UNITED ST A TES ENVIRONMENT AL PROTECTION AGENCY



### MEMORANDUM

DATE: 7 / 09115 WASHINGTON, DC 20460

OFFICE OF

CHEMICAL SAFETY AND POLLUTION

PREVENTION



### SUBJECT: Chlorimuron-Ethyl Toxicology Data Evaluation Records

.

PC Code: 128901

Decision No.: NIA

Petition No.: NIA DP Barcode: D396290

Registration Nos.: NIA
Regulatory Action: NIA

Case No.: NA Risk Assessment Type: NIA

TXR No.: 0056135 CAS No.: 90982-32-4

40 CFR: NIA MRID No.: See table



### FROM :

THRU:

TO: Karlyn Middleton

, Toxicologist Registration Action Branch 2

Health Effects Division (7509 P)

Christina Swartz

, Chief

# ~ . 

## A

--- Registration Action Branch 2

## ~**~** Health Effects Division (7509 P)

Heather Garvie, Mindy Ondish PM Team 24

Herbicide Branch Registration Division (7505P)



### ACTION REQUESTED: The Health Effects Division (HED) was asked to review a subchronic

dermal toxicity study submitted for chlorimuron-ethyl. The study has been reviewed and a data

evaluation record (DERs) has been prepared (see Table 1).



### BACKGROUND: Chlorimuron ethyl is an herbicide of the sulfonylurea class. Its mode of

action is through inhibition of the plant enzyme acetolactate synthase, which is also known as acetohydroxy acid synthase

. Inhibition of this enzyme blocks branched-chain amino acid biosynthesis of valine

, leucine, and isoleucine (involved in plant growth) processes and leads to

death of the plant. Chlorimuron ethyl is registered for use on soybeans

, field corn, peanuts

, low growing berries (subgroup l 3-07H, except strawberry) and non-crop areas such as fence rows and

roadsides for the control of broadleaf weeds and grasses.



### Page 1of2

### Tab le 1. Chlorimuron

- ethyl Toxicology Study with New Data Evaluation Record

MRID Number Guideline [OCSPP] STUDY TITLE

48646201 870.3200 21

- DAY REPEAT DE RM AL TOXICI TY IN RABBITS

### DATA EVALUATION RECORD

Chlorimuron

PC Code: 128901

TXR#: 0056135

MRID#: 48646201

Study Type: 21- Day Dermal Toxicity in Rabbits ; OPPTS 870.3200

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: 12/26/2011 Henry Spencer, Ph.D.

Secondary Reviewer: _____________________________________ Date: 12/27/2011 William Burnam, M.S.

Quality Assurance: _________________________________________ Date: 12/29/2011 Nasrin Begum, Ph.D.

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

Task Number: 1-1-73

EPA Reviewer//WAM: Middleton /Swartz// Farwell

Disclaimer

This review may have been altered by the EPA subsequent to the contractors’ signature

above.CHLORIMURON ETHYL/128901 Repeated d osi ng (21-day) Dermal Toxicity Study in Rats (1997) I Page 2 of 11

OPPTS 870.3200/ DA CO 4 .3. 5 / OECD 410



### EPA Reviewer: Karlyn Middleton



### Risk Assessment Branch 2, Health Effects Division (7509P)

EPA Secondary Reviewer : Lori Brunsman



### Risk Assessment Branch 7, Health Effects Division (7509P)

TXR #: 0056135 

### Signature:**~'----,-r--==--**

# Date~:**~~fiiZ~~~~~'q;;:i**



# I DATA EVALUATION RECORD

STUDY TYPE: 21-Day Dermal Toxicity in Rabbits ; OPPTS 870.3200 ( §82-2]; OECD 410.



