### DATA EVALUATION RECORD Tribenuron Methyl(DPX
- L5 300) PC Code: 128887 TXR#: 00562 13 MRID#: 48732501 Study Ty pe: Acute Neurotoxicity

Study in Rats; OPPTS 870.6200 a 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 b y 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
- 8 7 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.**Acute Neurotoxicity Study (rats) (201 2 ) /Page 2 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### EPA Reviewer: Jaime D’Agostino **Signature** : **Risk Assessment Branch 2**  **, Health Effects Division (7509P) Date:**  **Work Assignment Manager** : Lori B run sman **Signature** : **Science Info. Mgmt. Branch, Health Effects Division (7509P)**  **Date: Template version 09/11**  

### TXR# **:** 005 6 2 1 3 **DATA EVALUATION RECORD STUDY TYPE**  **:** Acute Neurotoxicity, (oral, gavage)

– (rat); OPPTS 870.6200 a [§ 8 1
- 8 ] , OECD

424 ; MAFF12 Nousan 8147; EEC B.43 Directive 2004/73/EC **PC CODE :**  128887 **DP BARCODE :**  D397 466; D39 8740; D39 8929 **TEST MATERIAL (PURITY) :**  Tribenuron Methyl (DPX
- L5300) ( 9 8.2 % a.i.). **SYNONYMS :**  Methyl2
- [[[[(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. (20 1 2 ). 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, 20 1 2
. MRID 48 7325 01 . Unpublished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 487 034 01 . 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 4 8 732501 ; revised report) , groups of Crl : CD(SD ) rats ( 1 2 /sex/dose ) were administered a single oral (gavage; 10 ml/kg) dose of Tribenuron Methyl (DPX
- L5 300 ) ( 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 o n 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, 0 00 mg/kg groups were subjected to histopathological evaluation. There were no treatment - related effects on mortal ity or clinical signs at any dose level in malesAcute Neurotoxicity Study (rats) (201 2 ) /Page 3 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### 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 th e 300 and 1,000 mg/kg males and females. Food consumption was significantl y decreased b y ↓25% and ↓65% in the 300 and 1,000 mg/kg males, respectivel y, 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 b y ↓ 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. Lo wer (p ≤0.05) food efficiency

w as 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 b y ↓ 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 observe d 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 beh avior 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 s ys tem 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 effect s on motor activity and rearing,**  **attributed to the systemic changes**  **observed.** This study is classified as **acceptable/guideline** and satisfies the guideline requirement ( OPPTS 870.6200 a; OECD 424 ) for an acute neurotoxicity study in rat s. **COMPLIANCE :**  Signed and dated GLP, Quality Assurance, Flagging, and Data Confidentiality (no claim of confidentiality under FIFRA, but waiver does not appl y to other regulatory agencies and information is labeled trade secret) were provided. **I. MATERIALS AND METHODS:** Acute Neurotoxicity Study (rats) (201 2 ) /Page 4 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### A. **MATERIALS :**  **1. Test material**  **:** Tribenuron Methyl(DPX
- L5 300) Technical **Description:** White to tan
- Solid **Lot/Batch #:** MAY10MA047 **Purity:** 9 8.2 % 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/w eight 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 ® Nutrition International, LLC Certified Rodent LabDiet ® 5002 , ad libitum , except during neurobehavioral testing
. **Water:** Tap water, ad libitum , except during neurobehavioral testing
. **Environmental conditions: Temperature:**  **Hum idity:**  **Air changes: Photoperiod:**  20
- 2 6 °C

