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 

Risk Assessment Type: NIA Case No.: NA 

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

MRID No.: See table 40 CFR: NIA 

FROM: 

THRU: 

TO: 

Karlyn Middleton, Toxicologist 

Registration Action Branch 2 

Health Effects Division (7509 P) 

Christina Swartz, Chief ~ . A --- Registration 

Health Effects 

Action 

Division 

Branch 

(7509 

2 

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 

Page 1 of 13
Table 1. Chlorimuron-ethyl Toxicology Study with New Data Evaluation Record 

MRID Number Guideline

[OCSPP]

STUDY TITLE

48646201 870.3200 21-DAY REPEAT DERMAL TOXICITY IN RABBITS

Page 2 of 13
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.

Page 3 of 13
CHLORIMURON ETHYL/128901 

Repeated dosing (21-day) Dermal Toxicity Study in Rats (1997) I Page 2 of 11 

OPPTS 870.3200/ DACO 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): Chlorimuron Ethyl, (96.7% a.i.), (Benzoic acid, 2-[[[[(4-chloro6-methoxy-2-pyrimidinyl)amino ]carbonyl] amino ]sulfonyl]-,ethyl ester 

SYNONYMS: Classic® Technical, DPX-F6025 Technical, DPX-F6025-l 93 (Batch Number) 

CITATION: Naas, D.J. (2007) Repeated Dose Dermal Toxicity: 21-Day Study with 

Chlorimuron Ethyl Technical in Rabbits: WIL Research Laboratories, Inc. Ashland, 

Ohio, Laboratory Project ID: WIL-189080, April 28, 1997. MRID 48646201. 

Unpublished. 

SPONSOR: E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and 

Industrial Medicine, Elkton Road, Newark, Delaware, 19714 

EXECUTIVE SUMMARY: In a 21-day dermal toxicity study (MRID 48646201), Chlorimuron 

Ethyl Technical; 96.7% a.i., Lot# C-941108-lOC) was applied to the shaved intact skin of 5 New 

Zealand white rabbits (Hra:NZW-SPF) /sex/dose at dose levels of 0, 100, 400, or 1000 mg/kg/day 

(limit dose) for 6 hours/day. The animals were exposed in this manner for 7 days per week during 

Weeks 1-3 until scheduled sacrifice for a total of 21 applications. 

No adverse treatment-related effects on mortality, clinical signs of toxicity, body weight, body 

weight gain, food consumption, hematology, clinical chemistry, organ weights, and gross or 

microscopic pathology were observed in either sex. 

Very slight to slight dermal irritation occurred in both sexes in all dose groups, mostly between 

days 10-12 of testing. The findings were transient and observed spuriously in both sexes and were 

not considered to be adverse. 

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

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

Though the (1998) 870.3200 guidelines note the need for a larger number of animals (I 0 

animals/dose), the fact that the lack of any ophthalmic effects were noted or any or limited neuro 

observations were reported, it is extremely doubtful that adding an additional 5 animals per sex per 

dose would provide any more information with regard to the toxicity potential of this chemical. 

Therefore, the study is classified as acceptable/nonguideline and satisfies the guideline 

Page 4 of 13
requirement for a 21-day dermal toxicity study (OPPTS 870.3200; OECD 410) in rabbits. 

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

Assurance statements were provided. 

Page 5 of 13
I. MATERIALS AND METHODS

A. MATERIALS

1. Test material: Chlorimuron Ethyl Technical 

Description: Off-white powder

Batch/Lot #: C-941108-10C

Purity: 96.7% a.i.

Stability: 

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 animals

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-life dates: Start: administration, November 14, 1996 End: December 5, 1996 

2. Animal assignment: 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

Group 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.

Page 6 of 13
3. Dose 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 cm2 skin and covered with gauze dressing held in place with an 

impervious plastic tape and Dermiform® tape. Additionally, the mobility of the rabbits was 

limited by an 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, 

Erythrocytes, hemoglobin, hematocrit, MCH, MCV, MCHC, platelets, leukocytes, 

Albumin, creatinine, chloride, glucose, protein, urea, total bilirubin ALT, AST, 

alkaline phosphatase, cholesterol, calcium, potassium, sodium, phosphorus

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: All animals 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 

Page 7 of 13
observations performed 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 were determined daily 

beginning 1 week before test material administration. Mean food and water consumption were 

reported as g/animal/day. Food efficiency was calculated weekly. 

4. Ophthalmoscopic examination: Ophthalmoscopic 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

Page 8 of 13
6. Urinalysis: Urinalysis was not performed and is not required by the guideline. 

7. Sacrifice and pathology: 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. The (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 

animals 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. OBSERVATIONS 

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 

Page 9 of 13
clinical signs were observed at any dose in either sex.

3. Dermal irritation: 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 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 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 - - - - - - - - 

400

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

Grade 1 

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

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

1000b

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

1000b 

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.

Page 10 of 13
B. BODY 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 considered incidental because there were no significant decreases in body weight, food 

consumption was similar to controls in all groups, 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 noted 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 

increased, (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 

Page 11 of 13
controls. 

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 both 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 “need” for 10 animals/dose, the lack of several 

Page 12 of 13
parameters 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 historical control data for organ weights were not provided. 

Page 13 of 13