### PC CODE : 128901 

### DP BARCODE: 0396290



### TEST MATERIAL (PURITY): C hl or imur on Ethy l

, (96.7% a.i.), (Be n zoic acid

, 2-[[[[(4-c hl oro

6-met h oxy-2 -p yri midin y l ) amino ]carbonyl] a min o ] s ulfon y l]- ,e th y l ester



### SYNONYMS: C l ass i c ® Technical, DPX -F6025 Technical, DPX- F6025

- l 93 (Batc h Number)



### CITATION: Naas, D.J

. (2007) Repeated Dose D e rmal Toxicity: 21-Day Study w ith

C hlorimuron Ethyl Technical in Rabbits: WIL Re search Laboratories, Inc. Ashland,
Ohio, Laboratory Project ID : WIL-189080, April 28, 19 97. MRID 48646201. Unpublished.



### SPONSOR: E. I. du Pont de Nemours and Compa ny
, Haskell Laboratory fo r Toxicology a nd

Industrial M e dicin e, E lkton Road, Newark, Delaware, 19714



### EXECUTIVE SUMMARY: In a 21-day d erma l t oxic it y stu d y (MRID 4864620 1 ), Chlor imuron

E th yl Technical; 96.7% a.i., Lot# C-941108-lOC) was ap pli ed to the shaved intact skin of 5 New

Zea l and whi t e rabbits (Hra:NZW-SPF) / sex / dose a t dose l eve l s of 0, 100

, 400, or 1 000 mg / kg / day (limit dose) for 6 hours / da y. T h e a nim a l s were exposed in thi s manner for 7 days per week during

Weeks 1- 3 until sc heduled sacrifice for a total of 2 1 app lic a tion s.

No adverse tr eat m e nt -re l ate d effects on mortality

, clinical s igns of toxicity, body we i ght

, body

we i g ht ga in

, food con s umption

, hem a tolo gy
, clinical chemistry, organ weig ht s
, a nd gross or
mi croscop ic p a th o l ogy were o b served in eit h e r sex

.

Very s li g ht to s li g ht derm a l irrit atio n occ urr ed in both sexes in a ll dos e gro up s, mostly between

d ays 10

- 1 2 of t es tin g. The findings were tran sien t and obse r ved sp uri o u sly in both sexes and were

n ot considere d to be adverse.



### The Systemic LOAEL is not determined. The NOAEL is 1000 mg / kg / da y (limit do se)

.

The Dermal LOAEL is not determined. The NOAEL is 1000 mg / kg/da y (limit dose)

.

Though the ( 1 998) 870.3200 g uid e line s note the n eed for a lar ger numb er of an im als ( I 0

animals / dose)

, the fact t hat the l ack of any op hth a lmi c effec t s were noted or a n y or l imi t ed neuro observations we re reported, it is extremely doubtful that a ddin g an add iti ona l 5 anima l s per sex per dose would provide any more inform atio n w ith regard to the to x icit y potential of thi s c h em ic a l.

T h erefore

, the st ud y is cl ass ified as 

### acceptable/nonguideline and satisfies the g uid e lin e

### req uirement for a 2 1-day dermal toxicity study (OPPTS 870.3200; OECD 410) in ra bbits.

COMPLIANCE : Signed and dated Data Confidentiality, GLP Compliance, Flagging, and Quality

Assurance statements were provided.

### I. MAT ERIALS AND METHODS

A. MATERIALS

1. Test m aterial : Chlorimuron Ethyl Technical

Description: Off

- white powder

B atch /Lot #: C

- 941108

- 10C
Purity: 9 6.7 % a.i.

S tability: Not provided, and was claimed to be the responsibility of the sponsor

. Test material was stored in a sealed container at room temperature, but assumed stable

under the conditions of administration.

CAS #: 90982

- 32

- 4

Structure:



### 2. Vehicle : The test material was applied by gentle inunction as a paste with increasing vols. (up to 2 ml) deionized water on clipped skin.

3. Test a nimals

Species: Rabbit

Strain: New Zealand White Hra:NZW) SPF rabbits Age/weight at study

initiation: Approximately15 week / 2.3

- 2.7 kg males Approximately 15weeks/ 2.3

- 2.6 kg females

Source: Covance Research Products, Inc. Denver Pa. Housing: Individually in wire

- mesh cages with ground corn cob bedding

Diet: Certified Rabbit LabDiet® 5322 (PMI Feeds, Inc) ad libitum

Water : Tap water, with reverse osmosis

- treatment, ad libitum

Environmental

conditions: Temperature: Humidity: Air changes: Photoperiod: 68±4°F

30

- 70 % Not provided

12 hrs dark/ 12 hrs light Acclimation period: 9 days



### B. STUDY DESIGN

1. In -l ife d ates : Start: administration, November 14, 1996 End: December 5, 1996

2. Animal a ssignment : Animals were assigned by computer generated program to the test groups noted in Table 1. Body weights were within ±20% of the mean for each sex.

