at doses of 0, 100, 300, or 1000 mg/kg bw and observed for 14 days. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed on all animals prior to test substance administration (baseline), on Day 0 approximately 2 hours after the treatment, and on Days 7 and 14. At study termination, 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 1,000 mg/kg groups were subjected to histopathological evaluation.

There were no treatment-related effects on mortality or clinical signs at any dose level in males and females. 

There were no treatment-related effects on mean body weights in the 100, 300 and 1,000 mg/kg in males or females, except for a slight, statistically significant, lower body weight (↓7%) in the 1,000 mg/kg group females on Day 7. However, body weight gains were significantly reduced in males at 300 and 1000 mg/kg/day and females at 1000 mg/kg/day.  
In males, body weight loss (p<=0.05) was 4.5 g of weight in the 300 mg/kg group and 12.2 g of weight in the 1,000 mg/kg group over the interval test Days 0-1 compared to 4.7 g body weight gain in the control group. Mean body weight gain was significantly decreased by (↓42%) in the 1,000 mg/kg females on Day 0-7. No significant differences were noted on overall (Days 0-14) body weight gain when compared to the control group in the 1,000 mg/kg males or females. 

Treatment-related effects on food consumption were evident in the 300 and 1,000 mg/kg males and females. Food consumption was significantly decreased by ↓25% and ↓65% in the 300 and 1,000 mg/kg males, respectively, on Day 0-1. Similarly, lower (p<=0.05) food consumption was observed at dose level 300 (↓19%) and 1,000 (↓70%) mg/kg in females on Day 0-1. On Day 0-7, mean food consumption was significantly (p<=0.05) reduced by ↓10% in the 1,000 mg/kg females group, but not in the males. No significant differences were noted on overall (Days 0-14) food consumption when compared to the control group in the 1,000 mg/kg males or females. Lower (p<=0.05) food efficiency was noted in the 300 mg/kg and 1,000 mg/kg males and the 1,000 mg/kg females on Day 0-1. In addition, mean food efficiency was significantly (p<=0.05) decreased by ↓34% in the 1,000 mg/kg females group on Day 0-7, but not in the males. No significant differences were noted on overall (Days 0-14) food consumption in the 1,000 mg/kg males or females when compared to the control group.

No treatment-related neurotoxic effects were observed.  Transient, significant decreases in motor activity (duration of movement) were observed in males (↓44%) and females (↓56%) at the dose level of 1,000 mg/kg on Day 0, but not on Days 7 and 14.. Lower (p<=0.05) mean rearing was observed in the 1,000 mg/kg females (↓50%) on test Day 0, but not in the males. This finding was associated with the reduction in motor activity observed in the 1,000 mg/kg group females on Day 0.  Significantly (p<=0.05) higher incidences of abnormal sleeping behavior were observed in the 1,000 mg/kg group males in the home cage on Day 7. However, it is unclear if this is treatment related because it was only observed on Day 7 in males and all other treatment related findings were observed on Day 0 or 1. There were no macroscopic and microscopic pathology alterations of nervous system tissues in the 1,000 mg/kg male and female groups. The transient effects on motor activity and rearing are attributed to the body weight effects, significant reductions in food consumption, and/or food efficiency also observed at the same dose.  
The LOAEL for systemic toxicity is 1000 mg/kg for males and females, based on body weight changes (BW loss in males, decreased BWG in females), reduced food consumption, and/or food efficiency, and transient effects on motor activity and rearing, attributed to the systemic changes observed.
This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.6200a; OECD 424) for an acute 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:
White to tan - Solid

Lot/Batch #:
MAY10MA047

Purity:
98.2 % a.i.

Compound Stability: 
The Sponsor stated that the test substance was considered to be stable for 5 days at room temperature.

CAS # of TGAI: 
101200-48-0

Structure:

2.	Vehicle: 0.5% Methylcellulose. 

3.	Test animals:

Species:
Rat

Strain:
Crl:CD(SD) 

Age/weight at study initiation:
49 days of age. Males: 217.8-293.1 g; Females: 157.9-217.2 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:
20-26°C
30-70%
Not stated
12 hrs dark / 12 hrs light

Acclimation period:
13 days

B.	STUDY DESIGN:

1.	In life dates: Start: June 13, 2011; 							End: June 30, 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 containing an equal representation of each group and sex. The replicates were dosed over a 2-day period. Test substance was administered once via gavage to rats at dose levels of 0, 100, 300 and 1,000 mg/kg and the animals were observed twice daily for 14 days after dosing. Animals were weighed on test day 0, 1, 7, and 14. Survivors not assigned for neuropathology were sacrificed and a necropsy was not performed.
   
   Dose levels were chosen based on the results of a 28-day oral toxicity study in rats conducted with Tribenuron methyl (DPX-L5300) at dose levels of 0, 100, 300, and 1000 mg/kg/day (MRID: 42836601) and an acute oral toxicity study in rats conducted with Tribenuron methyl Technical at a single dose of 5000 mg/kg body weight (not submitted). 
   