30
- 70 % Not stated 12 hrs dark / 12 hrs light **Acclimation period:** 13 days 

### B. **STUDY DESIGN :**  **1. In life dates:**  Start: June 1 3 , 20 1 1 ; End: June 30 , 20 11
. **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 peri od. 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 dail y for 14 days after dosing. Animals were weighed on test day 0, 1, 7, and 14. Survivors not assigned for neuro pathology were sacrificed and a necrops y 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
- L5 300 ) at dose levels of 0, 100, 300, and 1000 mg/kg/dayAcute Neurotoxicity Study (rats) (201 2 ) /Page 5 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### (MRID: 42836601) and an acute oral toxicity study in rats conducted with Tribenuron methyl T echnical 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 param eter**  **Dose Level (m g/kg bw)**  **0 100**  **300 1,**  **0 00**  **Dose form ulation**  **c oncentration (m** **g/mL)** 0 10 30 100 **Total number of anim als/sex/group**  12 12 12 1 2 **Behavioral testing (FOB, Motor activity)** 1 2 /sex 1 2 /sex 1 2 /sex 1 2 /sex **Neuropathology (m** **icroscopic 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 page s 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 c oncentration anal ys es 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 storag e at room temperature. **Results Homogeneity analysis (**  **% RSD):** 1
- 4 %. **Stability analysis (% initial)**  **:** 9 4.9
- 97.7 %, 5 days at room temperature. **Concentration analysis (range as % nominal)**  **:** 96.3
- 103 %
. The se analy

tical 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 anal yz ed using the following statistical methods and significance was defined at p < 0.05 for all tests
.

**Parameters Statistical Methods** 

- Body weight

- Body weight gain Levene’s test for homogeneity and Shaprio
- Wilk test for normality. If test was not significant, o ne - way analysis of variance followed by Dunnett’s test (2
- sided) was used toAcute Neurotoxicity Study (rats) (201 2 ) /Page 6 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424

- Food consumption

- Food efficiency compare treated groups with control group s . 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 contra sts . 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. 

### The se stati stical analyses were considered to be appropriate
. **C. METHODS / OBSERVATIONS**  **: 1.**  **Mortality and C**  **linical O**  **bservations :**  Animals were observed twice daily for mortality and mor bidity throughout the study
. Detailed clinical observations were recorded daily during the 14 days following dosing except on the days of neurobehavioral evaluation s . **2. Body**  **W eight**  **:** Animals were weighed during the baseline FOB, prior to the test substance administration, and on Days 1, 7 and 14. **3. Food**  **C onsumption**  **:** Food consumption of each animal w as 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 A**  **ssessment :**  **a. Functional**  **O bservational**  **B attery (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 b y an observer who w as “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 s ys tem 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 measure d 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 Pi loerection X TremorsAcute Neurotoxicity Study (rats) (201 2 ) /Page 7 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 **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 P arameters based on OPPTS Guideline 870. 62 00
. Data were obtained from pages 2 0
- 21 of the study report. 

### b. **L ocom**  **otor A**  **ctivity :**  Lo com otor activity was evaluated after the last animal completed the FOB pre
- exposure (Day 0 ) and on D ay 7, and D ay 14. Animals were counterbalanced b y s ex and treatment and were tested in replicates over multiple days. An automated Coulbourn ® 

### 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 s ys tem. The technical characteristics of the measurement s ys tem are such that duration of movement is analogous to “counts” in other ty pes 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 P**  **athology :**  Animal s 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/xyl azine and perfused in situ . The perfusion and necrops y procedures were conducted according to Haskell Standard Operating Procedure
-Neurotoxicity Necrops y Procedures. Animals were subjected to gross necropsy . The remaining animals were sacrifice d using isoflurane anesthesia and CO 2 

### and were disposed of without any pathological examinations. The tissues from the control and high
- dose animal s (1, 0 00 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 μm, and stained with hematoxyl in
- 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 gl ycolmethacrylate (GMA) , sectioned at 3 μm, and stained with hematoxyl in
- 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.Acute Neurotoxicity Study (rats) (201 2 ) /Page 8 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424

**CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEM** 

**BRAIN SCIATIC**  **NERVE** X Olfactory bulb Mid
- thigh Region X Cerebral cortex X Sciatic N erve X Hippocampus X Basal ganglia X Cerebellum X Thalamus X Pons X Medulla oblongata **OTHER** X Midbrain X T ibial n erve X Hy pothalamus X Sural n erve