TABLE 1. Study design a

Gro up Dose (mg/kg/day) # Males # Females

Control 1 0 5 5

Low 2 100 5 5

Mid 3 400 5 5 High 4 1000 5 5

a Data were extracted from page 20 of the study report.

### 3. Dos e selection rationale : There was no rationale for the selection of the dose levels presented in Table 1 in the study report.

4. Preparation and treatment of animal skin : Approximately 24 hours prior to initiation of dosing, the fur from the dorsal and lateral areas of the trunk (greater than 20% of total body surface area) was removed (method reported was by both shaving and clipping). Hair removal by shaving was repeated once weekly thereafter. The applied quantities of the test substance were adjusted twice weekly based on individual animal body weight. The test substance was applied to approximately 100 cm 2 

### skin and covered with gauze dressing held in place with an impervious plastic tape and Dermiform® tape. Additionally, the mobility of the ra bbits was limited by a n Elizabethan collar. The dressings were removed after 6 hours, and the application

areas were cleaned with Ivory® dishwashing liquid and water, and dried with paper towels. The animals were exposed in this manner 7 days (during Week 1-3) until scheduled sacrifice for a total of 21 applications.

Rabbits in the control group were exposed to water only using the same procedure as described

for the treated animals.

5. Statistics : The following statistical methods were used to analyze the data:

Parameter Statistical Test
Body weight, body weight changes, food consumption, absolute and relative organ weights,

E rythrocytes, hemoglobin, hematocrit, MCH, MCV, MCHC, platelets, leukocytes,

A lbumin, creatinine, chloride, glucose, protein, urea , total bilirubin ALT, AST, alkaline phosphat ase, cholesterol, calcium, potassium, sodium, phosph orus ANOVA (one

- way) followed by Dunnett’s

.

Differential leukocytes, Not analyzed Treatment groups were analyzed using two

- tailed tests for significance level of 5% and 1% comparing to control groups by sex



### Significance was denoted at p<0.05 or p<0.01. Data should be tested to ensure that the assumptions of normal distribution and homogeneous variances are met prior to proceeding with parametric analyses. Otherwise, the reviewers consider the statistical methods to be appropriate.

C. METHODS

1. Observations

a. Cageside observations : A ll a nimals were observed twice daily for mortality and moribundity. The animals were examined for signs of local skin irritation daily using the Draize scoring method.

b. Clinical examinations : Clinical examinations were conducted daily for other dermal findings, if present at unwrapping. Detailed physical examinations were conducted on all animals weekly.

c. Neurological evaluations : Neurological evaluations were limited to the open

- field

### obse rvations p erformed weekly.

2. Body weight : Animals were weighed 1 week prior to initiation of the study, and 2 times weekly (at 3

- 4 day intervals) thereafter, and at termination

.

3. Food and water consumption : Individual food and water consumption w ere determine d daily beginning 1 week before test material administration . Mean food and water consumption w ere reported as g /animal/day . Food efficiency was calculated weekly.

4. Ophthalmoscopic examination : Op hthalmoscopic examinations were not carried out in this study.

5. Hematology and clinical chemistry : On Day 1, and approximately Day 21, blood samples

were collected from the marginal ear vein or medial ear artery of all animals (16 -18 hourfasted, non- anesthetized). The following CHECKED (X) parameters were examined.

a. Hematology

X Hematocrit (HCT)* X Leukocyte differential count*

X Hemoglobin (HGB)* X Mean corpuscular HGB (MCH)*

X Leukocyte count (WBC)* X Mean corpuscular HGB concentration (MCHC)*

X Erythrocyte count (RBC)* X Mean corpuscular volume (MCV)*

X Platelet count* Reticulocyte count
Blood clotting measurements* X Erythrocyte morphology
(Thromboplastin time)
(Clotting time)