   In the 28-day oral toxicity study, significant lower body weight and body weight gain were noted at 300 and 1000 mg/kg/day. In the acute oral toxicity study, body weight losses (10-13%) were observed at 5000 mg/kg during test days 9-11. No deaths were recorded in this study.
   
   Based on these combined results, the dose levels selected for the current study were 0, 100, 300 and 1,000 mg/kg body weight (Table 1).
   
                                       
TABLE 1. Study Design

                            Experimental parameter
                            Dose Level (mg/kg bw) 
                                       
                                       0
                                      100
                                      300
                                     1,000
Dose formulation concentration (mg/mL)
                                       0
                                      10
                                      30
                                      100
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
Doses were adjusted for purity and dose volume was 10 mL/kg.
Data were extracted from pages 15 and 18-22 of the study report.  

3.	Test Substance preparation and analysis: All dose formulations were prepared once prior to dosing by mixing appropriate amounts of test substance with 0.5% methylcellulose. They were stored at room temperature. Homogeneity and concentration analyses of test substance in 0.5% methylcellulose were verified prior to the study at concentrations of 0, 10, 30 and 100 mg/mL. The stability of the test substance was verified at the concentrations of 10 and 100 mg/mL after 5 days of storage at room temperature.
   
   Results
   Homogeneity analysis (% RSD): 1-4%.
   
   Stability analysis (% initial): 94.9-97.7%, 5 days at room temperature.
   
   Concentration analysis (range as % nominal): 96.3-103%. 
   
   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 test was not significant, one-way analysis of variance followed by Dunnett's test (2-sided) was used to compare treated groups with control groups. If 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 test was not significant, repeated measures analysis of variance was followed by linear contrasts. If test was significant, a normalizing, variance stabilizing transformation followed by repeated measures analysis of variance or sequential application of the Jonckheere-Terpstra trend test were used. If there was a significant lack of monotonicity, Dunn's test was used instead.
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.

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. Detailed clinical observations were recorded daily during the 14 days following dosing except on the days of neurobehavioral evaluations. 

2.	 Body Weight: Animals were weighed during the baseline FOB, prior to the test substance administration, and on Days 1, 7 and 14.

3.	Food Consumption: Food consumption of each animal was determined by weighing each feeder on test Days 0, 1, 7, and 14. The mean food consumption (g/day) and food efficiency (average weight gain/average food consumed) were calculated for each rat for the intervals of test days 0-1, 0-7, 7-14, and 0-14. 

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 on Days 0 (approximately 2 hours after dosing), 7 and 14. 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. The time in the open-field was at least 2 minutes. Fore- and hindlimb grip strength were measured using 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
                                       
NEUROMUSCULAR OBSERVATIONS
                                       X
Fur/skin appearance
                                       X
Ease of respiration
                                       X
Landing foot splay
                                       X
Mucous membranes
                                       X
Rate of respiration 
                                       X
Forelimb grip strength
                                       X
Palpebral closure
                                       X
Posture
                                       X
Hindlimb grip strength
                                       X
Exophthalmus
                                       X
Palpebral closure
                                       
SENSORY OBSERVATIONS
                                       X
Lacrimation
                                       X
Arousal 
                                       X
Approach response
                                       X
Salivation
                                       X
Vocalization
                                       X
Touch response
                                       X
Dehydration
                                       X
Diarrhea
X
Sharp auditory stimulus
                                       X
Emaciation
                                       X
Polyuria
X
Tail pinch
                                       
PHYSIOLOGICAL OBSERVATIONS
                                       X
Number of rearing movements

                                       

                                       

X
Pupillary constriction
 X
Body temperature
                                       

X
Body weight
                                       

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 (Day 0) and on Day 7, and Day 14.  Animals were counterbalanced by sex and treatment and were tested in replicates over multiple days. An automated Coulbourn[(R)] Instruments activity monitor was used with infrared beams per cage 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 is analogous to "counts" in other types of devices that employ interruption of light beams. Duration of movement and number of movement 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/sexin 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 using isoflurane anesthesia and CO2 and were disposed of without any pathological examinations. 
   
   The tissues from the control and high-dose animals (1,000 mg/kg bw) were processed for microscopic evaluation. The brain, spinal cord sections, eyes, optic nerve, and gastrocnemius muscle were embedded in paraffin, sectioned at 5 um, 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
                                       X
Cervical ventral root fibers
                                       X
Optic nerve
                                       

                                       X
Eyes
                                       

                                       X
Gastrocnemius muscle
                                       

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 100, 300 or 1,000 mg/kg groups of both sexes. The only clinical sign observed was a missing toe (hindlimb, left) in one male in the 1,000 mg/kg group from Day 1 to 13.  
	