**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**  **C ontrols**  **:** It was stated in this report that three separate reports ( MRID 44628703 , MRID 47053501 and MRID 48710304 , performed in 1997, 2002 and 2011, respectivel y) were previousl y 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 document s 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 C linical**  **Observation s**  **:** There were no significant treatment - related clinical findings in the 100 , 300 or 1,0 00 mg/kg group s of both sexes
. The only c linical 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, 0 00 mg/kg groups in males or females
. A s light 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 ≤0.0 5 ) at dose levels of 300 and 1,000 mg/kg, respectivel y, over the interval test Days 0
- 1 compared to a 4.7Acute Neurotoxicity Study (rats) (201 2 ) /Page 9 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### g body weight gain in the control group. For females, the only significant (p ≤0.0 5 ) difference from the control group was a lower mean body weight gain ( ↓ 42 %) in the 1, 0 00 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** **/k g** **) 0**  **100 300**  **1, 0**  **00 Body**  **w eight (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 w**  **eight (g) -**  **Fem ales**  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) -**  **Fem ales**  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=1 2
. Percent difference from the control is included in parentheses and was calculated by the Reviewer s. * Significantly different from the control group, p ≤0.0 5
. 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 level s of 30 0 ( ↓25%) and 1,000 ( ↓65%) mg/kg on Day 0
- 1. Similarly, lower (p ≤0.05) food consumption was observed in females at dose level s 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 group s 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 b y 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 no ted in the 300 mg/kg and 1,000 mg/kg males and the 1,000 mg/kg females on Day 0
- 1. In addition, meanAcute Neurotoxicity Study (rats) (201 2 ) /Page 10 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### 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 males on D ay 0
- 1 in the 300 and 1,000 mg/kg group s 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**  **(m g/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** **) -**  **Fem ales**  **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 consum** **ed )**  **- 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 consum ed** **) -**  **Fem ales**  **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 Investigator s. * 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**  **:** S ignificantly (p ≤0.05) higher incidence s 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 l ying on one side (4/12 treated vs. 0/12 control) and palpebral closure commensurate with sleeping (3/12 treate d vs. 0/12 control). No other treatment
- related effects on FOB parameters were noted. **2. Loco**  **m otor activity**  **:** A s ummary of mean motor activity (duration and number of movements) in males and females is presented in Table s 4 (a and b) and 5 (a and b)
. MotorAcute Neurotoxicity Study (rats) (201 2 ) /Page 11 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### activity was affected b y t est substance in both males and females ; however this was a transient effect occurring only on Day 0
. The onl y significant (p ≤0.0 5 ) difference s from the control group w ere decreased total duration of movements in the 1,000 mg/kg males ( ↓ 44 %) and females ( ↓ 56 %) on Day 0
. N o 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 significantl y de creased values during the first 3 10
- minutes intervals for the 1,000 mg/kg males ( ↓43
- 90%) and females ( ↓44
- 77%) on Day 0 (Table s 4a and b)
. On Day 7, m ean duration of movement was significantly (p ≤0.0 5) reduced b y 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**  **(m g/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± 5 9 226±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**  **(m g/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 ±1 01 27±52 1286±560 **Day 0**Acute Neurotoxicity Study (rats) (201 2 ) /Page 12 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 **0** 372±56 207±133 131±117 67±91 99 ±1 11 21±44 1143±563 **100** 361±61 185±86 91±74 77±107 88 ±10 6 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±13 8 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 1 12±8 9 59±106 1263±591 **Day 14 0**  382±42 219±84 134±87 139±107 132 ±12 2 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 m ean number of movements was unaffected by administration of test substance at 100, 300, and 1,000 mg/kg in males or females (Table s 5 a and b). The only significant (p ≤0.0 5) diff erences from the control was decreased mean number of movements during interval 7 in males at do se 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 ≤0.0 5) 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 (Ta b le 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 Movement s**  **for Male Rats Dose (m** **g/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 3 8 1±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**Acute Neurotoxicity Study (rats) (201 2 ) /Page 13 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### TABLE 5a. **Selected Mean Number of Movement**  **s for Male Rats**  **Dose (m g/kg)**  **Successive 10 -** **Minute Intervals**