(Prothrombin time)

* Recommended for 28

- day dermal toxicity studies based on Guideline 870.3200



### b. Clinical chemistry

ELECTROLYTES OTHER

X Calcium X Albumin*

X Chloride X Creatinine* Magnesium X Urea nitrogen*

X Inorganic phosphate X Total cholesterol*

X Potassium* (K) X Globulins

X Sodium* (Na) X Glucose*
ENZYMES (more than 2 hepatic enzymes*) X Total bilirubin

X Alkaline phosphatase (AP)* X Total protein*
Cholinesterase (ChE) Triglycerides Creatine phosphokinase Serum protein electrophoresis Lactic acid dehydrogenase (LDH)

X Alanine aminotransferase (ALT)*

X Aspartate aminotransferase (AST)* Gamma glutamyl transferase (GGT)* Glutamate dehydrogenase

X Sorbitol dehydrogenase*

* Recommended for 28

- day dermal toxicity studies based on Guideline 870.3200

### 6. Ur inalysis : Urinalysis was not performed and is not required by the guideline.

7. Sacrifice and p athology : All animals were sacrificed by exsanguination under anesthesia after receiving an IV injection of sodium pentobarbital and were subjected to a gross pathological

examination. The following CHECKED (X) tissues were collected for histological

examination. T he (XX) organs , additionally, were weighed.

DIGESTIVE

SYSTEM CARDIOVASC./HEMAT. NEUROLOGIC

Tongue X Aorta* XX Brain* + 3 areas

X Salivary glands* X Heart* + X Peripheral nerve* (sciatic)

X Esophagus* X Bone marrow* X Spinal cord (3 levels)*

X Stomach* X Lymph nodes* X Pituitary*

X Duodenum* X Spleen* + X Eyes (optic nerve )*

X Jejunum* X Thymus* + GLANDULAR

X Ileum* XX Adrenal gland* +

X Cecum* UROGENITAL Lacrimal gland

X Colon* XX Kidneys* + X Parathyroid*

X Rectum* X Urinary bladder* X Thyroid*

XX Liver* + XX Testes* + OTHER

X Gall bladder* (not rat) X Epididymides* + X Bone (sternum and femur) Bile duct* (rat) X Prostate* X Skeletal muscle

X Pancreas* Seminal vesicles* X Skin* (treated & untreated areas)

RESPIRATORY XX Ovaries* + X All gross lesions and masses*

X Trachea* X Uterus* + (w/ cervix) X Zymbal’s gland

X Lung* Mammary gland* ¥ X Harderian gland

Nose* (nasal cavity) X Oviducts X Eyelids $
Pharynx* X Vagina X Peyer’s patches Larynx* Ureters and urethra

* Recommended for 28

- day dermal toxicity studies based on Guideline 870.3200 + Organ weights required



### The eyes, optic nerve, were preserved in Davidson’s solution, and testes were placed in Bouin’s solution. All other tissues were preserved in 10% neutral buffered formalin

. The collected tissues denoted in the table above were routinely processed, embedded in paraffin,

sectioned at 5 -8 microns, stained with hematoxylin and eosin, cover-slipped and were examined microscopically. All the tissues listed above were examined microscopically for all

ani mals in the control and 1000 mg/kg/day groups. Additionally, treated skin, untreated skin, liver, lungs and kidneys were examined from all animals in the 100 and 400 mg/kg/day groups.

II. RESULTS

A. OBSERVATION S

1. Mortality : All animals survived to scheduled sacrifice.

2. Clinical signs of toxicity : Low incidences of soft feces, wet or dried yellow or brown material in the urogenital region, and red ocular discharge found were not present in a dose- related manner and are not uncommon in laboratory rabbits. It is concluded that no treatment

- related

### cli nical signs were observed at any dose in either sex.

3. Dermal i rritation : Incidence of dermal irritation (very slight to slight reddening) was limited to only 1 to 3 days in any one group with the exception of females at 1000 mg/kg/day . One female

exhibited minor irritation for 6 days ( 3 days (days 4-6) and 3 days ( days 10-12). This animal also showed very slight edema on day 6. The Sponsor did not regard these effects to be a test

substance- related effect, but a consequence of the technical application process. However, as these findings were transient (generally observed between days 10 and 12), did not increase in severity with dose, the very slight irritation is not considered to be adverse. Experience has also provided information that just the use of water and wiping the surface can provide such irritations as reported. The incidences of the irritation in both sexes suggest a technical artifactual

occurrence.