2.	Mortality: All animals survived to scheduled termination. 

B.	BODY WEIGHT AND BODY WEIGHT GAIN: There were no treatment-related effects on mean body weights in the 100, 300, and 1,000 mg/kg groups in males or females.A slight statistically significant lower body weight (↓7%) was noted in the 1,000 mg/kg group females on Day 7 (Table 2) but the mild reduction was not considered adverse. Effects on body weight gain were observed at 300 and 1000 mg/kg/day.   As shown in Table 2, test substance-treated males lost 4.8 g (↓202%) and 12.2 g (↓359%) of weight (p<=0.05) at dose levels of 300 and 1,000 mg/kg, respectively, over the interval test Days 0-1 compared to a 4.7 g body weight gain in the control group. For females, the only significant (p<=0.05) difference from the control group was a lower mean body weight gain (↓42%) in the 1,000 mg/kg group between Days 0-7 (Table 2). No significant differences were noted on overall (Days 0-14) body weight gain when compared to the control group in the 1,000 mg/kg males or females. 
   
TABLE 2. Mean (+-SD) Body Weights and Body Weight Gains in Male and Female Rats 
                                 Exposure Time
                                 Dose (mg/kg)
                                       
                                       0
                                      100
                                      300
                                     1,000
                            Body weight (g) - Males
Day 0 
                                  260.5+-21.4
                                  259.0+-11.7
                                  266.3+-12.7
                                  267.4+-14.5
Day 1
                                  265.2+-23.0
                                  262.3+-11.6
                                  261.5+-11.7
                                  255.2+-13.5
Day 7
                                  321.5+-25.4
                                  322.3+-18.6
                                  329.9+-14.5
                                  323.3+-17.5
Day 14
                                  379.7+-29.7
                                  378.6+-26.0
                                  393.4+-16.4
                                  385.2+-17.3
                           Body weight (g) - Females
Day 0
                                  190.0+-14.3
                                  188.5+-15.5
                                  187.5+-11.3
                                  186.2+-9.6
Day 1
                                  188.6+-13.0
                                  188.0+-14.0
                                  185.7+-9.6
                                  178.4+-10.3
Day 7
                                  214.8+-18.5
                                  216.6+-20.5
                                  211.4+-11.4
                                  200.7+-9.0*
                                    (↓7%)
Day 14
                                  237.8+-22.7
                                  237.9+-24.2
                                  234.0+-15.3
                                  226.5+-14.7
                         Body weight gain (g) - Males
Day 0-1
                                   4.7+-3.4
                                   3.3+-4.6
                                  -4.8+-3.8*
                                   (↓202%)
                                  -12.2+-7.0*
                                   (↓359%)
Day 0-7
                                   61.0+-6.5
                                  63.3+-10.0
                                   63.5+-6.1
                                   56.0+-6.5
Day 7-14
                                   58.2+-7.2
                                   56.3+-8.8
                                   63.5+-7.2
                                   61.9+-6.8
Day 0-14
                                  119.2+-12.7
                                  119.6+-18.2
                                  127.1+-8.7
                                  117.9+-10.0
                        Body weight gain (g) - Females
Day 0-1
                                   -1.4+-4.6
                                   -0.5+-5.9
                                   -1.9+-6.9
                                   -7.9+-6.5
Day 0-7
                                   24.8+-8.0
                                   28.1+-7.5
                                   23.9+-7.2
                                  14.5+-6.6*
                                   (↓42%)
Day 7-14
                                   23.0+-7.1
                                   21.3+-7.0
                                   22.6+-6.7
                                  25.8+-10.4
Day 0-14
                                   47.8+-9.9
                                  49.4+-12.7
                                  46.5+-10.5
                                  40.3+-11.1
Values represent mean+-SD, n=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.
Data were obtained from pages Tables 3 (page 34), 4 (page (35), 5 (page 36) and 6 (page 37) of the study report.
   
C.	FOOD CONSUMPTION AND FOOD EFFICIENCY: Summary results of food consumption and food efficiency in males and females are presented in Table 3. Treatment-related effects on food consumption were evident in the 300 and 1,000 mg/kg males and females. In males, significant decreases (p<=0.05) in food consumption were noted at dose levels of 300 (↓25%) and 1,000 (↓65%) mg/kg on Day 0-1. Similarly, lower (p<=0.05) food consumption was observed in females at dose levels of 300 (↓19%) and 1,000 (↓70%) mg/kg on Day 0-1. In contrast, food consumption was significantly (p<=0.05) increased by 6% in the 300 and 1,000 mg/kg male groups on Day 7-14. However, mean food consumption was unaffected by the test substance in the females at any dose level on Day 7-14. On Day 0-7, mean food consumption was significantly (p<=0.05) reduced by 10% in the 1,000 mg/kg females group (Table 3). No significant differences were noted on overall (Days 0-14) food consumption in the 1,000 mg/kg males or females when compared to the control group.
   
   Significant (p<=0.05) reductions in food efficiency compared to the control were noted in the 300 mg/kg and 1,000 mg/kg males and the 1,000 mg/kg females on Day 0-1. In addition, mean food efficiency was significantly (p<=0.05) decreased by ↓34% in the 1,000 mg/kg females group on Day 0-7, but not in the males. Food efficiency was decreased in maleson Day 0-1 in the 300 and 1,000 mg/kg groups by ↓249% and ↓1,064%, respectively. It is concluded that lower food efficiency observed in the 300 mg/kg and 1,000 mg/kg males and the 1,000 females on Day 0-1 was consistent with the significant reduction in food consumption observed in the 300 mg/kg and 1,000 mg/kg males and the 1,000 mg/kg females. 
   