**1 2**  **3 5**  **7 9**  **Total 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 (m g/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 1 27 ±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 7 6 ± 64 3 6 ± 56 23±39 624±308 **Day 0 0**  135±15 91 ±40 78±56 46 ± 53 57 ±5 2 16±27 578±216 **100** 142±30 97 ± 27 64±46 46 ±42 5 4 ±5 5 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 ±3 4 2 6 ± 33 14±17 363±131 **Day 7 0**  136±16 108±3 7 106±54 6 9 ±5 4 43 ±45 45±49 712±217 **100** 130±17 110 ± 31 77±47 51 ± 5 4 7 1 ±5 9 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 6 1 ±5 2 68 ± 51 36±45 621±284 **Day 14 0**  131±22 109 ± 36 81±44 77 ± 51 71 ±5 6 50±46 735±248 **100** 131±15 11 2± 33 83±56 78 ±5 8 53 ±49 52±53 724±214 **300** 127±22 124 ±46 106±43 63 ±5 2 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 1 8 on page 60 of the study report. 

### 3. **Rearing:** The onl y significant (p ≤0.0 5) 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 observe d in the 1,000 mg/kg group males and females on Day 0.Acute Neurotoxicity Study (rats) (201 2 ) /Page 14 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### TABLE **6 . Mean (** **±SD) Number of Rearing Movements**  **in Female Rats Exposure Time**  **Dose (m g/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=1 2. Percent difference from the control is included in parentheses and was calculated by the Reviewers. * Significantly different from the control group, p ≤0.0 5
. 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 b y 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 significantl y (p ≤0.0 5) reduce d 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 ≤0.0 5) body

temperature was noted in the females (each ↑3%) at dose level s 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**  **(m g/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 fem**  **ale 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 P**  **athology** : No adverse, treatment
- related effects were noted during gross pathology
. The only finding s noted at necrops y 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 finding s wereAcute Neurotoxicity Study (rats) (201 2 ) /Page 15 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### c onsistent with normal background changes observed in rats of this age and strain. **2 .**  **Neuropathology :**  No adverse, treatment
- related histologic al changes were noted in the 1 ,0 00 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 interv al 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 efficienc y 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 neuropatholo gy . **B. REVIEWER COMMENTS**  **:** Exposure of Crl:CD(SD) rats to Tribenuron Methyl (DPX
L5300 ) at dose levels of 100, 300, and 1 , 0 00 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 b y ( ↓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 conclude d 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 level s of 300 ( ↓25%) and 1,000 mg/kg ( ↓65%) on Day 0
- 1. Similar to males on Day 0
- 1, food consump tion was significantly decreased by ↓19% and ↓ 70% at 300 and 1,000 mg/kg, respectivel y, 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. Signif icant (p ≤0.05) reduction s in food efficiency were noted in the 300 mg/kg and 1,000Acute Neurotoxicity Study (rats) (201 2 ) /Page 16 of 16

Tribenuron Methyl/ 128887 OPPTS 870.6200a/ MAFF 12 Nousan 8147/OECD 424 

### 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 neurotoxi c - 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 significantl y decreased duration of movement during the first 3 10
- minutes intervals for males and females on test Day 0. Total number of movement s was not affected at any dose level. Mean number of rearing movements was significantly decreased b y ↓ 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 male s 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), reduce d 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 870.6200 a; OECD 424 ) for an acute neurotoxicity study in rats. **C. STUDY DEFICIENCIES**  **:** No deficienc ies w ere reported in this study
.