TABLE 2. Degree of skin reddening in female rabbits exposed dermally to Chlorimuron e thyl a
Day 9 10 11 12 13 14 15 16 17 18 19 20 21

Dose (mg/kg/day) Severity # Observed/ 5

Control Grade 0 (None) 5 5 5 5 5 5 5 5 5 4 4 4 4

Grade 1 (very slight) - - - - - - - - - 1 1 1 1

100 Grade 0 (None) 5 4 4 2 5 5 5 5 5 5 5 5 5

Grade 1 (Very slight ) - 1 1 3

- - - - - - - -

4 00 Grade 0 (None) 5 5 5 4 5 5 5 5 5 5 5 5 5

Grade 1 (Very slight ) -- -- - 1

- - - - - - - - -

Grade 2 ( slight )

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

1000 b Grade 0 (None) 5 4 4 4 5 5 5 5 5 5 5 5 5

Grade 1 (Very slight) -- 1 1 1

- - - - - - - - - Grade 1 (edema)

-- 1

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

a Data were obtained from pages 109

- 112 of the study report.

TABLE 3. Degree of skin reddening in male rabbits exposed dermally to Chlorimuron ethyl a

Day 9 10 11 12 13 14 15 16 17 18 19 20 21

Dose (mg/kg/day) Severity # Observed/5

Control Grade 0 (None) 5 5 5 5 5 5 5 5 5 5 4 4 4

Grade 1 (very slight) - - - - - - - - - - 1 1 1

100 Grade 0 (None) 5 4 4 5 5 5 5 5 5 5 5 5 5

Grade 1 (Very slight) - 1 1

- - - - - - - - -

400 Grade 0 (None) 5 4 4 0 5 5 5 5 5 5 5 5 5

Grade 1 (Very slight) -- 1 1 4

- - - - - - - - -

Grade 2 (slight) -- -- -- 1

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

1000 b Grade 0 (None) 5 4 1 1 5 5 5 5 5 5 5 5 5

Grade 1 (Very slight) -- 1 1 4

- - - - - - - - -

Grade 1 (edema) -- - - - - - -- -- - - - - -

a Data were obtained from pages 109

- 112 of the study report.

### B. B ODY WEIGHT AND WEIGHT GAIN : No statistically significant differences from control were observed in body weights at any dose in either sex (Table 4). In the males, overall body weight gain (calculated by the reviewers) was decreased by 29% at 1000 mg/kg. These findings

were considere d incidental because there were no significant decreases in body weight, food consumption was similar to controls in all gro ups, and there was no dose response.

Table 4. Mean (±SD) body weights and body weight gain (g) in rabbits dermally exposed to Chlorimuron ethyl for 3 weeks. a

Day Dose (mg/kg/day)

0 100 400 1000

Males

1 2648 ± 126 2691± 36 2664± 92 2703± 130

21 2798 ± 163 2862 ± 71 2855 ± 65 2810 ± 118 Overall gain b 150 171 191 107 (↓29%)

Females

1 2260± 98 2270 ± 134 2268 ± 110 2284± 99

21 2570 ± 126 2612 ± 30 2575 ± 88 2605 ± 128 Overall gain b 310 342 307 321

a Data were extracted from Table 5 on pages 47

- 48 of the study report; n=5. Percent difference from controls

(calculated by the reviewers) is presented parenthetically.

b Calculated by reviewers from data within this table



### C. FOOD CONSUMPTION : Food consumption values were similar in the 400 and 1000 mg/kg groups and control groups throughout the study. Though a small decrease in food consumption occurred in males at 1000 mg/kg, the values were neither considered treatment related, nor

adverse. Food efficiency was similar in treated groups and controls with no statistical differences found, though a small reduction in efficiency in 1000 mg/kg males occurred in the last week of the study, but is not considered to be significant.