TABLE 3. Mean (+-SD) Food Consumption and Food Efficiency in Male and Female Rats 
                                 Exposure Time
                                 Dose (mg/kg)
                                       
                                       0
                                      100
                                      300
                                     1,000
                    Food Consumption (g/animal/day) - Males
Day 0-1
                                   28.5+-3.3
                                   28.4+-3.6
                                  21.4+-2.5*
                                   (↓25%)
                                  10.0+-3.4*
                                   (↓65%)
Day 0-7
                                   29.4+-2.1
                                   29.3+-0.9
                                   29.9+-1.3
                                   29.0+-2.2
Day 7-14
                                   31.0+-1.6
                                   30.3+-1.2
                                  32.9+-0.9*
                                    (↑6%)
                                  33.0+-1.5*
                                    (↑6%)
Day 0-14
                                   30.2+-1.8
                                   29.8+-1.0
                                   31.4+-0.9
                                   31.0+-1.7
                   Food Consumption (g/animal/day) - Females
Day 0-1
                                   18.5+-3.6
                                   17.5+-3.5
                                  14.9+-2.9*
                                   (↓19%)
                                   5.6+-2.3*
                                   (↓70%)
Day 0-7
                                   20.2+-1.6
                                   20.2+-1.9
                                   20.1+-0.6
                                  18.1+-1.4*
                                   (↓10%)
Day 7-14
                                   20.3+-2.1
                                   19.9+-1.8
                                   19.8+-1.5
                                   20.2+-2.0
Day 0-14
                                   20.2+-1.8
                                   20.0+-1.8
                                   20.0+-1.0
                                   19.2+-1.5
            Food Efficiency (avg wt gain/avg food consumed) - Males
Day 0-1
                                 0.156+-0.101
                                 0.124+-0.167
                                -0.233+-0.205*
                                   (↓249%)
                                -1.501+-1.080*
                                  (↓1,064%)
Day 0-7
                                 0.296+-0.026
                                 0.308+-0.046
                                 0.303+-0.026
                                 0.276+-0.030
Day 7-14
                                 0.268+-0.032
                                 0.265+-0.037
                                 0.276+-0.033
                                 0.268+-0.030
Day 0-14
                                 0.282+-0.028
                                 0.286+-0.040
                                 0.289+-0.024
                                 0.272+-0.025
           Food Efficiency (avg wt gain/avg food consumed) - Females
Day 0-1
                                 -0.082+-0.284
                                 -0.011+-0.366
                                 -0.146+-0.485
                                 -3.249+-5.25*
                                  (↓3,862%)
Day 0-7
                                 0.176+-0.056
                                 0.197+-0.043
                                 0.170+-0.052
                                 0.116+-0.057*
                                   (↓34%)
Day 7-14
                                 0.160+-0.043
                                 0.152+-0.045
                                 0.162+-0.044
                                 0.179+-0.065
Day 0-14
                                 0.168+-0.030
                                 0.175+-0.036
                                 0.166+-0.037
                                 0.150+-0.039
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.
Data were obtained from pages Tables 7 (page 38), 8 (page (39), 9 (page 40) and 10 (page 41) of the study report.
   
D.	NEUROBEHAVIORAL RESULTS:

1.	FOB findings: Significantly (p<=0.05) higher incidences of abnormal sleeping behavior were observed in the 1,000 mg/kg group males in the home cage on Day 7 and included limbs spread out or lying on one side (4/12 treated vs. 0/12 control) and palpebral closure commensurate with sleeping (3/12 treated vs. 0/12 control). No other treatment-related effects on FOB parameters were noted.

2.	Locomotor activity: A summary of mean motor activity (duration and number of movements) in males and females is presented in Tables 4 (a and b) and 5 (a and b). Motor activity was affected by test substance in both males and females; however this was a transient effect occurring only on Day 0. The only significant (p<=0.05) differences from the control group were decreased total duration of movements in the 1,000 mg/kg males (↓44%) and females (↓56%) on Day 0. No statistically significant differences between control and test substance were observed in total duration of movement on Days 7 and 14 in either sex. The comparison of the single intervals with the control group resulted in some sporadic significantly decreased values during the first 3 10-minutes intervals for the 1,000 mg/kg males (↓43-90%) and females (↓44-77%) on Day 0 (Tables 4a and b). On Day 7, mean duration of movement was significantly (p<=0.05) reduced by 91% and 65% (at interval 7) in the 300 and 1,000 mg/kg males group, respectively, but not in the females (Table 4a and b).
   
TABLE 4a. Selected Mean Duration of Movement (sec) for Male Rats 
                                     Dose
                                    (mg/kg)
                        Successive 10-Minute Intervals

                                       1
                                       2
                                       3
                                       5
                                       7
                                       9
                                     Total
                                   Baseline
0
                                    395+-49
                                   288+-120
                                   172+-141
                                    71+-111
                                    40+-67
                                    18+-34
                                   1120+-476
100
                                    391+-55
                                   246+-108
                                   125+-134
                                    54+-92
                                    32+-47
                                    20+-45
                                   966+-399
300
                                    387+-37
                                   229+-104
                                   108+-143
                                    91+-134
                                    49+-80
                                    36+-72
                                   1138+-625
1,000
                                    367+-34
                                   235+-114
                                    64+-74*
                                   (↓63%)
                                    17+-38
                                    57+-75
                                    17+-22
                                   859+-257
                                     Day 0
0
                                    396+-52
                                   190+-130
                                    84+-111
                                    21+-36
                                    15+-20
                                    32+-74
                                   848+-353
100
                                    374+-56
                                   194+-121
                                    99+-117
                                     10+-9
                                     4+-5
                                     7+-7
                                   754+-322
300
                                    369+-50
                                   150+-104
                                    47+-79
                                     9+-15
                                    21+-28
                                    24+-47
                                   671+-193
1,000
                                   227+-77*
                                   (↓43%)
                                    47+-46*
                                   (↓75%)
                                    8+-11*
                                   (↓90%)
                                    39+-94
                                    44+-70
                                    23+-42
                                   479+-278*
                                   (↓44%)
                                     Day 7
0
                                    411+-46
                                    254+-79
                                   122+-146
                                    73+-119
                                    78+-94
                                    14+-13
                                   1163+-633
100
                                    391+-45
                                    195+-70
                                    94+-117
                                    79+-111
                                    25+-47
                                    16+-27
                                   971+-446
300
                                    399+-32
                                    260+-94
                                    111+-96
                                    37+-86
                                    7+-11*
                                   (↓91%)
                                    43+-85
                                   957+-438
1,000
                                    403+-60
                                    297+-69
                                   126+-113
                                    15+-35
                                    27+-75*
                                   (↓65%)
                                    36+-73
                                   1010+-411
                                    Day 14
0
                                    382+-59
                                    262+-68
                                   156+-104
                                    88+-123
                                    63+-82
                                    37+-63
                                   1242+-564
100
                                    377+-31
                                    213+-87
                                    67+-74
                                    63+-117
                                    62+-119
                                    81+-124
                                   995+-417
300
                                    403+-34
                                    256+-87
                                   145+-154
                                    52+-87
                                    37+-68
                                    40+-82
                                   1083+-565
1000
                                    382+-59
                                    226+-95
                                   125+-113
                                    77+-115
                                    60+-95
                                    82+-120
                                   1137+-448
   Values represent mean+-SD, n=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.
   Data were obtained from Table 15 on page 57 of the study report.
   

TABLE 4b. Selected Mean Duration of Movement (sec) for Female Rats 
                                     Dose
                                    (mg/kg)
                                       
                        Successive 10-Minute Intervals

                                       1
                                       2
                                       3
                                       5
                                       7
                                       9
                                     Total
                                   Baseline
0
                                    364+-38
                                   256+-118
                                   183+-120
                                   129+-125
                                    43+-70
                                     2+-3
                                   1238+-562
100
                                    375+-63
                                    263+-66
                                   176+-119
                                   114+-108
                                    39+-55
                                    51+-88
                                   1345+-470
300
                                    390+-37
                                    271+-77
                                   151+-143
                                    92+-108
                                    83+-90
                                    10+-15
                                   1237+-289
1,000
                                    373+-43
                                    249+-77
                                   147+-107
                                   152+-139
                                    56+-101
                                    27+-52
                                   1286+-560
                                     Day 0
0
                                    372+-56
                                   207+-133
                                   131+-117
                                    67+-91
                                    99+-111
                                    21+-44
                                   1143+-563
100
                                    361+-61
                                    185+-86
                                    91+-74
                                    77+-107
                                    88+-106
                                    12+-17
                                   1013+-403
300
                                   325+-100
                                    238+-65
                                    84+-66
                                    39+-58
                                    81+-79
                                    35+-52
                                   1000+-322
1,000
                                   210+-70*
                                   (↓44%)
                                    80+-70*
                                   (↓61%)
                                    30+-36*
                                   (↓77%)
                                    29+-54
                                    34+-67
                                    12+-16
                                   508+-252*
                                   (↓56%)
                                     Day 7
0
                                    400+-42
                                   250+-118
                                   173+-106
                                   128+-117
                                    73+-84
                                    77+-100
                                   1464+-388
100
                                    397+-64
                                    210+-91
                                   157+-135
                                    85+-115
                                   131+-138
                                    63+-84
                                   1340+-511
300
                                    404+-45
                                    275+-97
                                    127+-89
                                   100+-139
                                    67+-77
                                    53+-75
                                   1294+-376
1,000
                                    373+-76
                                   200+-113
                                   125+-104
                                    99+-95
                                    112+-89
                                    59+-106
                                   1263+-591
                                    Day 14
0
                                    382+-42
                                    219+-84
                                    134+-87
                                   139+-107
                                   132+-122
                                    81+-94
                                   1466+-569
100
                                    414+-55
                                    243+-94
                                   162+-141
                                   134+-129
                                    72+-86
                                    96+-127
                                   1496+-564
300
                                    373+-64
                                   255+-108
                                   237+-115
                                    100+-89
                                    29+-35
                                    63+-71
                                   1306+-393
1000
                                    356+-68
                                   190+-107
                                   111+-101
                                   140+-112
                                    91+-91
                                    64+-92
                                   1277+-602
   Values represent mean+-SD, n=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.
   Data were obtained from Table 16 on page 58 of the study report.
   