D. OPHTHALMOSCOPIC EXAMINATION : No examinations were made during the study.

E. BLOOD ANALYSES

1. Hematology : The hematology values were compared from the 2 week values and were not significantly different from the controls in the same time frame. No treatment

- related effects were observed in any hematology parameter. Any statistically significant differences note d were minor/spurious, not dose-dependent, and are not considered either adverse or treatment related.

2. Clinical chemistry : No treatment

- related effects were observed in any clinical chemistry

parameter. Statistically significant differences reported were minor and were spurious occurrences, and showed no dose related increases. Information was taken from pages 76-89 of the study report.

F. SACRIFICE AND PATHOLOGY

1. Organ weight : In the 400 and 1000 mg/kg/day females, absolute adrenal weights were

i ncreased , (p<0.01 and p<0.05) by 63 and 39%, respectively; relative (to body weight) adrenal weights were also increased . As there were no corroborative gross or histopathological findings, and as there was no dose response, these findings were not considered to be

treatment

- related . All other absolute organ weights in the treated groups were similar to

### cont rols.

2. Gross pathology : No treatment

- related gross lesions were observed at any dose in either sex.

3. Microscopic pathology : No adverse treatment

- related microscopic lesions were observed at any dose in either sex. Incidences of minimal to slight inflammatory infiltration in the lungs were reported in both sexes. This lesion was not dose-dependent and/or was similar to controls. Additionally, spurious incidences (often singular in occurrence) of a variety of findings were not considered to be related to treatment because they were not biologically adverse, minimal in severity, and/or not dose dependent.

III. DISCUSSION AND CONCLUSIONS

A. INVESTIGATORS’ CONCLUSIONS : The investigators concluded that” there were no test substance-related effects on the clinical condition of the rabbits. Food consumption, food efficiency and body weight data were unaffected by treatment with the chemical. Chlorimuron Ethyl Technical administration had no effect on hematology and serum chemistry parameters or organ weight data. There were no test substance

- related lesions noted at the macroscopic or microscopic examinations.”

“Under the conditions of this study, the no- observed

- effect level (NOEL) is defined as the highest dose at which toxicologically important effects attributable to the test substance were

not detected. The NOEL for toxicity for this study was 1000 mg/kg/day, the highest dose tested, for bot h male and female rabbits.”

B. REVIEWER COMMENTS : The reviewers conclude after investigating the individual animal data that supports the summary conclusions that no adverse treatment- related effects on mortality, clinical signs of toxicity, body weight, food consumption, clinical chemistry, absolute or relative organ weights, and gross or microscopic pathology were observed in either sex.

Systemic: The LOAEL was not determined . The NOAEL is 1000 mg/kg/day (limit dose).

Dermal: The LOAEL was not determined . The NOAEL is 1000 mg/kg/day (limit dose). There was some indication of dermal irritation at all doses, however, the findings were

transient and did not worsen and were not considered to be adverse.

The study is considered to be an acceptable/nonguideline 21 day dermal toxicity study in

rabbits.

C. STUDY DEFICIENCIES :

• The study was performed prior to the 1998 guidelines. The present guidelines note that

the smaller number of animals would be adequate if the study was to be used as a screening study, but “the objective of the study was stated to determine the potential toxicity of the test substance in albino rabbits after repeated dermal application over a period of 21 days.” The route was selected “since the intended use ...... is a potential route of exposure for humans.” Therefore the numbers used should have been 10/sex/dose. However, in spite of the “ne ed ” for 10 animals /dose, the lack of several

### par ameters showing any effects at up to a limit dose of 1000 mg/kg for 21 days provides adequate information on the toxicity potential by this route of exposure and also supports the lack of a need for additional animals to be tested in this case.

• Test substance quantitation values were not provided for either individuals or groups, Ophthalmologic examinations should have been done at least once at the end of the study, and h istorical control data for organ weight s were not provided.