   The mean number of movements was unaffected by administration of test substance at 100, 300, and 1,000 mg/kg in males or females (Tables 5 a and b). The only significant (p<=0.05) differences from the control was decreased mean number of movements during interval 7 in males at dose levels of 300 (↓84%) and 1,000 (↓60%) mg/kg and during interval 3 in the 1000 mg/kg females (↓67%) group (Table 5 a and b). Significant decreases (p<=0.05) were noted on the mean duration of movement (↓63%) and number of movement (↓49%) during interval 3 of the baseline in the 1,000 mg/kg males group, but not in the females (Table 4 and 5). This finding was not relevant because animals were not given test substance during the acclimation period (baseline). 
   
TABLE 5a. Selected Mean Number of Movements for Male Rats 
                                 Dose (mg/kg)
                        Successive 10-Minute Intervals

                                       1
                                       2
                                       3
                                       5
                                       7
                                       9
                                     Total
                                   Baseline
0
                                    137+-25
                                    123+-30
                                    88+-59
                                    40+-47
                                    28+-41
                                    17+-27
                                   527+-193
100
                                    132+-10
                                    120+-33
                                    70+-50
                                    33+-47
                                    22+-32
                                    17+-32
                                   458+-173
300
                                    130+-17
                                    109+-36
                                    52+-56
                                    44+-57
                                    36+-48
                                    29+-42
                                   530+-244
1,000
                                    136+-18
                                    116+-40
                                    45+-40*
                                   (↓49%)
                                    13+-21
                                    37+-41
                                    17+-18
                                   433+-132
                                     Day 0
0
                                    132+-20
                                    92+-49
                                    54+-63
                                    14+-17
                                    15+-15
                                    23+-43
                                   406+-168
100
                                    138+-21
                                    102+-46
                                    59+-66
                                     10+-7
                                     7+-6
                                     9+-9
                                   381+-143
300
                                    132+-23
                                    78+-46
                                    30+-42
                                     10+-7
                                    16+-17
                                    19+-26
                                    327+-81
1,000
                                    126+-37
                                    43+-35*
                                   (↓53%)
                                    12+-12
                                    26+-39
                                    31+-36
                                    25+-30
                                   347+-146
                                     Day 7
0
                                    135+-23
                                    133+-32
                                    62+-45
                                    40+-55
                                    45+-47
                                     14+-8
                                   542+-226
100
                                    139+-12
                                    115+-28
                                    53+-53
                                    45+-52
                                    19+-22
                                    14+-15
                                   485+-208
300
                                    130+-16
                                    116+-33
                                    71+-52
                                    23+-39
                                     7+-9*
                                   (↓84%)
                                    25+-33
                                   432+-153
1,000
                                    125+-21
                                    131+-28
                                    71+-53
                                    19+-35
                                    18+-34*
                                   (↓60%)
                                    27+-45
                                   457+-222
                                    Day 14
0
                                    137+-20
                                    131+-28
                                    91+-42
                                    45+-51
                                    45+-50
                                    32+-42
                                   621+-244
100
                                    135+-10
                                    107+-34
                                    49+-45
                                    32+-44
                                    33+-51
                                    46+-62
                                   489+-185
300
                                    131+-15
                                    117+-27
                                    65+-50
                                    26+-36
                                    23+-31
                                    23+-34
                                   468+-194
1000
                                    135+-13
                                    114+-35
                                    71+-56
                                    47+-61
                                    37+-44
                                    43+-54
                                   567+-267
   Values represent mean+-SD, n=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.
   Data were obtained from Table 17 on page 59 of the study report.
   

TABLE 5b. Selected Mean Number of Movements for Female Rats 
                                 Dose (mg/kg)
                                       
                                       
                        Successive 10-Minute Intervals

                                       1
                                       2
                                       3
                                       5
                                       7
                                       9
                                     Total
                                   Baseline
0
                                    129+-17
                                    113+-31
                                    94+-49
                                    71+-57
                                    33+-43
                                     4+-3
                                   583+-220
100
                                    132+-19
                                    127+-23
                                    99+-58
                                    74+-57
                                    36+-46
                                    36+-53
                                   702+-265
300
                                    128+-12
                                    127+-33
                                    78+-59
                                    55+-50
                                    54+-45
                                    13+-14
                                   605+-128
1,000
                                    124+-12
                                    112+-26
                                    81+-44
                                    76+-64
                                    36+-56
                                    23+-39
                                   624+-308
                                     Day 0
0
                                    135+-15
                                    91+-40
                                    78+-56
                                    46+-53
                                    57+-52
                                    16+-27
                                   578+-216
100
                                    142+-30
                                    97+-27
                                    64+-46
                                    46+-42
                                    54+-55
                                    13+-13
                                   551+-185
300
                                    124+-33
                                    124+-30
                                    65+-45
                                    28+-39
                                    57+-47
                                    26+-33
                                   552+-158
1,000
                                    118+-29
                                    56+-37
                                    26+-28*
                                   (↓67%)
                                    22+-34
                                    26+-33
                                    14+-17
                                   363+-131
                                     Day 7
0
                                    136+-16
                                    108+-37
                                    106+-54
                                    69+-54
                                    43+-45
                                    45+-49
                                   712+-217
100
                                    130+-17
                                    110+-31
                                    77+-47
                                    51+-54
                                    71+-59
                                    44+-47
                                   660+-198
300
                                    133+-14
                                    131+-38
                                    86+-50
                                    51+-51
                                    50+-47
                                    42+-50
                                   661+-231
1,000
                                    122+-22
                                    102+-36
                                    70+-48
                                    61+-52
                                    68+-51
                                    36+-45
                                   621+-284
                                    Day 14
0
                                    131+-22
                                    109+-36
                                    81+-44
                                    77+-51
                                    71+-56
                                    50+-46
                                   735+-248
100
                                    131+-15
                                    112+-33
                                    83+-56
                                    78+-58
                                    53+-49
                                    52+-53
                                   724+-214
300
                                    127+-22
                                    124+-46
                                    106+-43
                                    63+-52
                                    26+-28
                                    41+-43
                                   660+-234
1000
                                    126+-22
                                    93+-40
                                    70+-52
                                    75+-47
                                    63+-58
                                    41+-51
                                   646+-304
      Values represent mean+-SD, n=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.
      Data were obtained from Table 18 on page 60 of the study report.

3.	Rearing: The only significant (p<=0.05) difference from the control group was lower mean rearing (↓50%) in the 1,000 mg/kg group females, but not in the males, on test Day 0 (Table 6). This finding was consistent with the reduction in motor activity observed in the 1,000 mg/kg group males and females on Day 0.
   
TABLE 6. Mean (+-SD) Number of Rearing Movements in Female Rats 
                                 Exposure Time
                                 Dose (mg/kg)
                                       
                                       0
                                      100
                                      300
                                     1,000
Baseline
                                     7+-3
                                     7+-2
                                     5+-1
                                     6+-3
Day 0
                                     8+-4
                                     7+-3
                                     6+-2
                                     4+-2*
                                   (↓50%)
Day 7
                                     9+-5
                                     8+-4
                                     7+-3
                                     8+-3
Day 14
                                     7+-4
                                     7+-4
                                     8+-3
                                     7+-3
Values represent mean+-SD, n=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.
Data were obtained from Tables 12 on page 43 of the study report.

4.	Forelimb and Hindlimb Grip Strength: There were no treatment-related effects on forelimb or hindlimb grip strength in either sex at any dose level.
		
5.	Foot Splay: Foot splay was unaffected by the administration of test substance at 100, 300, and 1,000 mg/kg in males and females. There were no statistically significant differences between the control and test substance-treated groups. 

6.	Body Temperature: There were no treatment-related effects on body temperature in either sex at any dose level. On Day 0, mean body temperature was significantly (p<=0.05) reduced by ↓2% in the 100 mg/kg females group. This finding was due to normal biological variation and was not treatment related since there was no similar effect seen in the higher doses and no dose relationship. On Day 7, higher (p<=0.05) body temperature was noted in the females (each ↑3%) at dose levels of 300 and 1,000 mg/kg (Table 7). However, this finding was not treatment related since the mean body temperature values were within the historical control data (Table 7). 
	
TABLE 7. Mean (+-SD) Body Temperature (ºC) in Female Rats 
                                 Exposure Time
                                 Dose (mg/kg)
                                       
                                       0
                                      100
                                      300
                                     1,000
Baseline
                                   33.8+-0.8
                                   33.3+-0.5
                                   33.3+-0.5
                                   33.5+-0.6
Day 0
                                   34.2+-0.9
                                  33.4+-0.8*
                                    (↓2%)
                                   34.0+-0.9
                                   33.5+-0.7
Day 7
                                   35.2+-1.2
                                   35.3+-0.6
                                  36.3+-1.2*
                                    (↑3%)
                                  36.3+-1.0*
                                    (↑3%)
Day 14
                                   34.8+-0.7
                                   35.0+-1.0
                                   34.8+-1.0
                                   35.0+-0.8
Historical control data for female body temperature for day 7 [#]
           Mean = 36.2+-0.7 ºC (34.8+-0.8  -  37.8+-0.6); n= 10-12
Values represent mean+-SD, n=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.
# Data were obtained from Appendix K on page 218-219 of the study report.
Data were obtained from Tables 12 on page 43 of the study report.

E.	SACRIFICE AND PATHOLOGY: 

1.	Gross Pathology: No adverse, treatment-related effects were noted during gross pathology. The only findings noted at necropsy were dilated kidneys in 3 males at 300 mg/kg and in one male at 1,000 mg/kg, and small testes in one male at 300 mg/kg. Those gross findings were consistent with normal background changes observed in rats of this age and strain.

2.	Neuropathology: No adverse, treatment-related histological changes were noted in the 1,000 mg/kg group males or females. 
   
III.	 DISCUSSION AND CONCLUSIONS:

A.	INVESTIGATORS' CONCLUSIONS: The investigator concluded that although transient decreases in motor activity were observed on test day 0 in males and females administered 1000 mg/kg, which was also consistent with decreased rearing incidence in 1000 mg/kg females, there were no other effects on neurobehavioral parameters. The decreased motor activity and rearing incidence, however, correlate with the systemic toxicity (decreased body weight gain, food consumption, and food efficiency) observed over the interval of test days 0-1. For females in the 1000 mg/kg group, body weight at test day 7 and body weight gain over the 0-7 day interval were also statistically significantly reduced. Body weight gain over the 0-7 day interval was also lower in 1000 mg/kg males, but was not statistically significant. Therefore, the decreased motor activity and rearing incidence observed in 1000 mg/kg males and/or females was considered to be secondary to the systemic toxicity and was not a primary effect of the test substance.
   
   Under the conditions of the study, the no-observed-adverse effect level (NOAEL) for systemic toxicity in males and females was 300 mg/kg based on decreased body weight gain over the 0-1 and 0-7 day intervals, reduced food consumption, and/or food efficiency on test day 1, with secondary effects on motor activity and rearing observed at 1000 mg/kg. The NOAEL for neurotoxicity in males and females was 1000 mg/kg based on the absence of corroborative effects in other neurobehavioral parameters and neuropathology.

B.	REVIEWER COMMENTS: Exposure of Crl:CD(SD) rats to Tribenuron Methyl (DPX-L5300) at dose levels of 100, 300, and 1,000 mg/kg bw for 14 days resulted in no death or clinical findings.
   
   The only significant difference in body weights in males and females at any dose level tested was slightly lower body weight (↓7%) in the 1,000 mg/kg group females on Day 7, but not on Day 0 or Day 14. Significant body weight loss was noted in males at the dose of 300 (↓4.5 g) and 1,000 mg/kg (↓12.2 g) over the interval test Days 0-1, compared to a 4.7 g body weight gain in the control group. In addition, body weight gain was significantly reduced by (↓42% in the 1,000 mg/kg group females on Days 0-7. Body weight gain was also decreased by ↓8% in the 1,000 mg/kg males on Day 0-7, but not statistically significant. It is concluded that lower body weight in the 1,000 mg/kg females on Day 7 was correlated with the decreased body weight gain observed in the same females over the 0-7 day interval. 
   
   Treatment-related effects on food consumption were evident in the 300 and 1,000 mg/kg males and females. In males, significant decreases (p<=0.05) in food consumption were noted at dose levels of 300 (↓25%) and 1,000 mg/kg (↓65%) on Day 0-1. Similar to males on Day 0-1, food consumption was significantly decreased by ↓19% and ↓70% at 300 and 1,000 mg/kg, respectively, in females. No significant differences were noted on overall (Days 0-14) food consumption in the 1,000 mg/kg males or females when compared to the control group. Significant (p<=0.05) reductions in food efficiency were noted in the 300 mg/kg and 1,000 mg/kg males and the 1,000 mg/kg females on Day 0-1. This reduction was correlated with lower food consumption observed in the 300 mg/kg and 1,000 mg/kg males and 1,000, mg/kg females on Day 0-1. Moreover, lower food efficiency observed in the 1,000 mg/kg females (↓34%) on Day 0-7 was correlated with the decreased food consumption observed in the 1,000 mg/kg females (↓10%) on Day 0-7.
   
   No treatment-related neurotoxic-effects were observed. Transient, significant lower motor activity (duration of movement) was observed in males (↓44%) and females (↓56%) at a dose level of 1,000 mg/kg on Day 0, but not on Days 7 and 14. This reduction was accompanied by significantly decreased duration of movement during the first 3 10-minutes intervals for males and females on test Day 0. Total number of movements was not affected at any dose level. Mean number of rearing movements was significantly decreased by ↓50% in the 1,000 mg/kg females on Day 0, but not in the males. The decreased mean number of rearing movements observed was correlated with the decreased total duration of movement observed in the 1,000 mg/kg females on Day 0. The transient effects on motor activity and rearing are attributed to the body weight effects, significant reductions in food consumption, and/or food efficiency also observed at the same dose. Significantly (p<=0.05) higher incidences of abnormal sleeping behavior were observed in the 1,000 mg/kg group males in the home cage on Day 7. However, it is unclear if this is treatment related because it was only observed on Day 7 in males and all other treatment related findings were observed on Day 0 or 1.
   
   No treatment-related alterations were observed in gross histopathology observations or microscopic neurohistopathology in the 1,000 mg/kg male and female groups.

The LOAEL for systemic toxicity is 1000 mg/kg for males and females, based on body weight changes (BW loss in males, decreased BWG in females), reduced food consumption, and/or food efficiency, and abnormal sleeping behavior, transient effects on motor activity and rearing, attributed to the systemic changes observed.

   This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.6200a; OECD 424) for an acute neurotoxicity study in rats.
   
C.	STUDY DEFICIENCIES: 
	
   No deficiencies were reported in this study.